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Sample records for accumbens mglur5-homer2-pi3k signaling

  1. Functionally distinct dopamine signals in nucleus accumbens core and shell in the freely moving rat

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    Dreyer, Jakob K.; Vander Weele, Caitlin M.; Lovic, Vedran

    2016-01-01

    Dynamic signaling of mesolimbic dopamine (DA) neurons has been implicated in reward learning, drug abuse, and motivation. However, this system is complex because firing patterns of these neurons are heterogeneous; subpopulations receive distinct synaptic inputs, and project to anatomically...... and functionally distinct downstream targets, including the nucleus accumbens (NAc) shell and core. The functional roles of these cell populations and their real-time signaling properties in freely moving animals are unknown. Resolving the real-time DA signal requires simultaneous knowledge of the synchronized...... activity of DA cell subpopulations and assessment of the down-stream functional effect ofDArelease. Because this is not yet possible solely by experimentation in vivo,we combine computational modeling and fast-scan cyclic voltammetry data to reconstruct the functionally relevantDAsignal in...

  2. Ghrelin regulates phasic dopamine and nucleus accumbens signaling evoked by food-predictive stimuli.

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    Cone, Jackson J; Roitman, Jamie D; Roitman, Mitchell F

    2015-06-01

    Environmental stimuli that signal food availability hold powerful sway over motivated behavior and promote feeding, in part, by activating the mesolimbic system. These food-predictive cues evoke brief (phasic) changes in nucleus accumbens (NAc) dopamine concentration and in the activity of individual NAc neurons. Phasic fluctuations in mesolimbic signaling have been directly linked to goal-directed behaviors, including behaviors elicited by food-predictive cues. Food-seeking behavior is also strongly influenced by physiological state (i.e., hunger vs. satiety). Ghrelin, a stomach hormone that crosses the blood-brain barrier, is linked to the perception of hunger and drives food intake, including intake potentiated by environmental cues. Notwithstanding, whether ghrelin regulates phasic mesolimbic signaling evoked by food-predictive stimuli is unknown. Here, rats underwent Pavlovian conditioning in which one cue predicted the delivery of rewarding food (CS+) and a second cue predicted nothing (CS-). After training, we measured the effect of ghrelin infused into the lateral ventricle (LV) on sub-second fluctuations in NAc dopamine using fast-scan cyclic voltammetry and individual NAc neuron activity using in vivo electrophysiology in separate groups of rats. LV ghrelin augmented both phasic dopamine and phasic increases in the activity of NAc neurons evoked by the CS+. Importantly, ghrelin did not affect the dopamine nor NAc neuron response to the CS-, suggesting that ghrelin selectively modulated mesolimbic signaling evoked by motivationally significant stimuli. These data demonstrate that ghrelin, a hunger signal linked to physiological state, can regulate cue-evoked mesolimbic signals that underlie food-directed behaviors. Cues that predict food availability powerfully regulate food-seeking behavior. Here we show that cue-evoked changes in both nucleus accumbens (NAc) dopamine (DA) and NAc cell activity are modulated by intra-cranial infusions of the stomach

  3. Selecting danger signals: dissociable roles of nucleus accumbens shell and core glutamate in predictive fear learning.

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    Li, Susan S Y; McNally, Gavan P

    2015-06-01

    Conditioned stimuli (CSs) vary in their reliability as predictors of danger. Animals must therefore select among CSs those that are appropriate to enter into an association with the aversive unconditioned stimulus (US). The actions of prediction error instruct this stimulus selection so that when prediction error is large, attention to the CS is maintained and learning occurs but when prediction is small attention to the CS is withdrawn and learning is prevented. Here we studied the role of glutamate acting at rat nucleus accumbens shell (AcbSh) and core (AcbC) α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in this selection of danger signals. Using associative blocking and unblocking designs in rats, we show that antagonizing AcbSh AMPA receptors via infusions of 2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo[f]quinoxaline-2,3-dione (NBQX; 0.5 μg) prevents the unblocking of fear learning, whereas antagonizing AcbC AMPA receptors via infusions of NBQX (0.5 μg) prevents both the blocking and unblocking of fear learning. These results identify dissociable but complementary roles for AcbSh and AcbC glutamate acting at AMPA receptors in selecting danger signals: AcbSh AMPA receptors upregulate attention and learning to CSs that signal surprising USs, whereas AcbC AMPA receptors encode the predicted outcome of each trial.

  4. Extinction and reinstatement of phasic dopamine signals in the nucleus accumbens core during Pavlovian conditioning.

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    Sunsay, Ceyhun; Rebec, George V

    2014-10-01

    The prediction-error model of dopamine (DA) signaling has largely been confirmed with various appetitive Pavlovian conditioning procedures and has been supported in tests of Pavlovian extinction. Studies have repeatedly shown, however, that extinction does not erase the original memory of conditioning as the prediction-error model presumes, putting the model at odds with contemporary views that treat extinction as an episode of learning rather than unlearning of conditioning. Here, we combined fast-scan cyclic voltammetry (FSCV) with appetitive Pavlovian conditioning to assess DA release directly during extinction and reinstatement. DA was monitored in the nucleus accumbens core, which plays a key role in reward processing. Following at least 4 daily sessions of 16 tone-food pairings, fast-scan cyclic voltammetry was performed while rats received additional tone-food pairings followed by tone alone presentations (i.e., extinction). Acquisition memory was reinstated with noncontingent presentations of reward and then tested with cue presentation. Tone-food pairings produced transient (1- to 3-s) DA release in response to tone. During extinction, the amplitude of the DA response decreased significantly. Following presentation of 2 noncontingent food pellets, subsequent tone presentation reinstated the DA signal. Our results support the prediction-error model for appetitive Pavlovian extinction but not for reinstatement.

  5. Dopamine Signaling in the Nucleus Accumbens of Animals Self-Administering Drugs of Abuse

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    Willuhn, Ingo; Wanat, Matthew J.; Clark, Jeremy J.; Phillips, Paul E. M.

    2013-01-01

    Abuse of psychoactive substances can lead to drug addiction. In animals, addiction is best modeled by drug self-administration paradigms. It has been proposed that the crucial common denominator for the development of drug addiction is the ability of drugs of abuse to increase extracellular concentrations of dopamine in the nucleus accumbens (NAcc). Studies using in vivo microdialysis and chronoamperometry in the behaving animal have demonstrated that drugs of abuse increase tonic dopamine concentrations in the NAcc. However, it is known that dopamine neurons respond to reward-related stimuli on a subsecond timescale. Thus, it is necessary to collect neurochemical information with this level of temporal resolution, as achieved with in vivo fast-scan cyclic voltammetry (FSCV), to fully understand the role of phasic dopamine release in normal behavior and drug addiction. We review studies that investigated the effects of drugs of abuse on NAcc dopamine levels in freely-moving animals using in vivo microdialysis, chronoamperometry and FSCV. After a brief introduction of dopamine anatomy and signal transduction, and a section on current theories of dopamine in natural goal-directed behavior, a discussion of techniques for the in vivo assessment of extracellular dopamine behaving animals is presented. Then, we review studies using these techniques to investigate changes in phasic and tonic dopamine signaling in the NAcc during 1) response-dependent and –independent administration of abused drugs, 2) drug-conditioned stimuli and operant behavior in self-administration paradigms, 3) drug withdrawal, and 4) cue-induced reinstatement of drug seeking. These results are then integrated with current ideas on the role of dopamine in addiction with an emphasis on a model illustrating phasic and tonic NAcc dopamine signaling during different stages of drug addiction. This model predicts that phasic dopamine release in response to drug-related stimuli will be enhanced over

  6. Calcium signals in the nucleus accumbens: Activation of astrocytes by ATP and succinate

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    Emri Zsuzsa

    2011-10-01

    Full Text Available Abstract Background Accumulating evidence suggests that glial signalling is activated by different brain functions. However, knowledge regarding molecular mechanisms of activation or their relation to neuronal activity is limited. The purpose of the present study is to identify the characteristics of ATP-evoked glial signalling in the brain reward area, the nucleus accumbens (NAc, and thereby to explore the action of citric acid cycle intermediate succinate (SUC. Results We described the burst-like propagation of Ca2+ transients evoked by ATP in acute NAc slices from rat brain. Co-localization of the ATP-evoked Ca2+ signalling with immunoreactivities of the astroglia-specific gap junction forming channel protein connexin43 (Cx43 and the glial fibrillary acidic protein (GFAP indicated that the responsive cells were a subpopulation of Cx43 and GFAP immunoreactive astrocytes. The ATP-evoked Ca2+ transients were present under the blockade of neuronal activity, but were inhibited by Ca2+ store depletion and antagonism of the G protein coupled purinergic P2Y1 receptor subtype-specific antagonist MRS2179. Similarly, Ca2+ transients evoked by the P2Y1 receptor subtype-specific agonist 2-(Methylthioadenosine 5'-diphosphate were also blocked by MRS2179. These characteristics implied that intercellular Ca2+ signalling originated from the release of Ca2+ from internal stores, triggered by the activation of P2Y1 receptors. Inhibition by the gap junction blockers carbenoxolone and flufenamic acid and by an antibody raised against the gating-associated segment of Cx43 suggested that intercellular Ca2+ signalling proceeded through gap junctions. We demonstrated for the first time that extracellular SUC also evoked Ca2+ transients (EC50 = 50-60 μM in about 15% of the ATP-responsive NAc astrocytes. By contrast to glial cells, electrophysiologically identified NAc neurons surrounded by ATP-responsive astrocytes were not activated simultaneously. Conclusions We

  7. Nucleus accumbens core dopamine signaling tracks the need-based motivational value of food-paired cues.

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    Aitken, Tara J; Greenfield, Venuz Y; Wassum, Kate M

    2016-03-01

    Environmental reward-predictive stimuli provide a major source of motivation for instrumental reward-seeking activity and this has been linked to dopamine signaling in the nucleus accumbens (NAc) core. This cue-induced incentive motivation can be quite general, not restricted to instrumental actions that earn the same unique reward, and is also typically regulated by one's current need state, such that cues only motivate actions when this is adaptive. But it remains unknown whether cue-evoked dopamine signaling is similarly regulated by need state. Here, we used fast-scan cyclic voltammetry to monitor dopamine concentration changes in the NAc core of rats during a Pavlovian-to-instrumental transfer task in which the motivating influence of two cues, each signaling a distinct food reward (sucrose or food pellets), over an action earning a third unique food reward (polycose) was assessed in a state of hunger and of satiety. Both cues elicited a robust NAc dopamine response when hungry. The magnitude of the sucrose cue-evoked dopamine response correlated with the Pavlovian-to-instrumental transfer effect that was selectively induced by this stimulus. Satiety attenuated these cue-evoked dopamine responses and behavioral responding, even though rats had never experienced the specific food rewards in this state. These data demonstrate that cue-evoked NAc core responses are sensitive to current need state, one critical variable that determines the current adaptive utility of cue-motivated behavior. Food-predictive stimuli motivate food-seeking behavior. Here, we show that food cues evoke a robust nucleus accumbens core dopamine response when hungry that correlates with the cue's ability to invigorate general food seeking. This response is attenuated when sated, demonstrating that food cue-evoked accumbens dopamine responses are sensitive to the need state information that determines the current adaptive utility of cue-motivated action. © 2015 International Society for

  8. Cue-elicited reward-seeking requires extracellular signal-regulated kinase activation in the nucleus accumbens.

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    Shiflett, Michael W; Martini, Ross P; Mauna, Jocelyn C; Foster, Rebecca L; Peet, Eloise; Thiels, Edda

    2008-02-01

    The motivation to seek out rewards can come under the control of stimuli associated with reward delivery. The ability of cues to motivate reward-seeking behavior depends on the nucleus accumbens (NAcc). The molecular mechanisms in the NAcc that underlie the ability of a cue to motivate reward-seeking are not well understood. We examined whether extracellular signal-regulated kinase (ERK), an important intracellular signaling pathway in learning and memory, has a role in these motivational processes. We first examined p42 ERK (ERK2) activation in the NAcc after rats were trained to associate an auditory stimulus with food delivery and found that, as a consequence of training, presentation of the auditory cue itself was sufficient to increase ERK2 activation in the NAcc. To examine whether inhibition of ERK in the NAcc prevents cue-induced reward-seeking, we infused an inhibitor of ERK, U0126, into the NAcc before assessing rats' instrumental responding in the presence versus absence of the conditioned cue. We found that, whereas vehicle-infused rats showed increased instrumental responding during cue presentation, rats infused with U0126 showed a profound impairment in cue-induced instrumental responding. In contrast, intra-NAcc U0126 infusion had no effect on rats' food-reinforced instrumental responding or their ability to execute conditioned approach behavior. Our results demonstrate learning-related changes in ERK signaling in the NAcc, and that disruption of ERK activation in this structure interferes with the incentive-motivational effects of conditioned stimuli. The molecular mechanisms described here may have implications for cue-elicited drug craving after repeated exposure to drugs of abuse.

  9. Valproate Inhibits Methamphetamine Induced Hyperactivity via Glycogen Synthase Kinase 3β Signaling in the Nucleus Accumbens Core.

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    Xing, Bo; Liang, Xiao-Ping; Liu, Peng; Zhao, Yan; Chu, Zheng; Dang, Yong-Hui

    2015-01-01

    Valproate (VPA) has recently been shown to influence the behavioral effects of psycho-stimulants. Although glycogen synthase kinase 3β (GSK3β) signaling in the nucleus accumbens (NAc) plays a key role in mediating dopamine (DA)-dependent behaviors, there is less direct evidence that how VPA acts on the GSK3β signaling in the functionally distinct sub-regions of the NAc, the NAc core (NAcC) and the NAc shell (NAcSh), during psycho-stimulant-induced hyperactivity. In the present study, we applied locomotion test after acute methamphetamine (MA) (2 mg/kg) injection to identify the locomotor activity of rats received repeated VPA (300 mg/kg) pretreatment. We next measured phosphor-GSK3β at serine 9 and total GSK3β levels in NAcC and NAcSh respectively to determine the relationship between the effect of VPA on MA-induced hyperlocomotor and changes in GSK3β activity. We further investigated whether microinjection of VPA (300 μg/0.5 μl/side, once daily for 7 consecutive days) into NAcC or NAcSh could affect hyperactivity induced by MA. Our data indicated that repeated VPA treatment attenuated MA-induced hyperlocomotor, and the effect was associated with decreased levels of phosphorylated GSK3β at Ser 9 in the NAcC. Moreover, repeated bilateral intra-NAcC, but not intra-NAcSh VPA treatment, significantly attenuated MA-induced hyperactivity. Our results suggested that GSK3β activity in NAcC contributes to the inhibitory effects of VPA on MA-induced hyperactivity.

  10. Activation of astroglial calcium signaling by endogenous metabolites succinate and gamma-hydroxybutyrate in the nucleus accumbens

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    Tünde eMolnár

    2011-12-01

    Full Text Available Accumulating evidence suggests that different energy metabolites play a role not only in neuronal but also in glial signalling. Recently, astroglial Ca2+ transients evoked by the major citric acid cycle metabolite succinate (SUC and gamma-hydroxybutyrate (GHB that enters the citric acid cycle via SUC have been described in the brain reward area, the nucleus accumbens (NAc. Cells responding to SUC by Ca2+ transient constitute a subset of ATP-responsive astrocytes that are activated in a neuron-independent way. In this study we show that GHB-evoked Ca2+ transients were also found to constitute a subset of ATP-responsive astrocytes in the NAc. Repetitive Ca2+ dynamics evoked by GHB suggested that Ca2+ was released from internal stores. Similarly to SUC, the GHB-response was also characterized by an effective concentration of 50 µM. We observed that the number of ATP-responsive cells decreased with increasing concentration of either SUC or GHB. Moreover, the concentration dependence of the number of ATP-responsive cells were highly identical as a function of both [SUC] and [GHB], suggesting a mutual receptor for SUC and GHB, therefore implying the existence of a distinct GHB-recognizing astroglial SUC receptor in the brain. The SUC-evoked Ca2+ signal remained in mice lacking GABAB receptor type 1 subunit in the presence and absence of the N-Methyl-D-Aspartate (NMDA receptor antagonist (2R-amino-5-phosphonovaleric acid (APV, indicating action mechanisms independent of the GABAB or NMDA receptor subtypes. By molecular docking calculations we found that residues R99, H103, R252 and R281 of the binding crevice of the kidney SUC-responsive membrane receptor SUCNR1 (GPCR91 also predict interaction with GHB, further implying similar GHB and SUC action mechanisms. We conclude that the astroglial action of SUC and GHB may represent a link between brain energy states and Ca2+ signalling in astrocytic networks.

  11. Tamping Ramping: Algorithmic, Implementational, and Computational Explanations of Phasic Dopamine Signals in the Accumbens.

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    Kevin Lloyd

    2015-12-01

    Full Text Available Substantial evidence suggests that the phasic activity of dopamine neurons represents reinforcement learning's temporal difference prediction error. However, recent reports of ramp-like increases in dopamine concentration in the striatum when animals are about to act, or are about to reach rewards, appear to pose a challenge to established thinking. This is because the implied activity is persistently predictable by preceding stimuli, and so cannot arise as this sort of prediction error. Here, we explore three possible accounts of such ramping signals: (a the resolution of uncertainty about the timing of action; (b the direct influence of dopamine over mechanisms associated with making choices; and (c a new model of discounted vigour. Collectively, these suggest that dopamine ramps may be explained, with only minor disturbance, by standard theoretical ideas, though urgent questions remain regarding their proximal cause. We suggest experimental approaches to disentangling which of the proposed mechanisms are responsible for dopamine ramps.

  12. Extinction of cocaine self-administration reveals functionally and temporally distinct dopaminergic signals in the nucleus accumbens.

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    Stuber, Garret D; Wightman, R Mark; Carelli, Regina M

    2005-05-19

    While Pavlovian and operant conditioning influence drug-seeking behavior, the role of rapid dopamine signaling in modulating these processes is unknown. During self-administration of cocaine, two dopaminergic signals, measured with 100 ms resolution, occurred immediately before and after the lever press (termed pre- and post-response dopamine transients). Extinction of self-administration revealed that these two signals were functionally distinct. Pre-response transients, which could reflect the motivation to obtain the drug, did not decline during extinction. Remarkably, post-response dopamine transients attenuated as extinction progressed, suggesting that they encode the learned association between environmental cues and cocaine. A third type of dopamine transient, not time locked to overt stimuli, decreased in frequency during extinction and correlated with calculated cocaine concentrations. These results show that dopamine release transients involved in different aspects of cocaine self-administration are highly plastic--differentially governed by motivation, learned associations linked with environmental stimuli, and the pharmacological actions of cocaine.

  13. Acquisition and expression of Conditioned Taste Aversion differentially affects Extracellular signal Regulated Kinase and Glutamate receptor phosphorylation in rat Prefrontal Cortex and Nucleus Accumbens

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    Roberto eMarotta

    2014-05-01

    Full Text Available Conditioned taste aversion (CTA can be applied to study associative learning and its relevant underpinning molecular mechanisms in discrete brain regions. The present study examined, by immunohistochemistry and immunocytochemistry, the effects of acquisition and expression of lithium-induced CTA on activated Extracellular signal Regulated Kinase (p-ERK in the prefrontal cortex (PFCx and nucleus accumbens (Acb of male Sprague-Dawley rats. The study also examined, by immunoblotting, whether acquisition and expression of lithium-induced CTA resulted in modified levels of phosphorylation of glutamate receptor subunits (NR1 and GluR1 and Thr34- and Thr75-Dopamine-and-cAMP-Regulated PhosphoProtein (DARPP-32. CTA acquisition was associated with an increase of p-ERK-positive neurons and phosphorylated NR1 receptor subunit (p-NR1 in the PFCx, whereas p-GluR1, p-Thr34- and p-Thr75-DARPP-32 levels were not changed in this brain region. CTA expression increased the number of p-ERK-positive neurons in the shell (AcbSh and core (AcbC but left unmodified p-NR1, p-GluR1, p-Thr34- and p-Thr75-DARPP-32 levels. Furthermore, post-embedding immunogold quantitative analysis in AcbSh revealed that CTA expression significantly increased nuclear p-ERK immunostaining as well as p-ERK-labeled axo-spinous contacts. Overall, these results indicate that ERK and NR1, but not GluR1 and DARPP-32, are differentially phosphorylated as a consequence of acquisition and expression of aversive associative learning. Moreover, these results confirm that CTA represents an useful approach to study the molecular basis of associative learning in rats and suggest the involvement of ERK cascade in learning-associated synaptic plasticity.

  14. Individual differences in ethanol locomotor sensitization are associated with dopamine D1 receptor intra-cellular signaling of DARPP-32 in the nucleus accumbens.

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    Karina Possa Abrahao

    Full Text Available In mice there are clear individual differences in the development of behavioral sensitization to ethanol, a progressive potentiation of its psychomotor stimulant effect. Variability in the behavioral responses to ethanol has been associated with alcohol preference. Here we investigated if the functional hyperresponsiveness of D1 receptors observed in ethanol sensitized mice leads to an increased activation of DARPP-32, a central regulatory protein in medium spiny neurons, in the nucleus accumbens - a brain region known to play a role in drug reinforcement. Swiss Webster mice received ethanol (2.2 g/kg/day or saline i.p. administrations for 21 days and were weekly evaluated regarding their locomotor activity. From those treated with ethanol, the 33% with the highest levels of locomotor activity were classified as "sensitized" and the 33% with the lowest levels as "non-sensitized". The latter presented similar locomotor levels to those of saline-treated mice. Different subgroups of mice received intra-accumbens administrations of saline and, 48 h later, SKF-38393, D1 receptor agonist 0.1 or 1 µg/side. Indeed, sensitized mice presented functional hyperresponsiveness of D1 receptors in the accumbens. Two weeks following the ethanol treatment, other subgroups received systemic saline or SKF 10 mg/kg, 20 min before the euthanasia. The nucleus accumbens were dissected for the Western Blot analyses of total DARPP-32 and phospho-Thr34-DARPP-32 expression. D1 receptor activation induced higher phospho-Thr34-DARPP-32 expression in sensitized mice than in non-sensitized or saline. The functionally hyperresponsiveness of D1 receptors in the nucleus accumbens is associated with an increased phospho-Thr34-DARPP-32 expression after D1 receptor activation. These data suggest that an enduring increase in the sensitivity of the dopamine D1 receptor intracellular pathway sensitivity represents a neurobiological correlate associated with the development of

  15. Neurons of human nucleus accumbens

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    Sazdanović Maja

    2011-01-01

    Full Text Available Background/Aim. Nucleus accumbens is a part of the ventral striatum also known as a drug active brain region, especially related with drug addiction. The aim of the study was to investigate the Golgi morphology of the nucleus accumbens neurons. Methods. The study was performed on the frontal and sagittal sections of 15 human brains by the Golgi Kopsch method. We classified neurons in the human nucleus accumbens according to their morphology and size into four types: type I - fusiform neurons; type II - fusiform neurons with lateral dendrite, arising from a part of the cell body; type III - pyramidal-like neuron; type IV - multipolar neuron. The medium spiny neurons, which are mostly noted regarding to the drug addictive conditions of the brain, correspond to the type IV - multipolar neurons. Results. Two regions of human nucleus accumbens could be clearly recognized on Nissl and Golgi preparations each containing different predominant neuronal types. Central part of nucleus accumbens, core region, has a low density of impregnated neurons with predominant type III, pyramidal-like neurons, with spines on secondary branches and rare type IV, multipolar neurons. Contrary to the core, peripheral region, shell of nucleus, has a high density of impregnated neurons predominantly contained of type I and type IV - multipolar neurons, which all are rich in spines on secondary and tertiary dendritic branches. Conclusion. Our results indicate great morphological variability of human nucleus accumbens neurons. This requires further investigations and clarifying clinical significance of this important brain region.

  16. Music and the nucleus accumbens.

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    Mavridis, Ioannis N

    2015-03-01

    Music is a universal feature of human societies over time, mainly because it allows expression and regulation of strong emotions, thus influencing moods and evoking pleasure. The nucleus accumbens (NA), the most important pleasure center of the human brain (dominates the reward system), is the 'king of neurosciences' and dopamine (DA) can be rightfully considered as its 'crown' due to the fundamental role that this neurotransmitter plays in the brain's reward system. Purpose of this article was to review the existing literature regarding the relation between music and the NA. Studies have shown that reward value for music can be coded by activity levels in the NA, whose functional connectivity with auditory and frontal areas increases as a function of increasing musical reward. Listening to music strongly modulates activity in a network of mesolimbic structures involved in reward processing including the NA. The functional connectivity between brain regions mediating reward, autonomic and cognitive processing provides insight into understanding why listening to music is one of the most rewarding and pleasurable human experiences. Musical stimuli can significantly increase extracellular DA levels in the NA. NA DA and serotonin were found significantly higher in animals exposed to music. Finally, passive listening to unfamiliar although liked music showed activations in the NA.

  17. Optogenetically-induced tonic dopamine release from VTA-nucleus accumbens projections inhibits reward consummatory behaviors.

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    Mikhailova, Maria A; Bass, Caroline E; Grinevich, Valentina P; Chappell, Ann M; Deal, Alex L; Bonin, Keith D; Weiner, Jeff L; Gainetdinov, Raul R; Budygin, Evgeny A

    2016-10-01

    Recent optogenetic studies demonstrated that phasic dopamine release in the nucleus accumbens may play a causal role in multiple aspects of natural and drug reward-related behaviors. The role of tonic dopamine release in reward consummatory behavior remains unclear. The current study used a combinatorial viral-mediated gene delivery approach to express ChR2 on mesolimbic dopamine neurons in rats. We used optical activation of this dopamine circuit to mimic tonic dopamine release in the nucleus accumbens and to explore the causal relationship between this form of dopamine signaling within the ventral tegmental area (VTA)-nucleus accumbens projection and consumption of a natural reward. Using a two bottle choice paradigm (sucrose vs. water), the experiments revealed that tonic optogenetic stimulation of mesolimbic dopamine transmission significantly decreased reward consummatory behaviors. Specifically, there was a significant decrease in the number of bouts, licks and amount of sucrose obtained during the drinking session. Notably, activation of VTA dopamine cell bodies or dopamine terminals in the nucleus accumbens resulted in identical behavioral consequences. No changes in water intake were evident under the same experimental conditions. Collectively, these data demonstrate that tonic optogenetic stimulation of VTA-nucleus accumbens dopamine release is sufficient to inhibit reward consummatory behavior, possibly by preventing this circuit from engaging in phasic activity that is thought to be essential for reward-based behaviors.

  18. Ceftriaxone attenuates acute cocaine‐evoked dopaminergic neurotransmission in the nucleus accumbens of the rat

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    Rasmussen, B A; Tallarida, C S; Scholl, J L; Forster, G L; Unterwald, E M; Rawls, S M

    2015-01-01

    Background and Purpose Ceftriaxone is a β‐lactam antibiotic and glutamate transporter activator that reduces the reinforcing effects of psychostimulants. Ceftriaxone also reduces locomotor activation following acute psychostimulant exposure, suggesting that alterations in dopamine transmission in the nucleus accumbens contribute to its mechanism of action. In the present studies we tested the hypothesis that pretreatment with ceftriaxone disrupts acute cocaine‐evoked dopaminergic neurotransmission in the nucleus accumbens. Experimental Approach Adult male Sprague–Dawley rats were pretreated with saline or ceftriaxone (200 mg kg−1, i.p. × 10 days) and then challenged with cocaine (15 mg kg−1, i.p.). Motor activity, dopamine efflux (via in vivo microdialysis) and protein levels of tyrosine hydroxylase (TH), the dopamine transporter and organic cation transporter as well as α‐synuclein, Akt and GSK3β were analysed in the nucleus accumbens. Key Results Ceftriaxone‐pretreated rats challenged with cocaine displayed reduced locomotor activity and accumbal dopamine efflux compared with saline‐pretreated controls challenged with cocaine. The reduction in cocaine‐evoked dopamine levels was not counteracted by excitatory amino acid transporter 2 blockade in the nucleus accumbens. Pretreatment with ceftriaxone increased Akt/GSK3β signalling in the nucleus accumbens and reduced levels of dopamine transporter, TH and phosphorylated α‐synuclein, indicating that ceftriaxone affects numerous proteins involved in dopaminergic transmission. Conclusions and Implications These results are the first evidence that ceftriaxone affects cocaine‐evoked dopaminergic transmission, in addition to its well‐described effects on glutamate, and suggest that its ability to attenuate cocaine‐induced behaviours, such as psychomotor activity, is due in part to reduced dopaminergic neurotransmission in the nucleus accumbens. PMID:26375494

  19. Metabotropic glutamate receptor blockade in nucleus accumbens shell shifts affective valence toward fear and displeasure

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    Richard, Jocelyn M.; Berridge, Kent C

    2010-01-01

    Glutamatergic inputs to the nucleus accumbens (NAc) modulate both appetitive and fearful motivation. Pathological disturbances of glutamate signaling in NAc have been suggested to contribute to motivation disorders, ranging from excessive desire in drug addiction to paranoia in schizophrenia. Metabotropic glutamate receptors are of special interest, as metabotropic Group II receptor (mglu2/3) agonists have been proposed as potential treatments for both addiction and schizophrenia. Here we tes...

  20. TrkB in the hippocampus and nucleus accumbens differentially modulates depression-like behavior in mice

    NARCIS (Netherlands)

    De Vry, Jochen; Vanmierlo, Tim; Martínez-Martínez, Pilar; Losen, Mario; Temel, Yasin; Boere, Janneke; Kenis, Gunter; Steckler, Thomas; Steinbusch, Harry W M; Baets, Marc De; Prickaerts, Jos

    2016-01-01

    Brain-derived neurotrophic factor (BDNF) exerts antidepressant-like effects in the hippocampus and pro-depressant effects in the nucleus accumbens (NAc). It is thought that downstream signaling of the BDNF receptor TrkB mediates the effects of BDNF in these brain structures. Here, we evaluate how Tr

  1. Regulation of nucleus accumbens activity by the hypothalamic neuropeptide MCH

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    Sears, Robert M.; Liu, Rong-Jian; Narayanan, Nandakumar S.; Sharf, Ruth; Yeckel, Mark F.; Laubach, Mark; Aghajanian, George K.; DiLeone, Ralph J.

    2010-01-01

    The lateral hypothalamus (LH) and the nucleus accumbens shell (AcbSh) are brain regions important for food intake. The AcbSh contains high levels of receptor for melanin-concentrating hormone (MCH), a lateral hypothalamic peptide critical for feeding and metabolism. MCH receptor (MCHR1) activation in the AcbSh increases food intake while AcbSh MCHR1 blockade reduces feeding. Here biochemical and cellular mechanisms of MCH action in the rodent AcbSh are described. A reduction of phosphorylation of GluR1 at Serine 845 (pSer845) is shown to occur after both pharmacological and genetic manipulations of MCHR1 activity. These changes depend upon signaling through Gi/o, and result in decreased surface expression of GluR1-containing AMPA receptors (AMPARs). Electrophysiological analysis of medium spiny neurons (MSNs) in the AcbSh revealed decreased amplitude of AMPAR-mediated synaptic events (mEPSC) with MCH treatment. In addition, MCH suppressed action potential firing MSNs through K+ channel activation. Finally, in vivo recordings confirmed that MCH reduces neuronal cell firing in the AcbSh in freely moving animals. The ability of MCH to reduce cell firing in the AcbSh is consistent with a general model from other pharmacological and electrophysiological studies whereby reduced AcbSh neuronal firing leads to food intake. The current work integrates the hypothalamus into this model, providing biochemical and cellular mechanisms whereby metabolic and limbic signals converge to regulate food intake. PMID:20554878

  2. A thalamic input to the nucleus accumbens mediates opiate dependence.

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    Zhu, Yingjie; Wienecke, Carl F R; Nachtrab, Gregory; Chen, Xiaoke

    2016-02-11

    Chronic opiate use induces opiate dependence, which is characterized by extremely unpleasant physical and emotional feelings after drug use is terminated. Both the rewarding effects of a drug and the desire to avoid withdrawal symptoms motivate continued drug use, and the nucleus accumbens is important for orchestrating both processes. While multiple inputs to the nucleus accumbens regulate reward, little is known about the nucleus accumbens circuitry underlying withdrawal. Here we identify the paraventricular nucleus of the thalamus as a prominent input to the nucleus accumbens mediating the expression of opiate-withdrawal-induced physical signs and aversive memory. Activity in the paraventricular nucleus of the thalamus to nucleus accumbens pathway is necessary and sufficient to mediate behavioural aversion. Selectively silencing this pathway abolishes aversive symptoms in two different mouse models of opiate withdrawal. Chronic morphine exposure selectively potentiates excitatory transmission between the paraventricular nucleus of the thalamus and D2-receptor-expressing medium spiny neurons via synaptic insertion of GluA2-lacking AMPA receptors. Notably, in vivo optogenetic depotentiation restores normal transmission at these synapses and robustly suppresses morphine withdrawal symptoms. This links morphine-evoked pathway- and cell-type-specific plasticity in the paraventricular nucleus of the thalamus to nucleus accumbens circuit to opiate dependence, and suggests that reprogramming this circuit holds promise for treating opiate addiction.

  3. Encoding of aversion by dopamine and the nucleus accumbens

    Directory of Open Access Journals (Sweden)

    James Edgar Mccutcheon

    2012-09-01

    Full Text Available Adaptive motivated behavior requires rapid discrimination between beneficial and harmful stimuli. Such discrimination leads to the generation of either an approach or rejection response, as appropriate, and enables organisms to maximize reward and minimize punishment. Classically, the nucleus accumbens (NAc and the dopamine projection to it are considered an integral part of the brain’s reward circuit, i.e., they direct approach and consumption behaviors and underlie positive reinforcement. This reward-centered framing ignores important evidence about the role of this system in encoding aversive events. One reason for bias towards reward is the difficulty in designing experiments in which animals repeatedly experience punishments; another is the challenge in dissociating the response to an aversive stimulus itself from the reward/relief experienced when an aversive stimulus is terminated. Here, we review studies that employ techniques with sufficient time resolution to measure responses in ventral tegmental area (VTA and NAc to aversive stimuli as they are delivered. We also present novel findings showing that the same stimulus – intraoral infusion of sucrose – has differing effects on NAc shell dopamine release depending on the prior experience. Here, for some rats, sucrose was rendered aversive by explicitly pairing it with malaise in a conditioned taste aversion paradigm. Thereafter, sucrose infusions led to a suppression of dopamine with a similar magnitude and time course to intra-oral infusions of a bitter quinine solution. The results are discussed in the context of regional differences in dopamine signaling and the implications of a pause in phasic dopamine release within the NAc shell. Together with our data, the emerging literature suggests an important role for differential phasic dopamine signaling in aversion versus reward.

  4. Encoding of aversion by dopamine and the nucleus accumbens.

    Science.gov (United States)

    McCutcheon, James E; Ebner, Stephanie R; Loriaux, Amy L; Roitman, Mitchell F

    2012-01-01

    Adaptive motivated behavior requires rapid discrimination between beneficial and harmful stimuli. Such discrimination leads to the generation of either an approach or rejection response, as appropriate, and enables organisms to maximize reward and minimize punishment. Classically, the nucleus accumbens (NAc) and the dopamine projection to it are considered an integral part of the brain's reward circuit, i.e., they direct approach and consumption behaviors and underlie positive reinforcement. This reward-centered framing ignores important evidence about the role of this system in encoding aversive events. One reason for bias toward reward is the difficulty in designing experiments in which animals repeatedly experience punishments; another is the challenge in dissociating the response to an aversive stimulus itself from the reward/relief experienced when an aversive stimulus is terminated. Here, we review studies that employ techniques with sufficient time resolution to measure responses in ventral tegmental area and NAc to aversive stimuli as they are delivered. We also present novel findings showing that the same stimulus - intra-oral infusion of sucrose - has differing effects on NAc shell dopamine release depending on the prior experience. Here, for some rats, sucrose was rendered aversive by explicitly pairing it with malaise in a conditioned taste aversion paradigm. Thereafter, sucrose infusions led to a suppression of dopamine with a similar magnitude and time course to intra-oral infusions of a bitter quinine solution. The results are discussed in the context of regional differences in dopamine signaling and the implications of a pause in phasic dopamine release within the NAc shell. Together with our data, the emerging literature suggests an important role for differential phasic dopamine signaling in aversion vs. reward.

  5. AMPA/Kainate, NMDA, and Dopamine D1 Receptor Function in the Nucleus Accumbens Core: A Context-Limited Role in the Encoding and Consolidation of Instrumental Memory

    Science.gov (United States)

    Hernandez, Pepe J.; Andrzejewski, Matthew E.; Sadeghian, Kenneth; Panksepp, Jules B.; Kelley, Ann E.

    2005-01-01

    Neural integration of glutamate- and dopamine-coded signals within the nucleus accumbens (NAc) is a fundamental process governing cellular plasticity underlying reward-related learning. Intra-NAc core blockade of NMDA or D1 receptors in rats impairs instrumental learning (lever-pressing for sugar pellets), but it is not known during which phase of…

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  13. Morphology of Human Nucleus Accumbens Neurons Based on the Immunohistochemical Expression of Gad67

    Directory of Open Access Journals (Sweden)

    Sazdanovic Maja

    2016-12-01

    Full Text Available The nucleus accumbens is a part of the ventral striatum along with the caudate nucleus and putamen. The role of the human nucleus accumbens in drug addiction and other psychiatric disorders is of great importance. The aim of this study was to characterize medium spiny neurons in the nucleus accumbens according to the immunohistochemical expression of GAD67.

  14. Rapid feedback processing in human nucleus accumbens and motor thalamus

    NARCIS (Netherlands)

    Schüller, T.; Gründler, T.O.J.; Jocham, G.; Klein, T.A.; Timmermann, L.; Visser-Vandewalle, V.E.R.M.; Kuhn, J.

    2015-01-01

    The nucleus accumbens (NAcc) and thalamus are integral parts in models of feedback processing. Deep brain stimulation (DBS) has been successfully employed to alleviate symptoms of psychiatric conditions including obsessive-compulsive disorder (OCD) and Tourette's syndrome (TS). Common target structu

  15. Nucleus accumbens dopamine receptors in the consolidation of spatial memory.

    NARCIS (Netherlands)

    Mele, A.; Avena, M.; Roullet, P.; Leonibus, E. de; Mandillo, S.; Sargolini, F.; Coccurello, R.; Oliverio, A.

    2004-01-01

    Nucleus accumbens dopamine is known to play an important role in motor activity and in behaviours governed by drugs and natural reinforcers, as well as in non-associative forms of learning. At the same time, activation of D1 and D2 dopamine receptors has been suggested to promote intracellular event

  16. Phasic dopamine release in the rat nucleus accumbens predicts approach and avoidance performance.

    Science.gov (United States)

    Gentry, Ronny N; Lee, Brian; Roesch, Matthew R

    2016-10-27

    Dopamine (DA) is critical for reward processing, but significantly less is known about its role in punishment avoidance. Using a combined approach-avoidance task, we measured phasic DA release in the nucleus accumbens (NAc) of rats during presentation of cues that predicted reward, punishment or neutral outcomes and investigated individual differences based on avoidance performance. Here we show that DA release within a single microenvironment is higher for reward and avoidance cues compared with neutral cues and positively correlated with poor avoidance behaviour. We found that DA release delineates trial-type during sessions with good avoidance but is non-selective during poor avoidance, with high release correlating with poor performance. These data demonstrate that phasic DA is released during cued approach and avoidance within the same microenvironment and abnormal processing of value signals is correlated with poor performance.

  17. Genetic risk for obesity predicts nucleus accumbens size and responsivity to real-world food cues.

    Science.gov (United States)

    Rapuano, Kristina M; Zieselman, Amanda L; Kelley, William M; Sargent, James D; Heatherton, Todd F; Gilbert-Diamond, Diane

    2017-01-03

    Obesity is a major public health concern that involves an interaction between genetic susceptibility and exposure to environmental cues (e.g., food marketing); however, the mechanisms that link these factors and contribute to unhealthy eating are unclear. Using a well-known obesity risk polymorphism (FTO rs9939609) in a sample of 78 children (ages 9-12 y), we observed that children at risk for obesity exhibited stronger responses to food commercials in the nucleus accumbens (NAcc) than children not at risk. Similarly, children at a higher genetic risk for obesity demonstrated larger NAcc volumes. Although a recessive model of this polymorphism best predicted body mass and adiposity, a dominant model was most predictive of NAcc size and responsivity to food cues. These findings suggest that children genetically at risk for obesity are predisposed to represent reward signals more strongly, which, in turn, may contribute to unhealthy eating behaviors later in life.

  18. Genetic risk for obesity predicts nucleus accumbens size and responsivity to real-world food cues

    Science.gov (United States)

    Rapuano, Kristina M.; Zieselman, Amanda L.; Kelley, William M.; Sargent, James D.; Heatherton, Todd F.

    2017-01-01

    Obesity is a major public health concern that involves an interaction between genetic susceptibility and exposure to environmental cues (e.g., food marketing); however, the mechanisms that link these factors and contribute to unhealthy eating are unclear. Using a well-known obesity risk polymorphism (FTO rs9939609) in a sample of 78 children (ages 9–12 y), we observed that children at risk for obesity exhibited stronger responses to food commercials in the nucleus accumbens (NAcc) than children not at risk. Similarly, children at a higher genetic risk for obesity demonstrated larger NAcc volumes. Although a recessive model of this polymorphism best predicted body mass and adiposity, a dominant model was most predictive of NAcc size and responsivity to food cues. These findings suggest that children genetically at risk for obesity are predisposed to represent reward signals more strongly, which, in turn, may contribute to unhealthy eating behaviors later in life. PMID:27994159

  19. Nucleus accumbens μ-opioid receptors mediate social reward

    OpenAIRE

    Trezza, Viviana; Damsteegt, Ruth; Achterberg, E J Marijke; Vanderschuren, Louk J. M. J

    2011-01-01

    Positive social interactions are essential for emotional well-being and proper behavioral development of young individuals. Here, we studied the neural underpinnings of social reward, by investigating the involvement of opioid neurotransmission in the nucleus accumbens (NAc) in social play behavior, a highly rewarding social interaction in adolescent rats. Intra-NAc infusion of morphine (0.05–0.1 μg) increased pinning and pouncing, characteristic elements of social play behavior in rats, and ...

  20. Altered morphology of the nucleus accumbens in persistent developmental stuttering.

    Science.gov (United States)

    Neef, Nicole E; Bütfering, Christoph; Auer, Tibor; Metzger, F Luise; Euler, Harald A; Frahm, Jens; Paulus, Walter; Sommer, Martin

    2017-05-24

    Neuroimaging studies in persistent developmental stuttering repeatedly report altered basal ganglia functions. Together with thalamus and cerebellum, these structures mediate sensorimotor functions and thus represent a plausible link between stuttering and neuroanatomy. However, stuttering is a complex, multifactorial disorder. Besides sensorimotor functions, emotional and social-motivational factors constitute major aspects of the disorder. Here, we investigated cortical and subcortical gray matter regions to study whether persistent developmental stuttering is also linked to alterations of limbic structures. The study included 33 right-handed participants who stutter and 34 right-handed control participants matched for sex, age, and education. Structural images were acquired using magnetic resonance imaging to estimate volumetric characteristics of the nucleus accumbens, hippocampus, amygdala, pallidum, putamen, caudate nucleus, and thalamus. Volumetric comparisons and vertex-based shape comparisons revealed structural differences. The right nucleus accumbens was larger in participants who stutter compared to controls. Recent theories of basal ganglia functions suggest that the nucleus accumbens is a motivation-to-movement interface. A speaker intends to reach communicative goals, but stuttering can derail these efforts. It is therefore highly plausible to find alterations in the motivation-to-movement interface in stuttering. While behavioral studies of stuttering sought to find links between the limbic and sensorimotor system, we provide the first neuroimaging evidence of alterations in the limbic system. Thus, our findings might initialize a unified neurobiological framework of persistent developmental stuttering that integrates sensorimotor and social-motivational neuroanatomical circuitries. Copyright © 2017 Elsevier Inc. All rights reserved.

  1. d-Sulpiride inhibits oral behaviour elicited from the nucleus accumbens of freely moving rats.

    Science.gov (United States)

    Prinssen, E P; Heeren, D J; Cools, A R

    1996-01-01

    The present study analyzed the effect of intra-accumbens administration of the stereoisomers of sulpiride upon (3,4-dihydroxyphenylimino)-2-imidazoline (DPI)-induced changes in oral behaviours and electromyographic patterns of jaw muscles. In line with earlier findings, DPI (5 micrograms) administered into the nucleus accumbens increased chewing and tremor. l-Sulpiride (2-50 ng) had no effect on DPI-induced oro-facial behaviours. d-Sulpiride (10-50 ng) significantly antagonized the DPI-induced increase in chewing and had a biphasic effect on tremor with potentiation (10 ng) followed by attenuation (50 ng). When administered alone, l- or d-sulpiride did not affect oro-facial behaviours. The electromyographic signals, which were analyzed according to a previously described method, were described with the help of three classes: A (the seconds marked by frequency 3 Hz), B (the seconds marked by the frequencies 4-6 Hz); C (the seconds marked by the frequencies 7-15 Hz). DPI enhanced Class B and C of the masseter muscle but did not significantly affect any frequency class of the digastric muscle. l-Sulpiride (2-50 ng) had no effect on DPI-induced (5 micrograms) changes in electromyographic signals. d-Sulpiride (50 ng) antagonized the effects of DPI on Class B of the masseter muscle. Furthermore, d-sulpiride had a biphasic effect on Class C with potentiation (10 ng) followed by attenuation (50 ng). When administered alone, l- or d-sulpiride did not affect the frequency classes of the jaw muscles. It is concluded that d-sulpiride inhibits DPI-induced changes in oral behaviour and electromyographic patterns. It is suggested that d-sulpiride may be effective in the pharmacotherapy of oro-facial dyskinesias in man.

  2. Individual variation in incentive salience attribution and accumbens dopamine transporter expression and function.

    Science.gov (United States)

    Singer, Bryan F; Guptaroy, Bipasha; Austin, Curtis J; Wohl, Isabella; Lovic, Vedran; Seiler, Jillian L; Vaughan, Roxanne A; Gnegy, Margaret E; Robinson, Terry E; Aragona, Brandon J

    2016-03-01

    Cues (conditioned stimuli; CSs) associated with rewards can come to motivate behavior, but there is considerable individual variation in their ability to do so. For example, a lever-CS that predicts food reward becomes attractive and wanted, and elicits reward-seeking behavior, to a greater extent in some rats ('sign-trackers'; STs) than others ('goal-trackers'; GTs). Variation in dopamine (DA) neurotransmission in the nucleus accumbens (NAc) core is thought to contribute to such individual variation. Given that the DA transporter (DAT) exerts powerful regulation over DA signaling, we characterized the expression and function of the DAT in the accumbens of STs and GTs. STs showed greater DAT surface expression in ventral striatal synaptosomes than GTs, and ex vivo fast-scan cyclic voltammetry recordings of electrically evoked DA release confirmed enhanced DAT function in STs, as indicated by faster DA uptake, specifically in the NAc core. Consistent with this, systemic amphetamine (AMPH) produced greater inhibition of DA uptake in STs than in GTs. Furthermore, injection of AMPH directly into the NAc core enhanced lever-directed approach in STs, presumably by amplifying the incentive value of the CS, but had no effect on goal-tracking behavior. On the other hand, there were no differences between STs and GTs in electrically-evoked DA release in slices, or in total ventral striatal DA content. We conclude that greater DAT surface expression may facilitate the attribution of incentive salience to discrete reward cues. Investigating this variability in animal sub-populations may help explain why some people abuse drugs while others do not. © 2015 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  3. Oxytocin Acts in Nucleus Accumbens to Attenuate Methamphetamine Seeking and Demand.

    Science.gov (United States)

    Cox, Brittney M; Bentzley, Brandon S; Regen-Tuero, Helaina; See, Ronald E; Reichel, Carmela M; Aston-Jones, Gary

    2017-06-01

    Evidence indicates that oxytocin, an endogenous peptide well known for its role in social behaviors, childbirth, and lactation, is a promising addiction pharmacotherapy. We employed a within-session behavioral-economic (BE) procedure in rats to examine oxytocin as a pharmacotherapy for methamphetamine (meth) addiction. The BE paradigm was modeled after BE procedures used to assess motivation for drugs in humans with addiction. The same BE variables assessed across species have been shown to predict later relapse behavior. Thus, the translational potential of preclinical BE studies is particularly strong. We tested the effects of systemic and microinfused oxytocin on demand for self-administered intravenous meth and reinstatement of extinguished meth seeking in male and female rats using a BE paradigm. Correlations between meth demand and meth seeking were assessed. Female rats showed greater demand (i.e., motivation) for meth compared with male rats. In both male and female rats, meth demand predicted reinstatement of meth seeking, and systemic oxytocin decreased demand for meth and attenuated reinstatement to meth seeking. Oxytocin was most effective at decreasing meth demand and seeking in rats with the strongest motivation for drug. Finally, these effects of systemic oxytocin were mediated by actions in the nucleus accumbens. Oxytocin decreases meth demand and seeking in both sexes, and these effects depend on oxytocin signaling in the nucleus accumbens. Overall, these data indicate that development of oxytocin-based therapies may be a promising treatment approach for meth addiction in humans. Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  4. Role of orexin receptors in the nucleus accumbens in dopamine-dependent turning behaviour of rats.

    NARCIS (Netherlands)

    Kotani, A.; Ikeda, H.; Koshikawa, N.; Cools, A.R.

    2008-01-01

    The role of orexin receptors in the nucleus accumbens shell in rat turning behaviour of rats was studied. Unilateral injection of neither the orexin 1 and 2 receptor agonist orexin A (2 microg) nor the orexin 1 receptor antagonist SB 334867 (20 ng) into the nucleus accumbens shell elicited turning b

  5. A case of musical preference for Johnny Cash following deep brain stimulation of the nucleus accumbens

    Directory of Open Access Journals (Sweden)

    Mariska eMantione

    2014-05-01

    Full Text Available Music is among all cultures an important part of the live of most people. Music has psychological benefits and may generate strong emotional and physiological responses. Recently, neuroscientists have discovered that music influences the reward circuit of the nucleus accumbens, even when no explicit reward is present. In this clinical case study, we describe a 60-year old patient who developed a sudden and distinct musical preference for Johnny Cash following deep brain stimulation targeted at the nucleus accumbens for treatment-refractory obsessive-compulsive disorder. This case report substantiates the assumption that the nucleus accumbens is involved in musical preference, based on the observation of direct stimulation of the accumbens with deep brain stimulation. It also shows that accumbens DBS can change musical preference without habituation of its rewarding properties.

  6. Nucleus accumbens functional connectivity discriminates medication-overuse headache

    Directory of Open Access Journals (Sweden)

    D.M. Torta

    2016-01-01

    Full Text Available Medication-overuse headache (MOH is a secondary form of headache related to the overuse of triptans, analgesics and other acute headache medications. It is believed that MOH and substance addiction share some similar pathophysiological mechanisms. In this study we examined the whole brain resting state functional connectivity of the dorsal and ventral striatum in 30 patients (15 MOH and 15 non-MOH patients to investigate if classification algorithms can successfully discriminate between MOH and non-MOH patients on the basis of the spatial pattern of resting state functional connectivity of the dorsal and ventral striatal region of interest. Our results indicated that both nucleus accumbens and dorsal rostral putamen functional connectivity could discriminate between MOH and non-MOH patients, thereby providing possible support to two interpretations. First, that MOH patients show altered reward functionality in line with drug abusers (alterations in functional connectivity of the nucleus accumbens. Second, that MOH patients show inability to break habitual behavior (alterations in functional connectivity of the dorsal striatum. In conclusion, our data showed that MOH patients were characterized by an altered functional connectivity of motivational circuits at rest. These differences could permit the blind discrimination between the two conditions using classification algorithms. Considered overall, our findings might contribute to the development of novel diagnostic measures.

  7. Regulation of nucleus accumbens activity by the hypothalamic neuropeptide melanin-concentrating hormone.

    Science.gov (United States)

    Sears, Robert M; Liu, Rong-Jian; Narayanan, Nandakumar S; Sharf, Ruth; Yeckel, Mark F; Laubach, Mark; Aghajanian, George K; DiLeone, Ralph J

    2010-06-16

    The lateral hypothalamus and the nucleus accumbens shell (AcbSh) are brain regions important for food intake. The AcbSh contains high levels of receptor for melanin-concentrating hormone (MCH), a lateral hypothalamic peptide critical for feeding and metabolism. MCH receptor (MCHR1) activation in the AcbSh increases food intake, while AcbSh MCHR1 blockade reduces feeding. Here biochemical and cellular mechanisms of MCH action in the rodent AcbSh are described. A reduction of phosphorylation of GluR1 at serine 845 (pSer(845)) is shown to occur after both pharmacological and genetic manipulations of MCHR1 activity. These changes depend upon signaling through G(i/o), and result in decreased surface expression of GluR1-containing AMPA receptors (AMPARs). Electrophysiological analysis of medium spiny neurons (MSNs) in the AcbSh revealed decreased amplitude of AMPAR-mediated synaptic events (mEPSCs) with MCH treatment. In addition, MCH suppressed action potential firing MSNs through K(+) channel activation. Finally, in vivo recordings confirmed that MCH reduces neuronal cell firing in the AcbSh in freely moving animals. The ability of MCH to reduce cell firing in the AcbSh is consistent with a general model from other pharmacological and electrophysiological studies whereby reduced AcbSh neuronal firing leads to food intake. The current work integrates the hypothalamus into this model, providing biochemical and cellular mechanisms whereby metabolic and limbic signals converge to regulate food intake.

  8. VTA glutamatergic inputs to nucleus accumbens drive aversion by acting on GABAergic interneurons

    Science.gov (United States)

    Qi, Jia; Zhang, Shiliang; Wang, Hui-Ling; Barker, David J.; Miranda-Barrientos, Jorge; Morales, Marisela

    2016-01-01

    The ventral tegmental area (VTA) is best known for its dopamine neurons, some of which project to nucleus accumbens (nAcc). However, the VTA also has glutamatergic neurons that project to nAcc. The function of the mesoaccumbens-glutamatergic pathway remains unknown. Here, we report that nAcc photoactivation of mesoaccumbens-glutamatergic fibers promotes aversion. Although we found that these mesoaccumbens-glutamate-fibers lack GABA, the aversion evoked by their photoactivation depends on glutamate and GABA receptor signaling, and not on dopamine receptor signaling. We found that mesoaccumbens-glutamatergic-fibers establish multiple asymmetric synapses on single parvalbumin-GABAergic interneurons, and that nAcc photoactivation of these fibers drives AMPA-mediated cellular firing of parvalbumin-GABAergic interneurons. These parvalbumin-GABAergic-interneurons, in turn, inhibit nAcc medium spiny output neurons, as such, controlling inhibitory neurotransmission within nAcc. The mesoaccumbens-glutamatergic pathway is the first glutamatergic input to nAcc shown to mediate aversion, instead of reward, and the first pathway shown to establish excitatory synapses on nAcc parvalbumin-GABAergic interneurons. PMID:27019014

  9. The function of nucleus accumbens in drug addiction%伏核在药物成瘾中的作用

    Institute of Scientific and Technical Information of China (English)

    衡立君; 高国栋

    2005-01-01

    Nucleus accumbens, an important component of brain-reward regions, is involved in the reinforcement, tolerance, addiction and expression of withdrawal syndrome of drug addiction. Previous studies of nucleus accumbens in functional anatomy, receptor activation and signal transduction, gene transcription and molecular expression, neuronal plasticity and changes in behavior help us understand the mechanism of drug addiction in the central nervous system, and provide us with basic principles for clinical treatment of drug withdrawal syndrome.%伏核是脑奖赏中枢的重要组成部分,参与成瘾药物的强化、耐受、成瘾过程及药物戒断综合征的表达.对伏核功能解剖、受体激动与信号转导、基因转录与分子表达、神经元可塑性与行为变化等方面的深入研究,将帮助我们揭示药物成瘾的中枢机制,进而为临床戒毒治疗提供理论依据.

  10. Reward and reinforcement activity in the nucleus accumbens during learning

    Directory of Open Access Journals (Sweden)

    John Thomas Gale

    2014-04-01

    Full Text Available The nucleus accumbens core (NAcc has been implicated in learning associations between sensory cues and profitable motor responses. However, the precise mechanisms that underlie these functions remain unclear. We recorded single-neuron activity from the NAcc of primates trained to perform a visual-motor associative learning task. During learning, we found two distinct classes of NAcc neurons. The first class demonstrated progressive increases in firing rates at the go-cue, feedback/tone and reward epochs of the task, as novel associations were learned. This suggests that these neurons may play a role in the exploitation of rewarding behaviors. In contrast, the second class exhibited attenuated firing rates, but only at the reward epoch of the task. These findings suggest that some NAcc neurons play a role in reward-based reinforcement during learning.

  11. Regional influence of cocaine on evoked dopamine release in the nucleus accumbens core: A role for the caudal brainstem.

    Science.gov (United States)

    Gerth, Ashlynn I; Alhadeff, Amber L; Grill, Harvey J; Roitman, Mitchell F

    2017-01-15

    Cocaine increases dopamine concentration in the nucleus accumbens through competitive binding to the dopamine transporter (DAT). However, it also increases the frequency of dopamine release events, a finding that cannot be explained by action at the DAT alone. Rather, this effect may be mediated by cocaine-induced modulation of brain regions that project to dopamine neurons. To explore regional contributions of cocaine to dopamine signaling, we administered cocaine to the lateral or fourth ventricles and compared the effects on dopamine release in the nucleus accumbens evoked by electrical stimulation of the ventral tegmental area to that of systemically-delivered cocaine. Stimulation trains caused a sharp rise in dopamine followed by a slower return to baseline. The magnitude of dopamine release ([DA]max) as well as the latency to decay to fifty percent of the maximum (t(1/2); index of DAT activity) by each stimulation train were recorded. All routes of cocaine delivery caused an increase in [DA]max; only systemic cocaine caused an increase in t(1/2). Importantly, these data are the first to show that hindbrain (fourth ventricle)-delivered cocaine modulates phasic dopamine signaling. Fourth ventricular cocaine robustly increased cFos immunoreactivity in the nucleus of the solitary tract (NTS), suggesting a neural substrate for hindbrain cocaine-mediated effects on [DA]max. Together, the data demonstrate that cocaine-induced effects on phasic dopamine signaling are mediated via actions throughout the brain including the hindbrain. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  12. Facebook usage on smartphones and gray matter volume of the nucleus accumbens.

    Science.gov (United States)

    Montag, Christian; Markowetz, Alexander; Blaszkiewicz, Konrad; Andone, Ionut; Lachmann, Bernd; Sariyska, Rayna; Trendafilov, Boris; Eibes, Mark; Kolb, Julia; Reuter, Martin; Weber, Bernd; Markett, Sebastian

    2017-06-30

    A recent study has implicated the nucleus accumbens of the ventral striatum in explaining why online-users spend time on the social network platform Facebook. Here, higher activity of the nucleus accumbens was associated with gaining reputation on social media. In the present study, we touched a related research field. We recorded the actual Facebook usage of N=62 participants on their smartphones over the course of five weeks and correlated summary measures of Facebook use with gray matter volume of the nucleus accumbens. It appeared, that in particular higher daily frequency of checking Facebook on the smartphone was robustly linked with smaller gray matter volumes of the nucleus accumbens. The present study gives additional support for the rewarding aspects of Facebook usage. Moreover, it shows the feasibility to include real life behavior variables in human neuroscientific research. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. Persistent cue-evoked activity of accumbens neurons after prolonged abstinence from self-administered cocaine.

    Science.gov (United States)

    Ghitza, Udi E; Fabbricatore, Anthony T; Prokopenko, Volodymyr; Pawlak, Anthony P; West, Mark O

    2003-08-13

    Persistent neural processing of information regarding drug-predictive environmental stimuli may be involved in motivating drug abusers to engage in drug seeking after abstinence. The addictive effects of various drugs depend on the mesocorticolimbic dopamine system innervating the nucleus accumbens. We used single-unit recording in rats to test whether accumbens neurons exhibit responses to a discriminative stimulus (SD) tone previously paired with cocaine availability during cocaine self-administration. Presentation of the tone after 3-4 weeks of abstinence resulted in a cue-induced relapse of drug seeking under extinction conditions. Accumbens neurons did not exhibit tone-evoked activity before cocaine self-administration training but exhibited significant SD tone-evoked activity during extinction. Under extinction conditions, shell neurons exhibited significantly greater activity evoked by the SD tone than that evoked by a neutral tone (i.e., never paired with reinforcement). In contrast, core neurons responded indiscriminately to presentations of the SD tone or the neutral tone. Accumbens shell neurons exhibited significantly greater SD tone-evoked activity than did accumbens core neurons. Although the onset of SD tone-evoked activity occurred well before the earliest movements commenced (150 msec), this activity often persisted beyond the onset of tone-evoked movements. These results indicate that accumbens shell neurons exhibit persistent processing of information regarding reward-related stimuli after prolonged drug abstinence. Moreover, the accumbens shell appears to be involved in discriminating the motivational value of reward-related associative stimuli, whereas the accumbens core does not.

  14. Die Rolle des Nucleus accumbens bei der Akquisition und Expression von instrumentellem Verhalten der Ratte

    OpenAIRE

    Giertler, Christian

    2003-01-01

    Der Nucleus accumbens wird als Schnittstelle aufgefasst, über den limbische und corticale Strukturen, die eine belohnungsbezogene Analyse von sensorischen Signalen vornehmen, Zugang zum motorischen System erhalten. Aufgrund der bekannten Verschaltung der beteiligten Transmittersysteme kommt als Überträger dieser "corticalen Informationen" insbesondere der Neurotransmitter Glutamat in Frage. Darüber hinaus erhält der Nucleus Accumbens dopaminerge Afferenzen, die an einer Vielzahl von Funktione...

  15. Functional Magnetic Resonance Imaging of Electrical and Optogenetic Deep Brain Stimulation at the Rat Nucleus Accumbens

    Science.gov (United States)

    Albaugh, Daniel L.; Salzwedel, Andrew; van den Berge, Nathalie; Gao, Wei; Stuber, Garret D.; Shih, Yen-Yu Ian

    2016-09-01

    Deep brain stimulation of the nucleus accumbens (NAc-DBS) is an emerging therapy for diverse, refractory neuropsychiatric diseases. Although DBS therapy is broadly hypothesized to work through large-scale neural modulation, little is known regarding the neural circuits and networks affected by NAc-DBS. Using a healthy, sedated rat model of NAc-DBS, we employed both evoked- and functional connectivity (fc) MRI to examine the functional circuit and network changes achieved by electrical NAc stimulation. Optogenetic-fMRI experiments were also undertaken to evaluate the circuit modulation profile achieved by selective stimulation of NAc neurons. NAc-DBS directly modulated neural activity within prefrontal cortex and a large number of subcortical limbic areas (e.g., amygdala, lateral hypothalamus), and influenced functional connectivity among sensorimotor, executive, and limbic networks. The pattern and extent of circuit modulation measured by evoked-fMRI was relatively insensitive to DBS frequency. Optogenetic stimulation of NAc cell bodies induced a positive fMRI signal in the NAc, but no other detectable downstream responses, indicating that therapeutic NAc-DBS might exert its effect through antidromic stimulation. Our study provides a comprehensive mapping of circuit and network-level neuromodulation by NAc-DBS, which should facilitate our developing understanding of its therapeutic mechanisms of action.

  16. Nucleus accumbens is involved in human action monitoring: evidence from invasive electrophysiological recordings

    Directory of Open Access Journals (Sweden)

    Thomas F Münte

    2008-03-01

    Full Text Available The Nucleus accumbens (Nacc has been proposed to act as a limbic-motor interface. Here, using invasive intraoperative recordings in an awake patient suffering from obsessive-compulsive disease (OCD, we demonstrate that its activity is modulated by the quality of performance of the subject in a choice reaction time task designed to tap action monitoring processes. Action monitoring, that is, error detection and correction, is thought to be supported by a system involving the dopaminergic midbrain, the basal ganglia, and the medial prefrontal cortex. In surface electrophysiological recordings, action monitoring is indexed by an error-related negativity (ERN appearing time-locked to the erroneous responses and emanating from the medial frontal cortex. In preoperative scalp recordings the patient's ERN was found to be signifi cantly increased compared to a large (n= 83 normal sample, suggesting enhanced action monitoring processes. Intraoperatively, error-related modulations were obtained from the Nacc but not from a site 5 mm above. Importantly, crosscorrelation analysis showed that error-related activity in the Nacc preceded surface activity by 40 ms. We propose that the Nacc is involved in action monitoring, possibly by using error signals from the dopaminergic midbrain to adjust the relative impact of limbic and prefrontal inputs on frontal control systems in order to optimize goal-directed behavior.

  17. Functional Magnetic Resonance Imaging of Electrical and Optogenetic Deep Brain Stimulation at the Rat Nucleus Accumbens

    Science.gov (United States)

    Albaugh, Daniel L.; Salzwedel, Andrew; Van Den Berge, Nathalie; Gao, Wei; Stuber, Garret D.; Shih, Yen-Yu Ian

    2016-01-01

    Deep brain stimulation of the nucleus accumbens (NAc-DBS) is an emerging therapy for diverse, refractory neuropsychiatric diseases. Although DBS therapy is broadly hypothesized to work through large-scale neural modulation, little is known regarding the neural circuits and networks affected by NAc-DBS. Using a healthy, sedated rat model of NAc-DBS, we employed both evoked- and functional connectivity (fc) MRI to examine the functional circuit and network changes achieved by electrical NAc stimulation. Optogenetic-fMRI experiments were also undertaken to evaluate the circuit modulation profile achieved by selective stimulation of NAc neurons. NAc-DBS directly modulated neural activity within prefrontal cortex and a large number of subcortical limbic areas (e.g., amygdala, lateral hypothalamus), and influenced functional connectivity among sensorimotor, executive, and limbic networks. The pattern and extent of circuit modulation measured by evoked-fMRI was relatively insensitive to DBS frequency. Optogenetic stimulation of NAc cell bodies induced a positive fMRI signal in the NAc, but no other detectable downstream responses, indicating that therapeutic NAc-DBS might exert its effect through antidromic stimulation. Our study provides a comprehensive mapping of circuit and network-level neuromodulation by NAc-DBS, which should facilitate our developing understanding of its therapeutic mechanisms of action. PMID:27601003

  18. Rewarding and aversive effects of nicotine are segregated within the nucleus accumbens.

    Science.gov (United States)

    Sellings, Laurie H L; Baharnouri, Golriz; McQuade, Lindsey E; Clarke, Paul B S

    2008-07-01

    Forebrain dopamine plays a critical role in motivated behavior. According to the classic view, mesolimbic dopamine selectively guides behavior motivated by positive reinforcers. However, this has been challenged in favor of a wider role encompassing aversively motivated behavior. This controversy is particularly striking in the case of nicotine, with opposing claims that either the rewarding or the aversive effect of nicotine is critically dependent on mesolimbic dopamine transmission. In the present study, the effects of 6-hydroxydopamine lesions of nucleus accumbens core vs. medial shell on intravenous nicotine conditioned place preference and conditioned taste aversion were examined in male adult rats. Dopaminergic denervation in accumbens medial shell was associated with decreased nicotine conditioned place preference. Conversely, denervation in accumbens core was associated with an increase in conditioned place preference. In addition, dopaminergic denervation of accumbens core but not medial shell abolished conditioned taste aversion for nicotine. We conclude that nucleus accumbens core and medial shell dopaminergic innervation exert segregated effects on rewarding and aversive effects of nicotine. More generally, our findings indicate that dopaminergic transmission may mediate or enable opposing motivational processes within functionally distinct domains of the accumbens.

  19. Oscillatory activity in the medial prefrontal cortex and nucleus accumbens correlates with impulsivity and reward outcome.

    Directory of Open Access Journals (Sweden)

    Nicholas A Donnelly

    Full Text Available Actions expressed prematurely without regard for their consequences are considered impulsive. Such behaviour is governed by a network of brain regions including the prefrontal cortex (PFC and nucleus accumbens (NAcb and is prevalent in disorders including attention deficit hyperactivity disorder (ADHD and drug addiction. However, little is known of the relationship between neural activity in these regions and specific forms of impulsive behaviour. In the present study we investigated local field potential (LFP oscillations in distinct sub-regions of the PFC and NAcb on a 5-choice serial reaction time task (5-CSRTT, which measures sustained, spatially-divided visual attention and action restraint. The main findings show that power in gamma frequency (50-60 Hz LFP oscillations transiently increases in the PFC and NAcb during both the anticipation of a cue signalling the spatial location of a nose-poke response and again following correct responses. Gamma oscillations were coupled to low-frequency delta oscillations in both regions; this coupling strengthened specifically when an error response was made. Theta (7-9 Hz LFP power in the PFC and NAcb increased during the waiting period and was also related to response outcome. Additionally, both gamma and theta power were significantly affected by upcoming premature responses as rats waited for the visual cue to respond. In a subgroup of rats showing persistently high levels of impulsivity we found that impulsivity was associated with increased error signals following a nose-poke response, as well as reduced signals of previous trial outcome during the waiting period. Collectively, these in-vivo neurophysiological findings further implicate the PFC and NAcb in anticipatory impulsive responses and provide evidence that abnormalities in the encoding of rewarding outcomes may underlie trait-like impulsive behaviour.

  20. Nucleus accumbens-specific interventions in RGS9-2 activity modulate responses to morphine.

    Science.gov (United States)

    Gaspari, Sevasti; Papachatzaki, Maria M; Koo, Ja Wook; Carr, Fiona B; Tsimpanouli, Maria-Efstratia; Stergiou, Eugenia; Bagot, Rosemary C; Ferguson, Deveroux; Mouzon, Ezekiell; Chakravarty, Sumana; Deisseroth, Karl; Lobo, Mary Kay; Zachariou, Venetia

    2014-07-01

    Regulator of G protein signalling 9-2 (Rgs9-2) modulates the actions of a wide range of CNS-acting drugs by controlling signal transduction of several GPCRs in the striatum. RGS9-2 acts via a complex mechanism that involves interactions with Gα subunits, the Gβ5 protein, and the adaptor protein R7BP. Our recent work identified Rgs9-2 complexes in the striatum associated with acute or chronic exposures to mu opioid receptor (MOR) agonists. In this study we use several new genetic tools that allow manipulations of Rgs9-2 activity in particular brain regions of adult mice in order to better understand the mechanism via which this protein modulates opiate addiction and analgesia. We used adeno-associated viruses (AAVs) to express forms of Rgs9-2 in the dorsal and ventral striatum (nucleus accumbens, NAc) in order to examine the influence of this protein in morphine actions. Consistent with earlier behavioural findings from constitutive Rgs9 knockout mice, we show that Rgs9-2 actions in the NAc modulate morphine reward and dependence. Notably, Rgs9-2 in the NAc affects the analgesic actions of morphine as well as the development of analgesic tolerance. Using optogenetics we demonstrate that activation of Channelrhodopsin2 in Rgs9-2-expressing neurons, or in D1 dopamine receptor (Drd1)-enriched medium spiny neurons, accelerates the development of morphine tolerance, whereas activation of D2 dopamine receptor (Drd2)-enriched neurons does not significantly affect the development of tolerance. Together, these data provide new information on the signal transduction mechanisms underlying opiate actions in the NAc.

  1. Long-term memory for pavlovian fear conditioning requires dopamine in the nucleus accumbens and basolateral amygdala.

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    Jonathan P Fadok

    Full Text Available The neurotransmitter dopamine (DA is essential for learning in a pavlovian fear conditioning paradigm known as fear-potentiated startle (FPS. Mice lacking the ability to synthesize DA fail to learn the association between the conditioned stimulus and the fear-inducing footshock. Previously, we demonstrated that restoration of DA synthesis to neurons of the ventral tegmental area (VTA was sufficient to restore FPS. Here, we used a target-selective viral restoration approach to determine which mesocorticolimbic brain regions receiving DA signaling from the VTA require DA for FPS. We demonstrate that restoration of DA synthesis to both the basolateral amygdala (BLA and nucleus accumbens (NAc is required for long-term memory of FPS. These data provide crucial insight into the dopamine-dependent circuitry involved in the formation of fear-related memory.

  2. Optogenetic versus electrical stimulation of dopamine terminals in the nucleus accumbens reveals local modulation of presynaptic release.

    Science.gov (United States)

    Melchior, James R; Ferris, Mark J; Stuber, Garret D; Riddle, David R; Jones, Sara R

    2015-09-01

    The nucleus accumbens is highly heterogeneous, integrating regionally distinct afferent projections and accumbal interneurons, resulting in diverse local microenvironments. Dopamine (DA) neuron terminals similarly express a heterogeneous collection of terminal receptors that modulate DA signaling. Cyclic voltammetry is often used to probe DA terminal dynamics in brain slice preparations; however, this method traditionally requires electrical stimulation to induce DA release. Electrical stimulation excites all of the neuronal processes in the stimulation field, potentially introducing simultaneous, multi-synaptic modulation of DA terminal release. We used optogenetics to selectively stimulate DA terminals and used voltammetry to compare DA responses from electrical and optical stimulation of the same area of tissue around a recording electrode. We found that with multiple pulse stimulation trains, optically stimulated DA release increasingly exceeded that of electrical stimulation. Furthermore, electrical stimulation produced inhibition of DA release across longer duration stimulations. The GABAB antagonist, CGP 55845, increased electrically stimulated DA release significantly more than light stimulated release. The nicotinic acetylcholine receptor antagonist, dihydro-β-erythroidine hydrobromide, inhibited single pulse electrically stimulated DA release while having no effect on optically stimulated DA release. Our results demonstrate that electrical stimulation introduces local multi-synaptic modulation of DA release that is absent with optogenetically targeted stimulation. The nucleus accumbens is highly heterogeneous, integrating regionally distinct afferent projections and accumbal interneurons, resulting in diverse microenvironments. Local electrical stimulation excites all of the neuronal processes in the stimulation field, potentially modulating the dopamine signal - measured using cyclic voltammetry. Optogenetically targeting light stimulation to dopamine

  3. Pavlovian-to-instrumental transfer effects in the nucleus accumbens relate to relapse in alcohol dependence.

    Science.gov (United States)

    Garbusow, Maria; Schad, Daniel J; Sebold, Miriam; Friedel, Eva; Bernhardt, Nadine; Koch, Stefan P; Steinacher, Bruno; Kathmann, Norbert; Geurts, Dirk E M; Sommer, Christian; Müller, Dirk K; Nebe, Stephan; Paul, Sören; Wittchen, Hans-Ulrich; Zimmermann, Ulrich S; Walter, Henrik; Smolka, Michael N; Sterzer, Philipp; Rapp, Michael A; Huys, Quentin J M; Schlagenhauf, Florian; Heinz, Andreas

    2016-05-01

    In detoxified alcohol-dependent patients, alcohol-related stimuli can promote relapse. However, to date, the mechanisms by which contextual stimuli promote relapse have not been elucidated in detail. One hypothesis is that such contextual stimuli directly stimulate the motivation to drink via associated brain regions like the ventral striatum and thus promote alcohol seeking, intake and relapse. Pavlovian-to-Instrumental-Transfer (PIT) may be one of those behavioral phenomena contributing to relapse, capturing how Pavlovian conditioned (contextual) cues determine instrumental behavior (e.g. alcohol seeking and intake). We used a PIT paradigm during functional magnetic resonance imaging to examine the effects of classically conditioned Pavlovian stimuli on instrumental choices in n = 31 detoxified patients diagnosed with alcohol dependence and n = 24 healthy controls matched for age and gender. Patients were followed up over a period of 3 months. We observed that (1) there was a significant behavioral PIT effect for all participants, which was significantly more pronounced in alcohol-dependent patients; (2) PIT was significantly associated with blood oxygen level-dependent (BOLD) signals in the nucleus accumbens (NAcc) in subsequent relapsers only; and (3) PIT-related NAcc activation was associated with, and predictive of, critical outcomes (amount of alcohol intake and relapse during a 3 months follow-up period) in alcohol-dependent patients. These observations show for the first time that PIT-related BOLD signals, as a measure of the influence of Pavlovian cues on instrumental behavior, predict alcohol intake and relapse in alcohol dependence. © 2015 Society for the Study of Addiction.

  4. The nucleus accumbens beyond the anterior commissure: implications for psychosurgery.

    Science.gov (United States)

    Lucas-Neto, Lia; Mourato, Beatriz; Neto, Daniel; Oliveira, Edson; Martins, Hugo; Correia, Francisco; Gonçalves-Ferreira, António

    2014-01-01

    The nucleus accumbens (Acc) is a basal forebrain structure integrated in the dopaminergic cerebral rewarding circuits and implicated in some neuropsychiatric disorders. It has become a target for deep brain stimulation for some of these disorders when refractory to medical treatment. However, it is controversial as to which target is the best and similar results have been achieved with the stimulation of neighboring structures such as the bed nucleus of the stria terminalis (BNST). Previous studies have established the stereotactic anatomy of the human Acc, but some difficulties remain concerning its precise posterior limit, which is assumed to be at the level of the anterior commissure (AC). It is our purpose to clarify the anatomy of this zone, given the importance of its exact identification in psychosurgery. A total of 16 Acc were collected by autopsy, fixed, dissected, embedded and cut in coronal 5-µm slices. The slices were stained with hematoxylin and eosin, marked with anti-D1 and anti-D2 antibodies and analyzed under a microscope. The human Acc has the same cellular structure as the dorsal striatum, except in its posterior subcommissural part where voluminous neurons prevail, similar to and contiguous with the BNST. The Acc is longer than previously described, with a sub- and postcommissural extension behind the AC, continuous with the BNST. © 2014 S. Karger AG, Basel.

  5. Oxytocin excites nucleus accumbens shell neurons in vivo.

    Science.gov (United States)

    Moaddab, Mahsa; Hyland, Brian I; Brown, Colin H

    2015-09-01

    Oxytocin modulates reward-related behaviors. The nucleus accumbens shell (NAcSh) is a major relay in the brain reward pathway and expresses oxytocin receptors, but the effects of oxytocin on the activity of NAcSh neurons in vivo are unknown. Hence, we used in vivo extracellular recording to show that intracerebroventricular (ICV) oxytocin administration (0.2μg) robustly increased medial NAcSh neuron mean firing rate; this increase was almost exclusively evident in slow-firing neurons and was not associated with any change in firing pattern. To determine whether oxytocin excitation of medial NAcSh neurons is modulated by drugs that impact the brain reward pathway, we next tested the effects of ICV oxytocin following repeated morphine treatment. In morphine-treated rats, ICV oxytocin did not affect the mean firing rate of medial NAcSh neurons. Taken together, these results show that oxytocin excites medial NAcSh neurons but does not do so after repeated morphine. This could be an important factor in oxytocin modulation of reward-related behaviors, such as drug addiction.

  6. Functional and structural deficits at accumbens synapses in a mouse model of Fragile X

    Directory of Open Access Journals (Sweden)

    Daniela eNeuhofer

    2015-03-01

    Full Text Available Fragile X is the most common cause of inherited intellectual disability and a leading cause of autism. The disease is caused by mutation of a single X-linked gene called fmr1 that codes for the Fragile X mental retardation protein (FMRP, a 71 kDa protein, which acts mainly as a translation inhibitor. Fragile X patients suffer from cognitive and emotional deficits that coincide with abnormalities in dendritic spines. Changes in spine morphology are often associated with altered excitatory transmission and long-term plasticity, the most prominent deficit in fmr1-/y mice. The nucleus accumbens, a central part of the mesocortico-limbic reward pathway, is now considered as a core structure in the control of social behaviors. Although the socio-affective impairments observed in Fragile X suggest dysfunctions in the accumbens, the impact of the lack of FMRP on accumbal synapses has scarcely been studied. Here we report for the first time a new spike timing-dependent plasticity paradigm that reliably triggers NMDAR-dependent long-term potentiation (LTP of excitatory afferent inputs of medium spiny neurons (MSN in the nucleus accumbens core region. Notably, we discovered that this LTP was completely absent in fmr1-/y mice. In the fmr1-/y accumbens intrinsic membrane properties of MSNs and basal excitatory neurotransmission remained intact in the fmr1-/y accumbens but the deficit in LTP was accompanied by an increase in evoked AMPA/NMDA ratio and a concomitant reduction of spontaneous NMDAR-mediated currents. In agreement with these physiological findings, we found significantly more filopodial spines in fmr1-/y mice by using an ultrastructural electron microscopic analysis of accumbens core medium spiny neuron spines. Surprisingly, spine elongation was specifically due to the longer longitudinal axis and larger area of spine necks, whereas spine head morphology and postsynaptic density size on spine heads remained unaffected in the fmr1-/y accumbens

  7. Sexual activity increases dopamine transmission in the nucleus accumbens and striatum of female rats.

    Science.gov (United States)

    Pfaus, J G; Damsma, G; Wenkstern, D; Fibiger, H C

    1995-09-25

    In vivo microdialysis was used to monitor extracellular concentrations of dopamine (DA), and its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the nucleus accumbens and dorsal striatum of sexually active female rats during tests of locomotor activity, exposure to a novel chamber, exposure to sex odors, the presentation of a sexually active male rat, and copulation. DA increased slightly but significantly in the nucleus accumbens when a sexually active male was placed behind a wire-mesh screen, and further during copulation. DA also increased significantly in the dorsal striatum during copulation; however, the magnitude of this effect was significantly lower than that observed in the nucleus accumbens. The metabolites DOPAC and HVA generally followed DA with a delay, and increased significantly during copulation in both regions. In contrast, forced locomotion on a rotating drum, exposure to a novel testing chamber, and exposure to sex odors did not increase DA significantly in either region, although forced locomotion increased DOPAC significantly in both regions, and HVA significantly in the nucleus accumbens. The magnitude of DA release in the nucleus accumbens was significantly greater during copulation than running, whereas no significant difference was detected for striatal DA release between these two behavioral conditions. These results indicate that novelty or locomotor activity alone do not account for the increase in DA observed in the nucleus accumbens of female rats during copulation, and suggest that DA transmission in the nucleus accumbens is associated with anticipatory and consummatory aspects of sexual activity, as it is in male rats. In the dorsal striatum, however, DA release during copulation may reflect an increase in locomotor activity associated with active pacing of the male.

  8. Stability of CART peptide expression in the nucleus accumbens in aging.

    Science.gov (United States)

    Armbruszt, Simon; Figler, Mária; Ábrahám, Hajnalka

    2015-03-01

    Aging is accompanied by changes of several anorexigenic and orexigenic neuropeptides expressed in various brain areas that control food intake and these changes correlate with senescent anorexia. During aging expression of cocaine- and amphetamine-regulated transcript (CART) peptide was reported to be reduced in the hypothalamic nuclei related to food intake. Although CART peptide is abundant in the nucleus accumbens that also plays a crucial role in the food intake regulation, no data is available about the CART peptide expression in this region through aging. In the present study, CART peptide immunoreactivity was compared in the nucleus accumbens of young adult (4- and 7-month-old) middle-aged (15-month-old) and aging (25-32-month-old) Long-Evans rats. The density of CART-immunoreactive cells and axon terminals in the nucleus accumbens was measured with computer-aided densitometry. CART-immunodensity was similar in the old rats and in the younger animals without significant difference between age groups. In addition, no gender-difference was observed when CART-immunoreactivities in the nucleus accumbens of male and female animals were compared. Our results indicate that CART peptide expression in the nucleus accumbens is stable in adults and does not change with age.

  9. Medial accumbens lesions attenuate testosterone-dependent aggression in male rats.

    Science.gov (United States)

    Albert, D J; Petrovic, D M; Walsh, M L; Jonik, R H

    1989-10-01

    Male hooded rats were castrated and implanted with testosterone-filled Silastic tubes appropriate for maintaining a normal average serum testosterone concentration. They were then given lesions of the medial accumbens nucleus or sham lesions. Twenty-four hours postoperatively each male was housed with a female. Beginning 7 days following pairing and continuing once each week for 4 weeks, each lesioned or sham-lesioned male was observed for aggression toward an unfamiliar male intruder. On the day following each test of aggression toward an unfamiliar male, each lesioned and sham-lesioned male was assessed for defensiveness toward an experimenter. Rats with medial accumbens lesions displayed significantly less aggression toward an unfamiliar male intruder during each of the weekly tests than did sham-lesioned animals. The attenuation was most pronounced in animals with lesions damaging the posterior part of the medial accumbens nucleus (also designated as anterior portion of the bed nucleus of the stria terminalis) in the region of the crossover of the anterior commissure. Although medial accumbens lesions are known to make individually housed rats hyperdefensive toward an experimenter, lesion-induced hyperdefensiveness was not observed in the pair-housed animals in the present experiment. It is argued that the medial accumbens/bed nucleus of the stria terminalis area is an important region in the anterior forebrain for the modulation of hormone-dependent aggression.

  10. EFFECTS OF REVERSIBLE INACTIVATION OF BILATERAL ACCUMBENS NUCLEI ON MEMORY STORAGE: ANIMAL STUDY IN RAT MODEL

    Directory of Open Access Journals (Sweden)

    H.A ALAEI

    2002-12-01

    Full Text Available Introduction. Memory and learning play an important role in human"s life that will become problematic in case disability is weak for any reason. There are many factors that facilitate process of mamory and learning of which accumbens nucleus plays an important role. Accumbens nucleus, which is a part of the limbic system, is one of many nuclei found of the septum in the mesencephalon. This study was performed to determine the effects of reversible Inactivation of a accumbens nuclei by lidocaein on memory storage in rat. Method s. Male wistar rats were surgically implancted with cannulae at the accumbens nuclei (Acb bilaterally one weak later they recived one trial PAL (1 mA 1.S sec and exactly at times zero, 60 and 120 minutes after posttraining, lidocaine was infused into the Acb. Retention was tested two days after training. Latency period before entering into the dark part of the shuttle box and duration of time in darkness were index for evaluation of retention. Results. A significant impaired retention performance was at zero and 60 minutes after posttrianing infusion of lidocaine into the Acb. Infusion administered 120 minutes after training had no effect. Discussion. This study has shown that Accumbens nucleus plays major role in praimary learning and memory and it is probable that by blocking this nucleus dopamine release is diminished which causes the learning process to be delayed consequently.

  11. Neuropeptide Y infusion into the shell region of the rat nucleus accumbens increases extracellular levels of dopamine

    DEFF Research Database (Denmark)

    Sørensen, Gunnar; Wegener, Gregers; Hasselstrøm, Jørgen;

    2009-01-01

    Increases in extracellular dopamine in the shell region of the nucleus accumbens are centrally involved in mediating reinforcement of addictive drugs. Neuropeptide Y (NPY) and its receptors are present in the nucleus accumbens and have been implicated in addiction mechanisms. This study further...

  12. Deltorphin II enhances extracellular levels of dopamine in the nucleus accumbens via opioid receptor-independent mechanisms.

    NARCIS (Netherlands)

    Murakawa, K.; Hirose, N.; Takada, K.; Suzuki, T.; Nagase, H.; Cools, A.R.; Koshikawa, N.

    2004-01-01

    The effects of the delta2-opioid receptor agonist, deltorphin II, on extracellular levels of dopamine in the rat nucleus accumbens were investigated in awake animals by in vivo brain microdialysis. In agreement with previous studies, perfusion of deltorphin II (50.0 nmol) into the nucleus accumbens

  13. Directed Communication between Nucleus Accumbens and Neocortex in Humans Is Differentially Supported by Synchronization in the Theta and Alpha Band

    NARCIS (Netherlands)

    Horschig, Jörn M; Smolders, Ruud; Bonnefond, Mathilde; Schoffelen, Jan-Mathijs; van den Munckhof, Pepijn; Schuurman, P Richard; Cools, Roshan; Denys, D.; Jensen, Ole

    2015-01-01

    Here, we report evidence for oscillatory bi-directional interactions between the nucleus accumbens and the neocortex in humans. Six patients performed a demanding covert visual attention task while we simultaneously recorded brain activity from deep-brain electrodes implanted in the nucleus accumben

  14. Behavioral Flexibility Is Increased by Optogenetic Inhibition of Neurons in the Nucleus Accumbens Shell during Specific Time Segments

    Science.gov (United States)

    Aquili, Luca; Liu, Andrew W.; Shindou, Mayumi; Shindou, Tomomi; Wickens, Jeffery R.

    2014-01-01

    Behavioral flexibility is vital for survival in an environment of changing contingencies. The nucleus accumbens may play an important role in behavioral flexibility, representing learned stimulus-reward associations in neural activity during response selection and learning from results. To investigate the role of nucleus accumbens neural activity…

  15. Endocannabinoids in amygdala and nucleus accumbens mediate social play reward in adolescent rats.

    Science.gov (United States)

    Trezza, Viviana; Damsteegt, Ruth; Manduca, Antonia; Petrosino, Stefania; Van Kerkhof, Linda W M; Pasterkamp, R Jeroen; Zhou, Yeping; Campolongo, Patrizia; Cuomo, Vincenzo; Di Marzo, Vincenzo; Vanderschuren, Louk J M J

    2012-10-24

    The brain endocannabinoid system plays a crucial role in emotional processes. We have previously identified an important role for endocannabinoids in social play behavior, a highly rewarding form of social interaction in adolescent rats. Here, we tested the hypothesis that endocannabinoid modulation of social play behavior occurs in brain regions implicated in emotion and motivation. Social play increased levels of the endocannabinoid anandamide in the amygdala and nucleus accumbens (NAc), but not in prefrontal cortex or hippocampus of 4- to 5-week-old male Wistar rats. Furthermore, social play increased phosphorylation of CB1 cannabinoid receptors in the amygdala. Systemic administration of the anandamide hydrolysis inhibitor URB597 increased social play behavior, and augmented the associated elevation in anandamide levels in the amygdala, but not the NAc. Infusion of URB597 into the basolateral amygdala (BLA) increased social play behavior, and blockade of BLA CB1 cannabinoid receptors with the antagonist/inverse agonist SR141716A prevented the play-enhancing effects of systemic administration of URB597. Infusion of URB597 into the NAc also increased social play, but blockade of NAc CB1 cannabinoid receptors did not antagonize the play-enhancing effects of systemic URB597 treatment. Last, SR141716A did not affect social play after infusion into the core and shell subregions of the NAc, while it reduced social play when infused into the BLA. These data show that increased anandamide signaling in the amygdala and NAc augments social play, and identify the BLA as a prominent site of action for endocannabinoids to modulate the rewarding properties of social interactions in adolescent rats.

  16. Effects of inhibitor of κB kinase activity in the nucleus accumbens on emotional behavior.

    Science.gov (United States)

    Christoffel, Daniel J; Golden, Sam A; Heshmati, Mitra; Graham, Ami; Birnbaum, Shari; Neve, Rachael L; Hodes, Georgia E; Russo, Scott J

    2012-11-01

    Inhibitor of κB kinase (IκK) has historically been studied in the context of immune response and inflammation, but recent evidence demonstrates that IκK activity is necessary and sufficient for regulation of neuronal function. Chronic social defeat stress of mice increases IκK activity in the nucleus accumbens (NAc) and this increase is strongly correlated to depression-like behaviors. Inhibition of IκK signaling results in a reversal of chronic social defeat stress-induced social avoidance behavior. Here, we more completely define the role of IκK in anxiety and depressive-like behaviors. Mice underwent stereotaxic microinjection of a herpes simplex virus expressing either green fluorescent protein, a constitutively active form of IκK (IκKca), or a dominant negative form of IκK into the NAc. Of all three experimental groups, only mice expressing IκKca show a behavioral phenotype. Expression of IκKca results in a decrease in the time spent in the non-periphery zones of an open field arena and increased time spent immobile during a forced swim test. No baseline differences in sucrose preference were observed, but following the acute swim stress we noted a marked reduction in sucrose preference. To determine whether IκK activity alters responses to other acute stressors, we examined behavior and spine morphology in mice undergoing an acute social defeat stress. We found that IκKca enhanced social avoidance behavior and promoted thin spine formation. These data show that IκK in NAc is a critical regulator of both depressive- and anxiety-like states and may do so by promoting the formation of immature excitatory synapses.

  17. The effects of nicotine injection in rat nucleus accumbens on anxiety

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    Ghorbani Yekta B

    2013-05-01

    Full Text Available Background: Previous reports showed that nucleus accumbens involved in the etiology and pathophysiology of major depression, anxiety and addiction. It is not clear that how these mechanisms occur in the brain. In the present study, the influence of direct nicotine injection in the nucleus accumbens in rats’ anxiety-related behavior was investigated. Methods: Wistar rats were used in this study. Male Wistar rats bred in an animal house, in a temperature-controlled (22±2 ◦C room with a 12 hour light/darkcycle. Rats were anesthetized using intraperitoneal injection of ketamine hydrochloride and xylazine, then placed in an stereotactic instrument for microinjection cannula implantation The stainless steel guide cannula was implanted bilaterally in the right and left dorsal the nucleus accumbens shell according to Paxinos and Watson atlas. After recovery, anxiety behavior and locomotor activity were tested. We used the elevated plus maze to test anxiety. This apparatus has widely been employed to test parameters of anxiety-related behaviors including the open armtime percentage (%OAT, open arm entries percentage (%OAE, locomotor activity and we record effect of drugs after injection directly in the nucleus accumbens on anxiety-related behavior.Results: Experiments showed that bilateral injections into the nucleus accumbens Nicotine, acetylcholine receptor agonist, dose 0.1 of the dose (0.05 and 0.1, 0.25, 0.5 microgram per rat caused a significant increase in the percentage of time spent in the open arms (%OAT, compared to the control group. We did not record any significant change locomotor activity and open arm entries percentage (%OAE in rats.Conclusion: Nicotinic receptors in the nucleus accumbens shell involved to anxiety-like behavior in male rats.

  18. Axonal Type III Nrg1 Controls Glutamate Synapse Formation and GluA2 Trafficking in Hippocampal-Accumbens Connections

    Science.gov (United States)

    Akmentin, Wendy

    2017-01-01

    Abstract Altered neuregulin 1 (Nrg1)/ErbB signaling and glutamatergic hypofunction have been implicated in the pathophysiology of schizophrenia. Here, we employed gene chimeric ventral hippocampus (vHipp)-nucleus accumbens (nAcc) coculture from mouse, electrophysiology, immunocytochemistry, FM1-43 vesicle fusion, and electron microscopy techniques to examine the pre- and postsynaptic mechanisms of genetic deficits in Nrg1/ErbB signaling-induced glutamatergic dysfunctions. Reduced presynaptic type III Nrg1 expression along vHipp axons decreases the number of glutamate synapses and impairs GluA2 trafficking in the postsynaptic nAcc neurons, resulting in decreased frequency and amplitude of miniature EPSCs (mEPSCs). Reduced expression of axonal type III Nrg1 along vHipp projections also decreases functional synaptic vesicle (SV) clustering and vesicular trafficking to presynaptic vHipp axonal terminals. These findings suggest that Nrg1/ErbB signaling modulate glutamatergic transmission via both pre- and postsynaptic mechanisms. PMID:28275713

  19. Differential transcriptome expression in human nucleus accumbens as a function of loneliness.

    Science.gov (United States)

    Canli, T; Wen, R; Wang, X; Mikhailik, A; Yu, L; Fleischman, D; Wilson, R S; Bennett, D A

    2016-11-01

    Loneliness is associated with impaired mental and physical health. Studies of lonely individuals reported differential expression of inflammatory genes in peripheral leukocytes and diminished activation in brain reward regions such as nucleus accumbens, but could not address gene expression in the human brain. Here, we examined genome-wide RNA expression in post-mortem nucleus accumbens from donors (N=26) with known loneliness measures. Loneliness was associated with 1710 differentially expressed transcripts and genes from 1599 genes (DEGs; false discovery rate PMolecular Psychiatry advance online publication, 1 November 2016; doi:10.1038/mp.2016.186.

  20. Functional interactions between the nucleus tractus solitarius (NTS) and nucleus accumbens shell in modulating memory for arousing experiences.

    Science.gov (United States)

    Kerfoot, Erin C; Chattillion, Elizabeth A; Williams, Cedric L

    2008-01-01

    The shell division of the nucleus accumbens receives noradrenergic input from neurons in the nucleus of the solitary tract (NTS) that transmit information regarding fluctuations in peripheral hormonal and autonomic activity. Accumbens shell neurons also receive converging inputs from limbic areas such as the hippocampus and amygdala that process newly acquired information. However, few studies have explored whether peripheral information regarding changes in emotional arousal contributes to memory processing in the accumbens. The beneficial effects on memory produced by emotional arousal and the corresponding activation of NTS neurons may be mediated through influences on neuronal activity in the accumbens shell during memory encoding. To explore this putative relationship, Experiment 1 examined interactions between the NTS and the accumbens shell in modulating memory for responses acquired after footshock training in a water-motivated inhibitory avoidance task. Memory for the noxious shock was significantly improved by posttraining excitation of noradrenergic NTS neurons. The enhanced retention produced by activating NTS neurons was attenuated by suppressing neuronal activity in the accumbens shell with bupivacaine (0.25%/0.5 microl). Experiment 2 examined the direct involvement of accumbens shell noradrenergic activation in the modulation of memory for psychologically arousing events such as a reduction in perceived reward value. Noradrenergic activation of the accumbens shell with phenylephrine (1.0 microg/0.5 microl) produced an enhancement in memory for the frustrating experience relative to control injections as evidenced by runway performance on an extended seven-day retention test. These findings demonstrate a functional relationship between NTS neurons and the accumbens shell in modulating memory following physiological arousal and identifies a role of norepinephrine in modulating synaptic activity in the accumbens shell to facilitate this process.

  1. Nucleus accumbens μ-opioid receptors mediate social reward.

    Science.gov (United States)

    Trezza, Viviana; Damsteegt, Ruth; Achterberg, E J Marijke; Vanderschuren, Louk J M J

    2011-04-27

    Positive social interactions are essential for emotional well-being and proper behavioral development of young individuals. Here, we studied the neural underpinnings of social reward by investigating the involvement of opioid neurotransmission in the nucleus accumbens (NAc) in social play behavior, a highly rewarding social interaction in adolescent rats. Intra-NAc infusion of morphine (0.05-0.1 μg) increased pinning and pouncing, characteristic elements of social play behavior in rats, and blockade of NAc opioid receptors with naloxone (0.5 μg) prevented the play-enhancing effects of systemic morphine (1 mg/kg, s.c.) administration. Thus, stimulation of opioid receptors in the NAc was necessary and sufficient for morphine to increase social play. Intra-NAc treatment with the selective μ-opioid receptor agonist [D-Ala(2),N-MePhe(4),Gly(5)-ol]enkephalin (DAMGO) (0.1-10 ng) and the μ-opioid receptor antagonist Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH(2) (CTAP) (0.3-3 μg) increased and decreased social play, respectively. The δ-opioid receptor agonist DPDPE ([D-Pen(2),D-Pen(5)]-enkephalin) (0.3-3 μg) had no effects, whereas the κ-opioid receptor agonist U69593 (N-methyl-2-phenyl-N-[(5R,7S,8S)-7-(pyrrolidin-1-yl)-1-oxaspiro[4.5]dec-8-yl]acetamide) (0.01-1 μg) decreased social play. Intra-NAc treatment with β-endorphin (0.01-1 μg) increased social play, but met-enkephalin (0.1-5 μg) and the enkephalinase inhibitor thiorphan (0.1-1 μg) were ineffective. DAMGO (0.1-10 ng) increased social play after infusion into both the shell and core subregions of the NAc. Last, intra-NAc infusion of CTAP (3 μg) prevented the development of social play-induced conditioned place preference. These findings identify NAc μ-opioid receptor stimulation as an important neural mechanism for the attribution of positive value to social interactions in adolescent rats. Altered NAc μ-opioid receptor function may underlie social impairments in psychiatric disorders such as autism

  2. Serotonin 1A, 1B, and 7 receptors of the rat medial nucleus accumbens differentially regulate feeding, water intake, and locomotor activity.

    Science.gov (United States)

    Clissold, Kara A; Choi, Eugene; Pratt, Wayne E

    2013-11-01

    Serotonin (5-HT) signaling has been widely implicated in the regulation of feeding behaviors in both humans and animal models. Recently, we reported that co-stimulation of 5-HT1&7 receptors of the anterior medial nucleus accumbens with the drug 5-CT caused a dose-dependent decrease in food intake, water intake, and locomotion in rats (Pratt et al., 2009). The current experiments sought to determine which of three serotonin receptor subtypes (5-HT1A, 5-HT1B, or 5-HT7) might be responsible for these consummatory and locomotor effects. Food-deprived rats were given 2-h access to rat chow after stimulation of nucleus accumbens 5-HT1A, 5-HT1B, or 5-HT7 receptors, or blockade of the 5-HT1A or 5-HT1B receptors. Stimulation of 5-HT1A receptors with 8-OH-DPAT (at 0.0, 2.0, 4.0, and 8.0 μg/0.5 μl/side) caused a dose-dependent decrease in food and water intake, and reduced rearing behavior but not ambulation. In contrast, rats that received the 5-HT1B agonist CP 93129 (at 0.0, 1.0, 2.0 and 4.0 μg/0.5 μl/side) showed a significant dose-dependent decrease in water intake only; stimulation of 5-HT7 receptors (AS 19; at 0.0, 1.0, and 5.0 μg/0.5 μl/side) decreased ambulatory activity but did not affect food or water consumption. Blockade of 5-HT1A or 5-HT1B receptors had no lasting effects on measures of food consumption. These data suggest that the food intake, water intake, and locomotor effects seen after medial nucleus accumbens injections of 5-CT are due to actions on separate serotonin receptor subtypes, and contribute to growing evidence for selective roles of individual serotonin receptors within the nucleus accumbens on motivated behavior. © 2013.

  3. Role of nucleus accumbens glutamatergic plasticity in drug addiction

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    Quintero GC

    2013-09-01

    Full Text Available Gabriel C Quintero1–31Florida State University – Panama, Clayton, Panama; 2Medical University of South Carolina, Charleston, South Carolina, USA; 3Smithsonian Tropical Research Institute, Ancon, Republic of PanamaAbstract: Substance dependence is characterized by a group of symptoms, according to the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR. These symptoms include tolerance, withdrawal, drug consumption for alleviating withdrawal, exaggerated consumption beyond original intention, failure to reduce drug consumption, expending a considerable amount of time obtaining or recovering from the substance’s effects, disregard of basic aspects of life (for example, family, and maintenance of drug consumption, despite facing adverse consequences. The nucleus accumbens (NAc is a brain structure located in the basal forebrain of vertebrates, and it has been the target of addictive drugs. Different neurotransmitter systems at the level of the NAc circuitry have been linked to the different problems of drug addiction, like compulsive use and relapse. The glutamate system has been linked mainly to relapse after drug-seeking extinction. The dopamine system has been linked mainly to compulsive drug use. The glutamate homeostasis hypothesis centers around the dynamics of synaptic and extrasynaptic levels of glutamate, and their impact on circuitry from the prefrontal cortex (PFC to the NAc. After repetitive drug use, deregulation of this homeostasis increases the release of glutamate from the PFC to the NAc during drug relapse. Glial cells also play a fundamental role in this hypothesis; glial cells shape the interactions between the PFC and the NAc by means of altering glutamate levels in synaptic and extrasynaptic spaces. On the other hand, cocaine self-administration and withdrawal increases the surface expression of subunit glutamate receptor 1 (GluA1 of alpha-amino-3-hydroxy-5-methyl-4

  4. Neuropeptide Y activity in the nucleus accumbens modulates feeding behavior and neuronal activity

    NARCIS (Netherlands)

    van den Heuvel, José K; Furman, Kara; Gumbs, Myrtille C R; Eggels, Leslie; Opland, Darren M; Land, Benjamin B; Kolk, Sharon M; S Narayanan, Nandakumar; Fliers, Eric; Kalsbeek, A.; DiLeone, Ralph J; la Fleur, Susanne E

    2015-01-01

    BACKGROUND: Neuropeptide Y (NPY) is a hypothalamic neuropeptide that plays a prominent role in feeding and energy homeostasis. Expression of the NPY Y1 receptor (Y1R) is highly concentrated in the nucleus accumbens (Acb), a region important in the regulation of palatable feeding. In this study, we p

  5. Direct effect of nicotine on mesolimbic dopamine release in rat nucleus accumbens shell

    NARCIS (Netherlands)

    Kleijn, J.; Folgering, J. H. A.; van der Hart, M. C. G.; Rollema, H.; Cremers, T. I. F. H.; Westerink, B. H. C.

    2011-01-01

    Nicotine stimulates dopamine (DA) cell firing via a local action at somatodendritic sites in the ventral tegmental area (VTA), increasing DA release in the nucleus accumbens (NAcc). Additionally, nicotine may also modulate DA release via a direct effect in the NAcc. This study examined the

  6. Accumbens Shell AMPA Receptors Mediate Expression of Extinguished Reward Seeking through Interactions with Basolateral Amygdala

    Science.gov (United States)

    Millan, E. Zayra; McNally, Gavan P.

    2011-01-01

    Extinction is the reduction in drug seeking when the contingency between drug seeking behavior and the delivery of drug reward is broken. Here, we investigated a role for the nucleus accumbens shell (AcbSh). Rats were trained to respond for 4% (v/v) alcoholic beer in one context (Context A) followed by extinction in a second context (Context B).…

  7. CREB activity in the nucleus accumbens shell controls gating of behavioral responses to emotional stimuli

    NARCIS (Netherlands)

    Barrot, Michel; Olivier, Jocelien D A; Perrotti, Linda I; DiLeone, Ralph J; Berton, Olivier; Eisch, Amelia J; Impey, Soren; Storm, Daniel R; Neve, Rachael L; Yin, Jerry C; Zachariou, Venetia; Nestler, Eric J

    2002-01-01

    The transcription factor cAMP response element (CRE)-binding protein (CREB) has been shown to regulate neural plasticity. Drugs of abuse activate CREB in the nucleus accumbens, an important part of the brain's reward pathways, and local manipulations of CREB activity have been shown to affect cocain

  8. A case of musical preference for Johnny Cash following deep brain stimulation of the nucleus accumbens

    NARCIS (Netherlands)

    Mantione, Mariska; Figee, Martijn; Denys, D.

    2014-01-01

    Music is among all cultures an important part of the live of most people. Music has psychological benefits and may generate strong emotional and physiological responses. Recently, neuroscientists have discovered that music influences the reward circuit of the nucleus accumbens (NAcc), even when no e

  9. The Role of the Nucleus Accumbens in Knowing when to Respond

    Science.gov (United States)

    Singh, Teghpal; McDannald, Michael A.; Takahashi, Yuji K.; Haney, Richard Z.; Cooch, Nisha K.; Lucantonio, Federica; Schoenbaum, Geoffrey

    2011-01-01

    While knowing what to expect is important, it is equally important to know when to expect it and to respond accordingly. This is apparent even in simple Pavlovian training situations in which animals learn to respond more strongly closer to reward delivery. Here we report that the nucleus accumbens core, an area well-positioned to represent…

  10. Activity in the nucleus accumbens and amygdala underlies individual differences in prosocial and individualistic economic choices.

    Science.gov (United States)

    Haruno, Masahiko; Kimura, Minoru; Frith, Christopher D

    2014-08-01

    Much decision-making requires balancing benefits to the self with benefits to the group. There are marked individual differences in this balance such that individualists tend to favor themselves whereas prosocials tend to favor the group. Understanding the mechanisms underlying this difference has important implications for society and its institutions. Using behavioral and fMRI data collected during the performance of the ultimatum game, we show that individual differences in social preferences for resource allocation, so-called "social value orientation," is linked with activity in the nucleus accumbens and amygdala elicited by inequity, rather than activity in insula, ACC, and dorsolateral pFC. Importantly, the presence of cognitive load made prosocials behave more prosocially and individualists more individualistically, suggesting that social value orientation is driven more by intuition than reflection. In parallel, activity in the nucleus accumbens and amygdala, in response to inequity, tracked this behavioral pattern of prosocials and individualists. In addition, we conducted an impunity game experiment with different participants where they could not punish unfair behavior and found that the inequity-correlated activity seen in prosocials during the ultimatum game disappeared. This result suggests that the accumbens and amygdala activity of prosocials encodes "outcome-oriented emotion" designed to change situations (i.e., achieve equity or punish). Together, our results suggest a pivotal contribution of the nucleus accumbens and amygdala to individual differences in sociality.

  11. The Retrograde Connections and Anatomical Segregation of the Göttingen Minipig Nucleus Accumbens

    DEFF Research Database (Denmark)

    Meidahl, Anders C.; Orlowski, Dariusz; Sørensen, Jens C. H.;

    2016-01-01

    Nucleus accumbens (NAcc) has been implicated in several psychiatric disorders such as treatment resistant depression (TRD) and obsessive-compulsive disorder (OCD), and has been an ongoing experimental target for deep brain stimulation (DBS) in both rats and humans. In order to translate basic sci...

  12. Lateral hypothalamus, nucleus accumbens, and ventral pallidum roles in eating and hunger: interactions between homeostatic and reward circuitry

    Directory of Open Access Journals (Sweden)

    Daniel Charles Castro

    2015-06-01

    Full Text Available The study of the neural bases of eating behavior, hunger, and reward has consistently implicated the lateral hypothalamus (LH and its interactions with mesocorticolimbic circuitry, such as mesolimbic dopamine projections to nucleus accumbens (NAc and ventral pallidum (VP, in controlling motivation to eat. The NAc and VP play special roles in mediating the hedonic impact (‘liking’ and motivational incentive salience (‘wanting’ of food rewards, and their interactions with LH help permit regulatory hunger/satiety modulation of food motivation and reward. Here, we review some progress that has been made regarding this circuitry and its functions: the identification of localized anatomical hedonic hotspots within NAc and VP for enhancing hedonic impact; interactions of NAc/VP hedonic hotspots with specific LH signals such as orexin; an anterior-posterior gradient of sites in NAc shell for producing intense appetitive eating versus intense fearful reactions; and anatomically distributed appetitive functions of dopamine and mu opioid signals in NAc shell and related structures. Such findings help improve our understanding of NAc, VP, and LH interactions in mediating affective and motivation functions, including ‘liking’ and ‘wanting’ for food rewards.

  13. Genetic sex and the volumes of the caudate-putamen, nucleus accumbens core and shell: original data and a review.

    Science.gov (United States)

    Wong, Jordan E; Cao, Jinyan; Dorris, David M; Meitzen, John

    2016-11-01

    Sex differences are widespread across vertebrate nervous systems. Such differences are sometimes reflected in the neural substrate via neuroanatomical differences in brain region volume. One brain region that displays sex differences in its associated functions and pathologies is the striatum, including the caudate-putamen (dorsal striatum), nucleus accumbens core and shell (ventral striatum). The extent to which these differences can be attributed to alterations in volume is unclear. We thus tested whether the volumes of the caudate-putamen, nucleus accumbens core, and nucleus accumbens shell differed by region, sex, and hemisphere in adult Sprague-Dawley rats. As a positive control for detecting sex differences in brain region volume, we measured the sexually dimorphic nucleus of the medial preoptic area (SDN-POA). As expected, SDN-POA volume was larger in males than in females. No sex differences were detected in the volumes of the caudate-putamen, nucleus accumbens core or shell. Nucleus accumbens core volume was larger in the right than left hemisphere across males and females. These findings complement previous reports of lateralized nucleus accumbens volume in humans, and suggest that this may possibly be driven via hemispheric differences in nucleus accumbens core volume. In contrast, striatal sex differences seem to be mediated by factors other than striatal region volume. This conclusion is presented within the context of a detailed review of studies addressing sex differences and similarities in striatal neuroanatomy.

  14. Sexual behavior increases dopamine transmission in the nucleus accumbens and striatum of male rats: comparison with novelty and locomotion.

    Science.gov (United States)

    Damsma, G; Pfaus, J G; Wenkstern, D; Phillips, A G; Fibiger, H C

    1992-02-01

    Extracellular concentrations of dopamine (DA) and its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were examined concurrently, using in vivo microdialysis, in the nucleus accumbens and dorsal striatum of sexually active male rats during tests of locomotor activity, exposure to a novel chamber, exposure to sex odors, the presentation of a sexually receptive female, and copulation. DA increased significantly in the nucleus accumbens when the males were presented with a sexually receptive female behind a screen and increased further during copulation. Although DA also increased significantly in the dorsal striatum during copulation, the magnitude of the effect was significantly lower than that observed in the nucleus accumbens. In contrast, forced locomotion on a rotating drum, exposure to a novel chamber, and exposure to sex odors did not increase DA significantly in either region, although both DOPAC and HVA increased significantly in both regions during the locomotion test. These results indicate that novelty or locomotor activity alone cannot account for the increased extracellular DA concentrations observed in the nucleus accumbens of male rats during the presentation of a sexually receptive female behind a screen, nor can they account for the increased DA concentrations observed in both the nucleus accumbens and dorsal striatum of male rats during copulation. The preferential increase in DA transmission in the nucleus accumbens, compared with that in the striatum, suggests that anticipatory and consummatory aspects of sexual activity may belong to a class of naturally occurring events with reward values that are mediated by DA release in the nucleus accumbens.

  15. Role of nucleus accumbens glutamatergic plasticity in drug addiction.

    Science.gov (United States)

    Quintero, Gabriel C

    2013-01-01

    Substance dependence is characterized by a group of symptoms, according to the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR). These symptoms include tolerance, withdrawal, drug consumption for alleviating withdrawal, exaggerated consumption beyond original intention, failure to reduce drug consumption, expending a considerable amount of time obtaining or recovering from the substance's effects, disregard of basic aspects of life (for example, family), and maintenance of drug consumption, despite facing adverse consequences. The nucleus accumbens (NAc) is a brain structure located in the basal forebrain of vertebrates, and it has been the target of addictive drugs. Different neurotransmitter systems at the level of the NAc circuitry have been linked to the different problems of drug addiction, like compulsive use and relapse. The glutamate system has been linked mainly to relapse after drug-seeking extinction. The dopamine system has been linked mainly to compulsive drug use. The glutamate homeostasis hypothesis centers around the dynamics of synaptic and extrasynaptic levels of glutamate, and their impact on circuitry from the prefrontal cortex (PFC) to the NAc. After repetitive drug use, deregulation of this homeostasis increases the release of glutamate from the PFC to the NAc during drug relapse. Glial cells also play a fundamental role in this hypothesis; glial cells shape the interactions between the PFC and the NAc by means of altering glutamate levels in synaptic and extrasynaptic spaces. On the other hand, cocaine self-administration and withdrawal increases the surface expression of subunit glutamate receptor 1 (GluA1) of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors at the level of the NAc. Also, cocaine self-administration and withdrawal induce the formation of subunit glutamate receptor 2 (GluA2), lacking the Ca(2+)-permeable AMPA receptors (CP-AMPARs) at the level of the NAc

  16. Nucleus Accumbens and Dopamine-Mediated Turning Behavior of the Rat: Role of Accumbal Non-dopaminergic Receptors

    NARCIS (Netherlands)

    Ikeda, H.; Kamei, J.; Koshikawa, N.; Cools, A.R.

    2012-01-01

    Accumbal dopamine plays an important role in physiological responses and diseases such as schizophrenia, Parkinson's disease, and depression. Since the nucleus accumbens contains different neurotransmitters, it is important to know how they interact with dopaminergic function: this is because

  17. Ascorbate reduces morphine-induced extracellular DOPAC level in the nucleus accumbens: A microdialysis study in rats.

    Science.gov (United States)

    Rajaei, Z; Alaei, H; Nasimi, A; Amini, H; Ahmadiani, A

    2005-08-16

    Most drugs of abuse increase dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) release in the shell of the nucleus accumbens. The effects of ascorbate, which is known to modulate dopamine neurotransmission, on the extracellular level of DOPAC in the nucleus accumbens of naive rats and of rats treated acutely with morphine were studied by using in vivo microdialysis and high performance liquid chromatography with electrochemical detection (HPLC-ECD). Acute morphine (20 mg/kg ip) treatment increased the level of DOPAC in the nucleus accumbens to approximately 170% of basal level. Acute treatment with ascorbate (500 mg/kg ip) alone did not alter nucleus accumbens' DOPAC level, but pretreatment with ascorbate (500 mg/kg ip) 30 min before morphine administration attenuated the effects of acute morphine on the level of DOPAC. These results suggest that ascorbate modulates the mesolimbic dopaminergic pathway.

  18. Coding the direct/indirect pathways by D1 and D2 receptors is not valid for accumbens projections.

    Science.gov (United States)

    Kupchik, Yonatan M; Brown, Robyn M; Heinsbroek, Jasper A; Lobo, Mary Kay; Schwartz, Danielle J; Kalivas, Peter W

    2015-09-01

    It is widely accepted that D1 dopamine receptor-expressing striatal neurons convey their information directly to the output nuclei of the basal ganglia, whereas D2-expressing neurons do so indirectly via pallidal neurons. Combining optogenetics and electrophysiology, we found that this architecture does not apply to mouse nucleus accumbens projections to the ventral pallidum. Thus, current thinking attributing D1 and D2 selectivity to accumbens projections akin to dorsal striatal pathways needs to be reconsidered.

  19. Antagonism of nucleus accumbens M(2) muscarinic receptors disrupts operant responding for sucrose under a progressive ratio reinforcement schedule.

    Science.gov (United States)

    Cousens, Graham A; Beckley, Jacob T

    2007-07-19

    Diverse cholinergic signaling mechanisms regulate the excitability of striatal principal neurons and modulate striatal-dependent behavior. These effects are mediated, in part, by action at muscarinic receptors (mAChR), subtypes of which exhibit distinct patterns of expression across striatal neuronal populations. Non-selective mAChR blockade within the nucleus accumbens (NAc) has been shown to disrupt operant responding for food and to inhibit food consumption. However, the specific receptor subtypes mediating these effects are not known. Thus, we evaluated effects of intra-NAc infusions of pirenzepine and methoctramine, mAChR antagonisits with distinct binding affinity profiles, on operant responding for sucrose reward under a progressive ratio (PR) reinforcement schedule. Moderate to high doses of methoctramine disrupted operant responding and reduced behavioral breakpoint. In contrast, pirenzepine failed to impact operant performance at any dose tested. Methoctramine failed to affect latencies to complete appetitive-consummatory response sequences or to impact measures of acoustic startle, suggesting that its' disruptive effects on operant behavior were not consequent to gross motor impairment. Since methoctramine has a greater affinity for M(2) receptors compared to pirenzepine, which has a greater relative affinity for M(1) and M(3) receptors, these findings suggest that M(2) mAChRs within the NAc regulate behavioral processes underling the acquisition of reward.

  20. Calcium-permeable AMPA receptors in the nucleus accumbens regulate depression-like behaviors in the chronic neuropathic pain state.

    Science.gov (United States)

    Goffer, Yossef; Xu, Duo; Eberle, Sarah E; D'amour, James; Lee, Michelle; Tukey, David; Froemke, Robert C; Ziff, Edward B; Wang, Jing

    2013-11-27

    Depression is a salient emotional feature of chronic pain. Depression alters the pain threshold and impairs functional recovery. To date, however, there has been limited understanding of synaptic or circuit mechanisms that regulate depression in the pain state. Here, we demonstrate that depression-like behaviors are induced in a rat model of chronic neuropathic pain. Using this model, we show that chronic pain selectively increases the level of GluA1 subunits of AMPA-type glutamate receptors at the synapses of the nucleus accumbens (NAc), a key component of the brain reward system. We find, in addition, that this increase in GluA1 levels leads to the formation of calcium-permeable AMPA receptors (CPARs). Surprisingly, pharmacologic blockade of these CPARs in the NAc increases depression-like behaviors associated with pain. Consistent with these findings, an AMPA receptor potentiator delivered into the NAc decreases pain-induced depression. These results show that transmission through CPARs in the NAc represents a novel molecular mechanism modulating the depressive symptoms of pain, and thus CPARs may be a promising therapeutic target for the treatment of pain-induced depression. More generally, these findings highlight the role of central glutamate signaling in pain states and define the brain reward system as an important region for the regulation of depressive symptoms of pain.

  1. Neuronal calcium sensor-1 deletion in the mouse decreases motivation and dopamine release in the nucleus accumbens.

    Science.gov (United States)

    Ng, Enoch; Varaschin, Rafael K; Su, Ping; Browne, Caleb J; Hermainski, Joanna; Le Foll, Bernard; Pongs, Olaf; Liu, Fang; Trudeau, Louis-Eric; Roder, John C; Wong, Albert H C

    2016-03-15

    Calcium sensors detect intracellular calcium changes and interact with downstream targets to regulate many functions. Neuronal Calcium Sensor-1 (NCS-1) or Frequenin is widely expressed in the nervous system, and involved in neurotransmission, synaptic plasticity and learning. NCS-1 interacts with and regulates dopamine D2 receptor (D2R) internalization and is implicated in disorders like schizophrenia and substance abuse. However, the role of NCS-1 in behaviors dependent on dopamine signaling in the striatum, where D2R is most highly expressed, is unknown. We show that Ncs-1 deletion in the mouse decreases willingness to work for food. Moreover, Ncs-1 knockout mice have significantly lower activity-dependent dopamine release in the nucleus accumbens core in acute slice recordings. In contrast, food preference, responding for conditioned reinforcement, ability to represent changes in reward value, and locomotor response to amphetamine are not impaired. These studies identify novel roles for NCS-1 in regulating activity-dependent striatal dopamine release and aspects of motivated behavior.

  2. Gene expression changes in the prefrontal cortex, anterior cingulate cortex and nucleus accumbens of mood disorders subjects that committed suicide.

    Directory of Open Access Journals (Sweden)

    Adolfo Sequeira

    Full Text Available Suicidal behaviors are frequent in mood disorders patients but only a subset of them ever complete suicide. Understanding predisposing factors for suicidal behaviors in high risk populations is of major importance for the prevention and treatment of suicidal behaviors. The objective of this project was to investigate gene expression changes associated with suicide in brains of mood disorder patients by microarrays (Affymetrix HG-U133 Plus2.0 in the dorsolateral prefrontal cortex (DLPFC: 6 Non-suicides, 15 suicides, the anterior cingulate cortex (ACC: 6NS, 9S and the nucleus accumbens (NAcc: 8NS, 13S. ANCOVA was used to control for age, gender, pH and RNA degradation, with P ≤ 0.01 and fold change ± 1.25 as criteria for significance. Pathway analysis revealed serotonergic signaling alterations in the DLPFC and glucocorticoid signaling alterations in the ACC and NAcc. The gene with the lowest p-value in the DLPFC was the 5-HT2A gene, previously associated both with suicide and mood disorders. In the ACC 6 metallothionein genes were down-regulated in suicide (MT1E, MT1F, MT1G, MT1H, MT1X, MT2A and three were down-regulated in the NAcc (MT1F, MT1G, MT1H. Differential expression of selected genes was confirmed by qPCR, we confirmed the 5-HT2A alterations and the global down-regulation of members of the metallothionein subfamilies MT 1 and 2 in suicide completers. MTs 1 and 2 are neuro-protective following stress and glucocorticoid stimulations, suggesting that in suicide victims neuroprotective response to stress and cortisol may be diminished. Our results thus suggest that suicide-specific expression changes in mood disorders involve both glucocorticoids regulated metallothioneins and serotonergic signaling in different regions of the brain.

  3. Nitric oxide donors enhance the frequency-dependence of dopamine release in nucleus accumbens

    OpenAIRE

    Hartung, Henrike; Threlfell, Sarah; Cragg, Stephanie J

    2011-01-01

    Abstract Dopamine (DA) neurotransmission in the nucleus accumbens (NAc) is critically involved in normal as well as maladaptive motivated behaviours including drug addiction. Whether the striatal neuromodulator nitric oxide (NO) influences DA release in NAc is unknown. We investigated whether exogenous NO modulates DA transmission in NAc core and how this interaction varies depending on frequency of presynaptic activation. We detected DA with cyclic voltammetry at carbon-fiber micr...

  4. Reduced Nucleus Accumbens Reactivity and Adolescent Depression following Early-life Stress

    OpenAIRE

    Goff, Bonnie; Gee, Dylan G.; Eva H Telzer; Humphreys, Kathryn L.; Gabard-Durnam, Laurel; Flannery, Jessica; Tottenham, Nim

    2012-01-01

    Depression is a common outcome for those having experienced early life stress (ELS). For those individuals, depression typically increases during adolescence and appears to endure into adulthood, suggesting alterations in the development of brain systems involved in depression. Developmentally, the nucleus accumbens (NAcc), a limbic structure associated with reward learning and motivation, typically undergoes dramatic functional change during adolescence; therefore, age-related changes in NAc...

  5. Effects of Food Restriction and Sucrose Intake on Synaptic Delivery of AMPA Receptors in Nucleus Accumbens

    OpenAIRE

    Peng, Xing-Xiang; Ziff, Edward B.; Carr, Kenneth D.

    2011-01-01

    Insertion and removal of AMPA receptors from the synaptic membrane underlie dynamic tuning of synaptic transmission and enduring changes in synaptic strength. Preclinical addiction research suggests that AMPA receptor trafficking plays an important role in nucleus accumbens (NAc) neuroplasticity underlying the compulsive and persistent quality of drug-seeking. Considering the parallels between drug addiction and compulsive eating, plus the supranormal reward properties of sucrose, and the rol...

  6. Apathy in Parkinson's disease is associated with nucleus accumbens atrophy: a magnetic resonance imaging shape analysis.

    Science.gov (United States)

    Carriere, Nicolas; Besson, Pierre; Dujardin, Kathy; Duhamel, Alain; Defebvre, Luc; Delmaire, Christine; Devos, David

    2014-06-01

    Apathy is characterized by lack of interest, loss of initiative, and flattening of affect. It is a frequent, very disabling nonmotor complication of Parkinson's disease (PD). The condition may notably occur when dopaminergic medications are tapered after the initiation of subthalamic stimulation and thus can be referred to as "dopaminergic apathy." Even in the absence of tapering, some patients may develop a form of apathy as PD progresses. This form is often related to cognitive decline and does not respond to dopaminergic medications (dopa-resistant apathy). We aimed at determining whether dopa-resistant apathy in PD is related to striatofrontal morphological changes. We compared the shape of the striatum (using spherical harmonic parameterization and sampling in a three-dimensional point distribution model [SPHARM-PDM]), cortical thickness, and fractional anisotropy (using tract-based spatial statistics) in 10 consecutive patients with dopamine-refractory apathy, 10 matched nonapathetic PD patients and 10 healthy controls. Apathy in PD was associated with atrophy of the left nucleus accumbens. The SPHARM-PDM analysis highlighted (1) a positive correlation between the severity of apathy and atrophy of the left nucleus accumbens, (2) greater atrophy of the dorsolateral head of the left caudate in apathetic patients than in nonapathetic patients, and (3) greater atrophy in the bilateral nucleus accumbens in apathetic patients than in controls. There were no significant intergroup differences in cortical thickness or fractional anisotropy. Dopa-resistant apathy in PD was associated with atrophy of the left nucleus accumbens and the dorsolateral head of the left caudate.

  7. Blocking TRPV1 in nucleus accumbens inhibits persistent morphine conditioned place preference expression in rats.

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    Li-Jun Heng

    Full Text Available The function of TRPV1 (transient receptor potential vanilloid subfamily, member 1 in the central nervous system is gradually elucidated. It has been recently proved to be expressed in nucleus accumbens (NAc, a region playing an essential role in mediating opioid craving and taking behaviors. Based on the general role of TRPV1 antagonist in blocking neural over-excitability by both pre- and post-synaptic mechanisms, TRPV1 antagonist capsazepine (CPZ was tested for its ability to prohibit persistent opioid craving in rats. In the present study, we assessed the expression of TRPV1 in nucleus accumbens and investigated the effect of CPZ in bilateral nucleus accumbens on persistent morphine conditioned place preference (mCPP in rats. We also evaluated the side-effect of CPZ on activity by comparing cross-beam times between groups. We found that morphine conditioned place preference increased the TRPV1 expression and CPZ attenuated morphine conditioned place preference in a dose-dependent and target-specific manner after both short- and long-term spontaneous withdrawal, reflected by the reduction of the increased time in morphine-paired side. CPZ (10 nM could induce prolonged and stable inhibition of morphine conditioned place preference expression. More importantly, CPZ did not cause dysfunction of activity in the subjects tested, which indicates the inhibitory effect was not obtained at the sacrifice of regular movement. Collectively, these results indicated that injection of TRPV1 antagonist in nucleus accumbens is capable of attenuating persistent morphine conditioned place preference without affecting normal activity. Thus, TRPV1 antagonist is one of the promising therapeutic drugs for the treatment of opioid addiction.

  8. Stimulation of the nucleus accumbens as behavioral reward in awake behaving monkeys.

    Science.gov (United States)

    Bichot, Narcisse P; Heard, Matthew T; Desimone, Robert

    2011-08-15

    It has been known that monkeys will repeatedly press a bar for electrical stimulation in several different brain structures. We explored the possibility of using electrical stimulation in one such structure, the nucleus accumbens, as a substitute for liquid reward in animals performing a complex task, namely visual search. The animals had full access to water in the cage at all times on days when stimulation was used to motivate them. Electrical stimulation was delivered bilaterally at mirror locations in and around the accumbens, and the animals' motivation to work for electrical stimulation was quantified by the number of trials they performed correctly per unit of time. Acute mapping revealed that stimulation over a large area successfully supported behavioral performance during the task. Performance improved with increasing currents until it reached an asymptotic, theoretically maximal level. Moreover, stimulation with chronically implanted electrodes showed that an animal's motivation to work for electrical stimulation was at least equivalent to, and often better than, when it worked for liquid reward while on water control. These results suggest that electrical stimulation in the accumbens is a viable method of reward in complex tasks. Because this method of reward does not necessitate control over water or food intake, it may offer an alternative to the traditional liquid or food rewards in monkeys, depending on the goals and requirements of the particular research project.

  9. Perimovement decrease of alpha/beta oscillations in the human nucleus accumbens

    Science.gov (United States)

    Dürschmid, Stefan; Rutledge, Robb B.; Zaehle, Tino; Schmitt, Friedhelm C.; Kaufmann, Jörn; Voges, Jürgen; Heinze, Hans-Jochen; Dolan, Raymond J.; Schoenfeld, Mircea Ariel

    2016-01-01

    The human nucleus accumbens is thought to play an important role in guiding future action selection via an evaluation of current action outcomes. Here we provide electrophysiological evidence for a more direct, i.e., online, role during action preparation. We recorded local field potentials from the nucleus accumbens in patients with epilepsy undergoing surgery for deep brain stimulation. We found a consistent decrease in the power of alpha/beta oscillations (10–30 Hz) before and around the time of movements. This perimovement alpha/beta desynchronization was observed in seven of eight patients and was present both before instructed movements in a serial reaction time task as well as before self-paced, deliberate choices in a decision making task. A similar beta decrease over sensorimotor cortex and in the subthalamic nucleus has been directly related to movement preparation and execution. Our results support the idea of a direct role of the human nucleus accumbens in action preparation and execution. PMID:27486103

  10. Evidence for dopamine receptor pruning between adolescence and adulthood in striatum but not nucleus accumbens.

    Science.gov (United States)

    Teicher, M H; Andersen, S L; Hostetter, J C

    1995-11-21

    Postnatal development of dopamine D1 and D2 receptor families in striatum and nucleus accumbens of rats was studied at 25, 35, 40, 60, 80, 100 and 120 days using autoradiography. These ages were selected to test the hypothesis that dopamine receptors were overproduced prior to puberty (day 40), and pruned back to adult levels thereafter. This hypothesis was confirmed in striatum but not nucleus accumbens. D1 receptor Bmax ([3H]SCH-23390) peaked at 40 days, with levels 67 +/- 21% greater than at 25 days. However, Bmax levels were at least 35% lower at 60-120 days than at 40 days. Similarly, D2 receptor numbers ([3H]YM-09151-2) increased 144 +/- 26% between 25 and 40 days, but were reduced by 34-38% between 60-120 days. In contrast, D1 and D2 receptor Bmax increase approximately 150% between 25 and 40 days in nucleus accumbens, levels fell slightly at 60 or 80 days, but were no different at 100 and 120 days then they were at 40 days. These findings suggest that these two major dopamine target regions follow different developmental strategies, and this has implications for etiological theories of schizophrenia that focus on anomalous receptor pruning.

  11. The Inhibitory Effects of Nesfatin-1 in Ventromedial Hypothalamus on Gastric Function and Its Regulation by Nucleus Accumbens

    Science.gov (United States)

    Gao, Shengli; Guo, Feifei; Sun, Xiangrong; Zhang, Nana; Gong, Yanling; Xu, Luo

    2017-01-01

    Aim: The aim of this study was to investigate the effect of nesfatin-1 signaling in the ventromedial hypothalamus (VMH) on gastric functions, as well as the regulation of these effects by nucleus accumbens (NAc) projections to VMH. Methods: The expression of c-fos in nesfatinergic VMH neurons induced by gastric distension (GD) was measured using the double fluoro-immunohistochemical staining. The firing rates of neurons were monitored with single-unit extracellular electric discharge recording. The projection of nesfatinergic neurons from NAc to VMH was observed by fluorogold retrograde tracer combined with fluoro-immunohistochemical staining. The effect of nesfatin-1 in VMH or electric stimulation in NAc on gastric function was studied by measuring food intake, gastric acid output, gastric motility, and gastric emptying, and the ability of the melanocortin-3/4 receptor antagonist SHU9119 or the anti-nesfatin-1 antibody to block nesfatin-1 in the VMH was assessed. Results: Expression of c-fos was observed in VMH nesfatinergic neurons following GD in rats. Further, nesfatin-1 delivery to single GD-responsive neurons changed the firing rates of these neurons in the VMH. In awake, behaving rats, intra-VMH administration of nesfatin-1 inhibited food intake, gastric acid output, gastric motility, and gastric emptying. These effects were abolished by SHU9119. Fluorogold retrograde tracing showed nesfatinergic neural projection from the NAc to the VMH. Electrical stimulation of NAc modified the firing rates of the VMH neurons and inhibited food intake and gastric functions. The pretreatment with an anti-nesfatin-1 antibody in the VMH reversed the effects of NAc electrical stimulation on the VMH neuronal firing rates and gastric function. Conclusions: Nesfatin-1 in the VMH inhibited food intake, gastric acid output, gastric motility, and gastric emptying. A nesfatinergic pathway between NAc and VMH transmitted metabolism-regulating signals. PMID:28105016

  12. Astrocytes Control Neuronal Excitability in the Nucleus Accumbens

    Directory of Open Access Journals (Sweden)

    Tommaso Fellin

    2007-01-01

    Full Text Available Though accumulating evidence shows that the metabotropic glutamate receptor 5 (mGluR5 mediates some of the actions of extracellular glutamate after cocaine use, the cellular events underlying this action are poorly understood. In this review, we will discuss recent results showing that mGluR5 receptors are key regulators of astrocyte activity. Synaptic release of glutamate activates mGluR5 expressed in perisynaptic astrocytes and generates intense Ca2+ signaling in these cells. Ca2+ oscillations, in turn, trigger the release from astrocytes of the gliotransmitter glutamate, which modulates neuronal excitability by activating NMDA receptors. By integrating these results with the most recent evidence demonstrating the importance of astrocytes in the regulation of neuronal excitability, we propose that astrocytes are involved in mediating some of the mGluR5-dependent drug-induced behaviors.

  13. Counteracting incentive sensitization in severe alcohol dependence using deep brain stimulation of the nucleus accumbens: clinical and basic science aspects

    Directory of Open Access Journals (Sweden)

    Hans-Jochen Heinze

    2009-09-01

    Full Text Available The ventral striatum / nucleus accumbens has been implicated in the craving for drugs and alcohol which is a major reason for relapse of addicted people. Craving might be induced by drug-related cues. This suggests that disruption of craving-related neural activity in the nucleus accumbens may significantly reduce craving in alcohol-dependent patients. Here we report on preliminary clinical and neurophysiological evidence in three male patients who were treated with high frequency deep brain stimulation of the nucleus accumbens bilaterally. All three had been alcohol dependent for many years, unable to abstain from drinking, and had experienced repeated relapses prior to the stimulation. After the operation, craving was greatly reduced and all three patients were able to abstain from drinking for extended periods of time. Immediately after the operation but prior to connection of the stimulation electrodes to the stimulator, local field potentials were obtained from the externalized cables in two patients while they performed cognitive tasks addressing action monitoring and incentive salience of drug related cues. LFPs in the action monitoring task provided further evidence for a role of the nucleus accumbens in goal-directed behaviors. Importantly, alcohol related cue stimuli in the incentive salience task modulated LFPs even though these cues were presented outside of the attentional focus. This implies that cue-related craving involves the nucleus accumbens and is highly automatic.

  14. mRNA changes in nucleus accumbens related to methamphetamine addiction in mice

    Science.gov (United States)

    Zhu, Li; Li, Jiaqi; Dong, Nan; Guan, Fanglin; Liu, Yufeng; Ma, Dongliang; Goh, Eyleen L. K.; Chen, Teng

    2016-11-01

    Methamphetamine (METH) is a highly addictive psychostimulant that elicits aberrant changes in the expression of microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) in the nucleus accumbens of mice, indicating a potential role of METH in post-transcriptional regulations. To decipher the potential consequences of these post-transcriptional regulations in response to METH, we performed strand-specific RNA sequencing (ssRNA-Seq) to identify alterations in mRNA expression and their alternative splicing in the nucleus accumbens of mice following exposure to METH. METH-mediated changes in mRNAs were analyzed and correlated with previously reported changes in non-coding RNAs (miRNAs and lncRNAs) to determine the potential functions of these mRNA changes observed here and how non-coding RNAs are involved. A total of 2171 mRNAs were differentially expressed in response to METH with functions involved in synaptic plasticity, mitochondrial energy metabolism and immune response. 309 and 589 of these mRNAs are potential targets of miRNAs and lncRNAs respectively. In addition, METH treatment decreases mRNA alternative splicing, and there are 818 METH-specific events not observed in saline-treated mice. Our results suggest that METH-mediated addiction could be attributed by changes in miRNAs and lncRNAs and consequently, changes in mRNA alternative splicing and expression. In conclusion, our study reported a methamphetamine-modified nucleus accumbens transcriptome and provided non-coding RNA-mRNA interaction networks possibly involved in METH addiction.

  15. Metabolic activation of amygdala, lateral septum and accumbens circuits during food anticipatory behavior.

    Science.gov (United States)

    Olivo, Diana; Caba, Mario; Gonzalez-Lima, Francisco; Rodríguez-Landa, Juan F; Corona-Morales, Aleph A

    2017-01-01

    When food is restricted to a brief fixed period every day, animals show an increase in temperature, corticosterone concentration and locomotor activity for 2-3h before feeding time, termed food anticipatory activity. Mechanisms and neuroanatomical circuits responsible for food anticipatory activity remain unclear, and may involve both oscillators and networks related to temporal conditioning. Rabbit pups are nursed once-a-day so they represent a natural model of circadian food anticipatory activity. Food anticipatory behavior in pups may be associated with neural circuits that temporally anticipate feeding, while the nursing event may produce consummatory effects. Therefore, we used New Zealand white rabbit pups entrained to circadian feeding to investigate the hypothesis that structures related to reward expectation and conditioned emotional responses would show a metabolic rhythm anticipatory of the nursing event, different from that shown by structures related to reward delivery. Quantitative cytochrome oxidase histochemistry was used to measure regional brain metabolic activity at eight different times during the day. We found that neural metabolism peaked before nursing, during food anticipatory behavior, in nuclei of the extended amygdala (basolateral, medial and central nuclei, bed nucleus of the stria terminalis), lateral septum and accumbens core. After pups were fed, however, maximal metabolic activity was expressed in the accumbens shell, caudate, putamen and cortical amygdala. Neural and behavioral activation persisted when animals were fasted by two cycles, at the time of expected nursing. These findings suggest that metabolic activation of amygdala-septal-accumbens circuits involved in temporal conditioning may contribute to food anticipatory activity. Copyright © 2016 Elsevier B.V. All rights reserved.

  16. Changes of phosphorylation of cAMP response element binding protein in rat nucleus accumbens after chronic ethanol intake: naloxone reversal

    Institute of Scientific and Technical Information of China (English)

    LIJing; LIYue-Hua; YUANXiao-Ru

    2003-01-01

    AIM: To study the changes in the expression and phosphorylation of cAMP response element binding protein(CREB) in the rat nucleus accumbens after chronic ethanol intake and its withdrawal. METHODS: Ethanol wasgiven in drinking water at the concentration of 6 % (v/v), for one month. Changes in the levels of CREB andphospho-CREB (p-CREB) protein in the nucleus accumbens were measured by immunohistochemistry methods.RESULTS: Ethanol given to rats in drinking water decreased the level of p-CREB protein in the nucleus accumbens(-75 %) at the time of exposure to ethanol. The decrement of p-CREB protein in the nucleus accumbens remainedat 24 h (-35 %) and 72 h (-28 %) of ethanol withdrawal, which recovered toward control level after 7 d of ethanolwithdrawal. However, chronic ethanol, as well as ethanol withdrawal failed to produce any significant alteration inthe level of CREB protein in the nucleus accumbens. Naloxone (alone) treatment of rats had no effect on the levelsof CREB and p-CREB protein in the nucleus accumbens. However, when naloxone was administered concurrentlywith ethanol treatment, it antagonized the down-regulation of p-CREB protein in the nucleus accumbens (142 %) ofrats exposed to ethanol. CONCLUSION: A long-term intake of ethanol solution down-regulates the phosphoryla-tion of CREB in the nucleus accumbens, and those changes can be reversed by naloxone, which may be one kindof the molecular mechanisms associated with ethano1 dependence.

  17. Extracellular citrulline levels in the nucleus accumbens during the acquisition and extinction of a classical conditioned reflex with pain reinforcement.

    Science.gov (United States)

    Savel'ev, S A; Saul'skaya, N B

    2007-03-01

    Studies on Sprague-Dawley rats using in vivo microdialysis and HPLC showed that the acquisition and performance of a classical conditioned reflex with pain reinforcement was accompanied by increases in the concentrations of citrulline (a side product of nitric oxide formation) and arginine (the substrate of NO synthase) in the intercellular space of the nucleus accumbens. During extinction of the reflex, there was a decrease in the elevation of extracellular citrulline in this brain structure, which correlated with the extent of extinction of the reflex. Recovery of the reflex led to increases in arginine and citrulline levels in the nucleus accumbens. These data suggest that there is an increase in nitric oxide production in the nucleus accumbens during the acquisition and performance of a classical conditioned reflex with pain reinforcement, which decreases as the reflex is extinguished and recovers with recovery of the reflex.

  18. Cytosolic proteomic alterations in the nucleus accumbens of cocaine overdose victims.

    Science.gov (United States)

    Tannu, N; Mash, D C; Hemby, S E

    2007-01-01

    Chronic cocaine use in humans and animal models is known to lead to pronounced alterations in neuronal function in the nucleus accumbens (NAc), a brain region associated with drug reinforcement. Two-dimensional gel electrophoresis was used to compare protein alterations in the NAc between cocaine overdose (COD) victims (n=10) and controls (n=10). Following image normalization, spots with significantly differential image intensities (Pcocaine abuse provides insight into the molecular basis of the disease and offers new targets for pharmacotherapeutic intervention for drug abuse-related disorders.

  19. Diazepam alters cocaine self-administration, but not cocaine-stimulated locomotion or nucleus accumbens dopamine

    OpenAIRE

    2008-01-01

    Cocaine is known to enhance nucleus accumbens dopamine (NAcc DA), serve as a positive reinforcer and produce negative effects, such as anxiety. The influence of diazepam on cocaine intake, cocaine-stimulated behavioral activity and NAcc DA was investigated using self-administration and experimenter-administered intravenous (i.v.) cocaine. In Experiment 1, rats were pretreated with diazepam (0.25 mg/kg) or saline (0.1 ml) 30 minutes prior to 20 daily 1-hr cocaine (0.75 mg/kg/inj) self-administ...

  20. Deep brain stimulation of the nucleus accumbens for the treatment of addiction.

    Science.gov (United States)

    Müller, Ulf J; Voges, Jürgen; Steiner, Johann; Galazky, Imke; Heinze, Hans-Jochen; Möller, Michaela; Pisapia, Jared; Halpern, Casey; Caplan, Arthur; Bogerts, Bernhard; Kuhn, Jens

    2013-04-01

    Despite novel medications and other therapeutic strategies, addiction to psychotropic substances remains one of the most serious public health problems worldwide. In this review, beginning with an introduction of deep brain stimulation (DBS), we highlight the importance of the nucleus accumbens (NAc) in the context of the reward circuitry and addictive behavior. We will provide a short historic overview of other neurosurgical approaches to treat addiction and describe the experimental and preclinical data on DBS in addiction. Finally, we call attention to key ethical issues related to using DBS to treat addiction that are important for future research and the design of clinical trials.

  1. Sexual dimorphism of medium-sized neurons with spines in human nucleus accumbens

    Directory of Open Access Journals (Sweden)

    Sazdanović Маја

    2013-01-01

    Full Text Available The nucleus accumbens is a limbic nucleus, representing part of the striatum body, and together with the caudate nucleus and putamen, it lies on the septum. The aim of this study was to examine morphological sexual dimorphism in spine density and also to undertake an immunohistochemical study of expression for estrogen and progesterone receptors in the medium-sized neurons in the nucleus accumbens. The research was conducted on twenty human brains of persons of both sexes, between the age of 20-75 years. The Golgi method was applied to determine the types and subtypes of neurons, morphologies of soma, dendrites and axons, as well as the relations between the cells and glial elements. The following were quantitatively examined: the maximum diameter of the neurons, the minimal diameter of the neurons, and the total length of the dendrites. The expression of receptors for estrogen and progesterone, their distribution and intensity were defined immunohistochemically. The parameters of the bodies of neurons in the shell and core of the nucleus accumbens were studied in both men and women. No statistically significant differences were found. Examination of the spine density showed statistical significance in terms of a higher density of spines in women. Immunohistochemically, in the female brain estrogen expression is diffusely spread in a large number of neurons; it is extra nuclear, of granular appearance and high intensity. In the male brain, expression of estrogen is visible and distributed over about one half of different types of neurons; it is extra nuclear, of granular appearance, mostly of middle and low staining intensity. Expression of progesterone in the female brain was very discreet and on a very small number of neurons; it was extra nuclear and with a weak staining intensity. Expression of progesterone in the male brain was distributed on a small number of neurons. It had a granular appearance, it was extra nuclear, with a very low

  2. TRPV1 modulates morphine-induced conditioned place preference via p38 MAPK in the nucleus accumbens.

    Science.gov (United States)

    Hong, Sa-Ik; Nguyen, Thi-Lien; Ma, Shi-Xun; Kim, Hyoung-Chun; Lee, Seok-Yong; Jang, Choon-Gon

    2017-09-15

    Emerging evidence suggests that the transient receptor potential vanilloid type 1 channel (TRPV1) is a novel target for the treatment of drug addiction, such as cocaine and morphine. Previously we reported that TRPV1 inhibition reduced morphine reward in the dorsal striatum (DSt) of mice and morphine self-administration through a decrease in accumbal activity in rats. However, the role of TRPV1 on morphine-conditioned reward in addiction-related brain regions, such as the nucleus accumbens (NAc), has not been previously established. Here, we investigated the effects of TRPV1 on morphine conditioned place preference (CPP) and intracellular mechanisms of TRPV1 using Western blot analysis and immunohistochemistry (IHC) in morphine-administered mice. TRPV1 knockout mice did not exhibit morphine reward responses, and both i.p. and intra-NAc injections of SB366791, a selective TRPV1 antagonist, reduced morphine-induced CPP in wild-type mice. Furthermore, i.p. injection of SB203580, a selective p38 MAPK inhibitor, also dampened morphine-induced CPP. To determine the molecular mechanisms of the TRPV1/p38 MAPK pathway in morphine CPP, we investigated the expression of adenylyl cyclase type 1 (AC1) and phospho-p38 mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) in the NAc. Either SB366791 or SB203580 decreased the protein expression levels of phospho-p38 MAPK, phosphor-NF-κB, and AC1 in the NAc of morphine CPP mice. Taken together, our findings suggest that TRPV1 may modulate morphine-induced conditioned reward effects via the p38 MAPK signaling pathway in the NAc. Therefore, blockade of TRPV1 may provide a novel therapeutic approach for the prevention and treatment of opioid addiction. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. Opioid receptor antagonism in the nucleus accumbens fails to block the expression of sugar-conditioned flavor preferences in rats.

    Science.gov (United States)

    Bernal, Sonia Y; Touzani, Khalid; Gerges, Meri; Abayev, Yana; Sclafani, Anthony; Bodnar, Richard J

    2010-03-01

    In our prior studies, systemic administration of the opioid receptor antagonist naltrexone (NTX) did not block flavor preference conditioning by the sweet taste or post-oral actions of sugar despite reducing intake. Because opioid signaling in the nucleus accumbens (NAc) is implicated in food reward, this study determined if NTX administered into the NAc would block the expression of sugar-conditioned preferences. In Experiment 1, food-restricted rats with bilateral NAc shell or core cannulae were trained to drink a fructose (8%)+saccharin (0.2%) solution mixed with one flavor (CS+) and a less-preferred 0.2% saccharin solution mixed with another flavor (CS-) during one-bottle sessions. Two-bottle tests with the two flavors mixed in saccharin solutions occurred 10 min following total bilateral NAc shell or core doses of 0, 1, 25 and 50 microg of NTX. The rats preferred the CS+ over CS- following vehicle (80%) and all NTX doses in the shell and core. The CS+ preference was reduced to 64% and 72% by 50 microg NTX in the shell and core, although only the core effect was significant. In Experiment 2, food-restricted rats were trained to drink one flavored saccharin solution (CS+) paired with an intragastic (IG) glucose (8%) infusion and a second flavored saccharin solution (CS-) paired with an IG water infusion. In subsequent two-bottle tests, the rats displayed significant preferences for the CS+ (81-91%) that were unaltered by any NTX dose in the shell or core. CS+ intake, however, was reduced by NTX in the shell, but not the core. These data indicate that accumbal opioid antagonism slightly attenuated, but did not block the expression of sugar-conditioned flavor preferences. Therefore, while opioid drugs can have potent effects on sugar intake they appear less effective in altering sugar-conditioned flavor preferences. (c) 2009 Elsevier Inc. All rights reserved.

  4. δ-Opioid receptors in the accumbens shell mediate the influence of both excitatory and inhibitory predictions on choice.

    Science.gov (United States)

    Laurent, Vincent; Wong, Felix L; Balleine, Bernard W

    2015-01-01

    Stimuli that predict rewarding events can control choice between future actions, and this control could be mediated by δ-opioid receptors in the nucleus accumbens shell (NAc-S). Stimuli predicting the absence of important events can also guide choice, although it remains unknown whether they do so via changes in an accumbal δ-opioid receptor-related process. δ-opioid receptor-eGFP mice were trained to perform two instrumental actions that delivered different food outcomes. Choice between the two actions was then tested in the presence of stimuli paired with either the delivery or the non-delivery of each of the two outcomes. Bilateral infusions of the δ-opioid receptor antagonist naltrindole into the NAc-S were used to determine the role of these receptors at the time of choice and δ-opioid receptor expression in the NAc-S used to assess functional activity. A stimulus predicting a specific outcome biased choice performance towards the action previously earning that same outcome. In contrast, a stimulus signalling the absence of that outcome biased performance away from the action that delivered that outcome towards actions associated with the absence of that outcome. Both effects were associated with increased δ-opioid receptor expression on the membrane of cholinergic interneurons within the NAc-S. Furthermore, both effects were blocked by naltrindole infused into the NAc-S. These findings suggest that δ-opioid receptors in the NAc-S were involved in the effects of predictive learning on choice between actions, whether those predictions involve the presence or absence of specific rewarding events. This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2. © 2014 The British Pharmacological Society.

  5. Change in microRNAs associated with neuronal adaptive responses in the nucleus accumbens under neuropathic pain.

    Science.gov (United States)

    Imai, Satoshi; Saeki, Mai; Yanase, Makoto; Horiuchi, Hiroshi; Abe, Minako; Narita, Michiko; Kuzumaki, Naoko; Suzuki, Tsutomu; Narita, Minoru

    2011-10-26

    Neuropathic pain is the most difficult type of pain to control, and patients lose their motivation for the purposive pursuit with a decrease in their quality of life. Using a functional magnetic resonance imaging analysis, we demonstrated that blood oxygenation level-dependent signal intensity was increased in the ipsilateral nucleus accumbens (N.Acc.) following peripheral nerve injury. microRNAs are small, noncoding RNA molecules that direct the post-transcriptional suppression of gene expression, and play an important role in regulating synaptic plasticity. In this study, we found that sciatic nerve ligation induced a drastic decrease in the expression of miR200b and miR429 in N.Acc. neurons. The expression of DNA methyltransferase 3a (DNMT3a), which is the one of the predicted targets of miR200b/429, was significantly increased in the limbic forebrain including N.Acc. at 7 d after sciatic nerve ligation. Double-immunolabeling with antibodies specific to DNMT3a and NR1 showed that DNMT3a-immunoreactivity in the N.Acc. was located in NR1-labeled neurons, indicating that increased DNMT3a proteins were dominantly expressed in postsynaptic neurons in the N.Acc. area under a neuropathic pain-like state. The results of these analyses provide new insight into an epigenetic modification that is accompanied by a dramatic decrease in miR200b and miR429 along with the dysfunction of "mesolimbic motivation/valuation circuitry" under a neuropathic pain-like state. These phenomena may result in an increase in DNMT3a in neurons of the N.Acc. under neuropathic pain, which leads to the long-term transcription-silencing of several genes.

  6. Caudal Nucleus Accumbens Core Is Critical in the Regulation of Cue-Elicited Approach-Avoidance Decisions

    Science.gov (United States)

    Hamel, Laurie; Thangarasa, Tharshika; Samadi, Osai

    2017-01-01

    The nucleus accumbens (NAc) is thought to be a site of integration of positively and negatively valenced information and action selection. Functional differentiation in valence processing has previously been found along the rostrocaudal axis of the shell region of the NAc in assessments of unconditioned motivation. Given that the core region of the NAc has been implicated in the elicitation of motivated behavior in response to conditioned cues, we sought to assess the role of caudal, intermediate, and rostral sites within this subregion in cue-elicited approach-avoidance decisions. Rats were trained to associate visuo-tactile cues with appetitive, aversive, and neutral outcomes. Following the successful acquisition of the cue-outcome associations, rats received microinfusions of GABAA and GABAB receptor agonists (muscimol/baclofen) or saline into the caudal, intermediate, or rostral NAc core and were then exposed to a superimposition of appetitively and aversively valenced cues versus neutral cues in a “conflict test,” as well as to the appetitive versus neutral cues, and aversive cues versus neutral cues, in separate conditioned preference/avoidance tests. Disruption of activity in the intermediate to caudal parts of the NAc core resulted in a robust avoidance bias in response to motivationally conflicting cues, as well as a potentiated avoidance of aversive cues as compared with control animals, coupled with an attenuated conditioned preference for the appetitive cue. These results suggest that the caudal NAc core may have the capacity to exert bidirectional control over appetitively and aversively motivated responses to valence signals. PMID:28275709

  7. Phenotype-dependent inhibition of glutamatergic transmission on nucleus accumbens medium spiny neurons by the abused inhalant toluene.

    Science.gov (United States)

    Beckley, Jacob T; Randall, Patrick K; Smith, Rachel J; Hughes, Benjamin A; Kalivas, Peter W; Woodward, John J

    2016-05-01

    Abused inhalants are voluntarily inhaled at high concentrations to produce intoxicating effects. Results from animal studies show that the abused inhalant toluene triggers behaviors, such as self-administration and conditioned place preference, which are commonly associated with addictive drugs. However, little is known about how toluene affects neurons within the nucleus accumbens (NAc), a brain region within the basal ganglia that mediates goal-directed behaviors and is implicated in the development and maintenance of addictive behaviors. Here we report that toluene inhibits a component of the after-hyperpolarization potential, and dose-dependently inhibits N-methyl-D-aspartate (NMDA)-mediated currents in rat NAc medium spiny neurons (MSN). Moreover, using the multivariate statistical technique, partial least squares discriminative analysis to analyze electrophysiological measures from rat NAc MSNs, we show that toluene induces a persistent depression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-mediated currents in one subtype of NAc MSNs, and that the electrophysiological features of MSN neurons predicts their sensitivity to toluene. The CB1 receptor antagonist AM281 blocked the toluene-induced long-term depression of AMPA currents, indicating that this process is dependent on endocannabinoid signaling. The neuronal identity of recorded cells was examined using dual histochemistry and shows that toluene-sensitive NAc neurons are dopamine D2 MSNs that express preproenkephalin mRNA. Overall, the results from these studies indicate that physiological characteristics obtained from NAc MSNs during whole-cell patch-clamp recordings reliably predict neuronal phenotype, and that the abused inhalant toluene differentially depresses excitatory neurotransmission in NAc neuronal subtypes. © 2015 Society for the Study of Addiction.

  8. Glutamate and Opioid Antagonists Modulate Dopamine Levels Evoked by Innately Attractive Male Chemosignals in the Nucleus Accumbens of Female Rats

    Science.gov (United States)

    Sánchez-Catalán, María-José; Orrico, Alejandro; Hipólito, Lucía; Zornoza, Teodoro; Polache, Ana; Lanuza, Enrique; Martínez-García, Fernando; Granero, Luis; Agustín-Pavón, Carmen

    2017-01-01

    Sexual chemosignals detected by vomeronasal and olfactory systems mediate intersexual attraction in rodents, and act as a natural reinforcer to them. The mesolimbic pathway processes natural rewards, and the nucleus accumbens receives olfactory information via glutamatergic projections from the amygdala. Thus, the aim of this study was to investigate the involvement of the mesolimbic pathway in the attraction toward sexual chemosignals. Our data show that female rats with no previous experience with males or their chemosignals display an innate preference for male-soiled bedding. Focal administration of the opioid antagonist β-funaltrexamine into the posterior ventral tegmental area does not affect preference for male chemosignals. Nevertheless, exposure to male-soiled bedding elicits an increase in dopamine efflux in the nucleus accumbens shell and core, measured by microdialysis. Infusion of the opioid antagonist naltrexone in the accumbens core does not significantly affect dopamine efflux during exposure to male chemosignals, although it enhances dopamine levels 40 min after withdrawal of the stimuli. By contrast, infusion of the glutamate antagonist kynurenic acid in the accumbens shell inhibits the release of dopamine and reduces the time that females spend investigating male-soiled bedding. These data are in agreement with previous reports in male rats showing that exposure to opposite-sex odors elicits dopamine release in the accumbens, and with data in female mice showing that the behavioral preference for male chemosignals is not affected by opioidergic antagonists. We hypothesize that glutamatergic projections from the amygdala into the accumbens might be important to modulate the neurochemical and behavioral responses elicited by sexual chemosignals in rats. PMID:28280461

  9. Coincident activation of NMDA and dopamine D1 receptors within the nucleus accumbens core is required for appetitive instrumental learning.

    Science.gov (United States)

    Smith-Roe, S L; Kelley, A E

    2000-10-15

    The nucleus accumbens, a brain structure ideally situated to act as an interface between corticolimbic information-processing regions and motor output systems, is well known to subserve behaviors governed by natural reinforcers. In the accumbens core, glutamatergic input from its corticolimbic afferents and dopaminergic input from the ventral tegmental area converge onto common dendrites of the medium spiny neurons that populate the accumbens. We have previously found that blockade of NMDA receptors in the core with the antagonist 2-amino-5-phosphonopentanoic acid (AP-5; 5 nmol) abolishes acquisition but not performance of an appetitive instrumental learning task (Kelley et al., 1997). Because it is currently hypothesized that concurrent dopamine D(1) and glutamate receptor activation is required for long-term changes associated with plasticity, we wished to examine whether the dopamine system in the accumbens core modulates learning via NMDA receptors. Co-infusion of low doses of the D(1) receptor antagonist SCH-23390 (0.3 nmol) and AP-5 (0.5 nmol) into the accumbens core strongly impaired acquisition of instrumental learning (lever pressing for food), whereas when infused separately, these low doses had no effect. Infusion of the combined low doses had no effect on indices of feeding and motor activity, suggesting a specific effect on learning. We hypothesize that co-activation of NMDA and D(1) receptors in the nucleus accumbens core is a key process for acquisition of appetitive instrumental learning. Such an interaction is likely to promote intracellular events and gene regulation necessary for synaptic plasticity and is supported by a number of cellular models.

  10. Glutamate and Opioid Antagonists Modulate Dopamine Levels Evoked by Innately Attractive Male Chemosignals in the Nucleus Accumbens of Female Rats.

    Science.gov (United States)

    Sánchez-Catalán, María-José; Orrico, Alejandro; Hipólito, Lucía; Zornoza, Teodoro; Polache, Ana; Lanuza, Enrique; Martínez-García, Fernando; Granero, Luis; Agustín-Pavón, Carmen

    2017-01-01

    Sexual chemosignals detected by vomeronasal and olfactory systems mediate intersexual attraction in rodents, and act as a natural reinforcer to them. The mesolimbic pathway processes natural rewards, and the nucleus accumbens receives olfactory information via glutamatergic projections from the amygdala. Thus, the aim of this study was to investigate the involvement of the mesolimbic pathway in the attraction toward sexual chemosignals. Our data show that female rats with no previous experience with males or their chemosignals display an innate preference for male-soiled bedding. Focal administration of the opioid antagonist β-funaltrexamine into the posterior ventral tegmental area does not affect preference for male chemosignals. Nevertheless, exposure to male-soiled bedding elicits an increase in dopamine efflux in the nucleus accumbens shell and core, measured by microdialysis. Infusion of the opioid antagonist naltrexone in the accumbens core does not significantly affect dopamine efflux during exposure to male chemosignals, although it enhances dopamine levels 40 min after withdrawal of the stimuli. By contrast, infusion of the glutamate antagonist kynurenic acid in the accumbens shell inhibits the release of dopamine and reduces the time that females spend investigating male-soiled bedding. These data are in agreement with previous reports in male rats showing that exposure to opposite-sex odors elicits dopamine release in the accumbens, and with data in female mice showing that the behavioral preference for male chemosignals is not affected by opioidergic antagonists. We hypothesize that glutamatergic projections from the amygdala into the accumbens might be important to modulate the neurochemical and behavioral responses elicited by sexual chemosignals in rats.

  11. Neuropeptide Y infusion into the shell region of the rat nucleus accumbens increases extracellular levels of dopamine

    DEFF Research Database (Denmark)

    Sørensen, Gunnar; Wegener, Gregers; Hasselstrøm, Jørgen;

    2009-01-01

    Increases in extracellular dopamine in the shell region of the nucleus accumbens are centrally involved in mediating reinforcement of addictive drugs. Neuropeptide Y (NPY) and its receptors are present in the nucleus accumbens and have been implicated in addiction mechanisms. This study further...... explored the potential role of NPY in addiction mechanisms using microdialysis to measure extracellular dopamine in vivo after infusion of NPY directly into the accumbal shell region of adult rats. NPY was found to dose-dependently increase extracellular dopamine levels, indicating that NPY could play...

  12. Effect of ginseng saponina on nicotine-induced dopamine release in the rat nucleus accumbens and striatum

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Sang Eun [Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of); Shim, In Sop [Kyunghee University, Seoul (Korea, Republic of); Chung, June Key; Lee, Myung Chul [Seoul National University College of Medicine, Seoul (Korea, Republic of)

    2002-10-01

    We investigated the effect of ginseng total saponin (GTS) on nicotine-induced dopamine (DA) release in the striatum and nucleus accumbens of freely moving rats using in vivo microdialysis technique. Systemic pretreatment with GTS decreased striatal DA release induced by local infusion of nicotine into the striatum. However, GTS had no effect on the resting levels of extracellular DA in the striatum. GTS also blocked nicotine-induced DA release in the nucleus accumbens. The results of the present study suggest that GTS acts on the DA terminals to prevent DA release induced by nicotine. This may reflect the blocking effect of GTS on behavioral hyperactivity induced by psychostimulants.

  13. Beta2-containing nicotinic acetylcholine receptors mediate calcium/calmodulin-dependent protein kinase-II and synapsin I protein levels in the nucleus accumbens after nicotine withdrawal in mice.

    Science.gov (United States)

    Jackson, Kia J; Imad Damaj, M

    2013-02-15

    Nicotinic acetylcholine receptors are calcium-permeable and the initial targets for nicotine. Studies suggest that calcium-dependent mechanisms mediate some behavioral responses to nicotine; however, the post-receptor calcium-dependent mechanisms associated with chronic nicotine and nicotine withdrawal remain unclear. The proteins calcium/calmodulin-dependent protein kinase II (CaMKII) and synapsin I are essential for neurotransmitter release and were shown to be involved in drug dependence. In the current study, using pharmacological techniques, we sought to (a) complement previously published behavioral findings from our lab indicating a role for calcium-dependent signaling in nicotine dependence and (b) expand on previously published acute biochemical and pharmacological findings indicating the relevance of calcium-dependent mechanisms in acute nicotine responses by evaluating the function of CaMKII and synapsin I after chronic nicotine and withdrawal in the nucleus accumbens, a brain region implicated in drug dependence. Male mice were chronically infused with nicotine for 14 days, and treated with the β2-selective antagonist dihydro-β-erythroidine (DHβE), or the α7 antagonist, methyllycaconitine citrate (MLA) 20min prior to dissection of the nucleus accumbens. Results show that phosphorylated and total CaMKII and synapsin I protein levels were significantly increased in the nucleus accumbens after chronic nicotine infusion, and reduced after treatment with DHβE, but not MLA. A spontaneous nicotine withdrawal assessment also revealed significant reductions in phosphorylated CaMKII and synapsin I levels 24h after cessation of nicotine treatment. Our findings suggest that post-receptor calcium-dependent mechanisms associated with nicotine withdrawal are mediated through β2-containing nicotinic receptors.

  14. Microinjection of CART (cocaine- and amphetamine-regulated transcript) peptide into the nucleus accumbens inhibits the cocaine-induced upregulation of dopamine receptors and locomotor sensitization.

    Science.gov (United States)

    Peng, Qinghua; Sun, Xi; Liu, Ziyong; Yang, Jianghua; Oh, Ki-Wan; Hu, Zhenzhen

    2014-09-01

    Repeated exposure to addictive drugs enhances dopamine receptor (DR) signaling and the ultimate phosphorylation of the cyclic adenosine 5'-monophosphate (cAMP)-response element-binding protein (CREB)-regulated cocaine- and amphetamine-regulated transcript (CART) expression in the nucleus accumbens (NAcc). These effects are known to contribute to the expression of behavioral sensitization. CART peptides are neuropeptides that modulate drug reward and reinforcement. The present experiments investigated the effects of CART 55-102 microinjection into the NAcc on (1) the phosphorylation of CREB, (2) cAMP/protein kinase A (PKA) signaling and (3) extracellular signal-regulated kinase (ERK) phosphorylated kinase signaling. Here, we show that repeated microinjections into the NAcc of CART 55-102 peptides (1.0 or 2.5μg, 0.5μl/side) attenuates cocaine-induced enhancements of D1R, D2R and D3R phosphorylation in this sites. Furthermore, the microinjection of CART 55-102 followed by repeated injections of cocaine (15mg/kg) dose-dependently blocked the enhancement of cAMP levels, PKA activity and pERK and pCREB levels on the fifth day of cocaine administration. The cocaine-induced locomotor activity and behavioral sensitization in rats were also inhibited by the 5-day-microinjection of CART peptides. These results suggest that the phosphorylation of CREB by cocaine in the NAcc was blocked by the CART 55-102 peptide via the inhibition of D1R and D2R stimulation, D3R phosphorylation, cAMP/PKA signaling and ERK phosphorylated kinase signaling. These effects may have played a compensatory inhibitory role in the behavioral sensitization of rats that received microinjections of CART 55-102.

  15. Does incentive-elicited nucleus accumbens activation differ by substance of abuse? An examination with adolescents

    Directory of Open Access Journals (Sweden)

    Hollis C. Karoly

    2015-12-01

    Full Text Available Numerous questions surround the nature of reward processing in the developing adolescent brain, particularly in regard to polysubstance use. We therefore sought to examine incentive-elicited brain activation in the context of three common substances of abuse (cannabis, tobacco, and alcohol. Due to the role of the nucleus accumbens (NAcc in incentive processing, we compared activation in this region during anticipation of reward and loss using a monetary incentive delay (MID task. Adolescents (ages 14–18; 66% male were matched on age, gender, and frequency of use of any common substances within six distinct groups: cannabis-only (n = 14, tobacco-only (n = 34, alcohol-only (n = 12, cannabis + tobacco (n = 17, cannabis + tobacco + alcohol (n = 17, and non-using controls (n = 38. All groups showed comparable behavioral performance on the MID task. The tobacco-only group showed decreased bilateral nucleus accumbens (NAcc activation during reward anticipation as compared to the alcohol-only group, the control group, and both polysubstance groups. Interestingly, no differences emerged between the cannabis-only group and any of the other groups. Results from this study suggest that youth who tend toward single-substance tobacco use may possess behavioral and/or neurobiological characteristics that differentiate them from both their substance-using and non-substance-using peers.

  16. Does incentive-elicited nucleus accumbens activation differ by substance of abuse? An examination with adolescents.

    Science.gov (United States)

    Karoly, Hollis C; Bryan, Angela D; Weiland, Barbara J; Mayer, Andrew; Dodd, Andrew; Feldstein Ewing, Sarah W

    2015-12-01

    Numerous questions surround the nature of reward processing in the developing adolescent brain, particularly in regard to polysubstance use. We therefore sought to examine incentive-elicited brain activation in the context of three common substances of abuse (cannabis, tobacco, and alcohol). Due to the role of the nucleus accumbens (NAcc) in incentive processing, we compared activation in this region during anticipation of reward and loss using a monetary incentive delay (MID) task. Adolescents (ages 14-18; 66% male) were matched on age, gender, and frequency of use of any common substances within six distinct groups: cannabis-only (n=14), tobacco-only (n=34), alcohol-only (n=12), cannabis+tobacco (n=17), cannabis+tobacco+alcohol (n=17), and non-using controls (n=38). All groups showed comparable behavioral performance on the MID task. The tobacco-only group showed decreased bilateral nucleus accumbens (NAcc) activation during reward anticipation as compared to the alcohol-only group, the control group, and both polysubstance groups. Interestingly, no differences emerged between the cannabis-only group and any of the other groups. Results from this study suggest that youth who tend toward single-substance tobacco use may possess behavioral and/or neurobiological characteristics that differentiate them from both their substance-using and non-substance-using peers.

  17. Reduced dopamine function within the medial shell of the nucleus accumbens enhances latent inhibition.

    Science.gov (United States)

    Nelson, A J D; Thur, K E; Horsley, R R; Spicer, C; Marsden, C A; Cassaday, H J

    2011-03-01

    Latent inhibition (LI) manifests as poorer conditioning to a CS that has previously been presented without consequence. There is some evidence that LI can be potentiated by reduced mesoaccumbal dopamine (DA) function but the locus within the nucleus accumbens of this effect is as yet not firmly established. Experiment 1 tested whether 6-hydroxydopamine (6-OHDA)-induced lesions of DA terminals within the core and medial shell subregions of the nucleus accumbens (NAc) would enhance LI under conditions that normally disrupt LI in controls (weak pre-exposure). LI was measured in a thirst motivated conditioned emotional response procedure with 10 pre-exposures (to a noise CS) and 2 conditioning trials. The vehicle-injected and core-lesioned animals did not show LI and conditioned to the pre-exposed CS at comparable levels to the non-pre-exposed controls. 6-OHDA lesions to the medial shell, however, produced potentiation of LI, demonstrated across two extinction tests. In a subsequent experiment, haloperidol microinjected into the medial shell prior to conditioning similarly enhanced LI. These results underscore the dissociable roles of core and shell subregions of the NAc in mediating the expression of LI and indicate that reduced DA function within the medial shell leads to enhanced LI.

  18. Regulation of /sup 3/H-dopamine release by presynaptic GABA and glutamate heteroreceptors in rat brain nucleus accumbens synaptosomes

    Energy Technology Data Exchange (ETDEWEB)

    Kovalev, G.I.; Hetey, L.

    1987-06-01

    The aim of this investigation was a neurochemical study of the effect of agonists of different types of GABA receptors - muscimol (type A receptor), baclofen (type B receptor), delta-aminolevulinic acid (DALA; GABA autoreceptor), and also of GABA itself - on tritium-labelled dopamine release, stimulated by potassium cations, from synaptosomes of the nuclei accumbenes of the rat brain.

  19. Elevated [(18)F]FDOPA utilization in the periaqueductal gray and medial nucleus accumbens of patients with early Parkinson's disease

    DEFF Research Database (Denmark)

    Kumakura, Yoshitaka; Danielsen, Erik H; Gjedde, Albert;

    2009-01-01

    %) in the bilateral medial nucleus accumbens, whereas the expected declines in the trapping of FDOPA were seen in the caudate and putamen. This observation suggests hyperfunction of catecholamine fibres innervating specifically the limbic striatum, which could guide the design of future prospective FDOPA-PET studies...

  20. Nucleus accumbens response to gains in reputation for the self relative to gains for others predicts social media use.

    Science.gov (United States)

    Meshi, Dar; Morawetz, Carmen; Heekeren, Hauke R

    2013-01-01

    Our reputation is important to us; we've experienced natural selection to care about our reputation. Recently, the neural processing of gains in reputation (positive social feedback concerning one's character) has been shown to occur in the human ventral striatum. It is still unclear, however, how individual differences in the processing of gains in reputation may lead to individual differences in real-world behavior. For example, in the real-world, one way that people currently maintain their reputation is by using social media websites, like Facebook. Furthermore, Facebook use consists of a social comparison component, where users observe others' behavior and can compare it to their own. Therefore, we hypothesized a relationship between the way the brain processes specifically self-relevant gains in reputation and one's degree of Facebook use. We recorded functional neuroimaging data while participants received gains in reputation, observed the gains in reputation of another person, or received monetary reward. We demonstrate that across participants, when responding to gains in reputation for the self, relative to observing gains for others, reward-related activity in the left nucleus accumbens predicts Facebook use. However, nucleus accumbens activity in response to monetary reward did not predict Facebook use. Finally, a control step-wise regression analysis showed that Facebook use primarily explains our results in the nucleus accumbens. Overall, our results demonstrate how individual sensitivity of the nucleus accumbens to the receipt of self-relevant social information leads to differences in real-world behavior.

  1. Role of mu- and delta-opioid receptors in the nucleus accumbens in turning behaviour of rats.

    NARCIS (Netherlands)

    Matsuzaki, S.; Ikeda, H.; Akiyama, G.; Sato, M.; Moribe, S.; Suzuki, T.; Nagase, H.; Cools, A.R.; Koshikawa, N.

    2004-01-01

    The role of mu-, delta1- and delta2-opioid receptors in the nucleus accumbens in pivoting was investigated in freely moving rats. Unilateral injections of the mu-opioid receptor agonist, [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO, 1 and 2 microg) and the delta2-opioid receptor agonist, deltorphin

  2. Interactions between Brainstem Noradrenergic Neurons and the Nucleus Accumbens Shell in Modulating Memory for Emotionally Arousing Events

    Science.gov (United States)

    Kerfoot, Erin C.; Williams, Cedric L.

    2011-01-01

    The nucleus accumbens shell (NAC) receives axons containing dopamine-[beta]-hydroxylase that originate from brainstem neurons in the nucleus of the solitary tract (NTS). Recent findings show that memory enhancement produced by stimulating NTS neurons after learning may involve interactions with the NAC. However, it is unclear whether these…

  3. Effects of amphetamine on dopamine release in the rat nucleus accumbens shell region depend on cannabinoid CB1 receptor activation

    NARCIS (Netherlands)

    Kleijn, J.; Wiskerke, J.; Cremers, T. I. F. H.; Schoffelmeer, A. N. M.; Westerink, B. H. C.; Pattij, T.

    2012-01-01

    The psychostimulant drug amphetamine is often prescribed to treat Attention-Deficit/Hyperactivity Disorder. The behavioral effects of the psychostimulant drug amphetamine depend on its ability to increase monoamine neurotransmission in brain regions such as the nucleus accumbens (NAC) and medial pre

  4. The hypomotility elicited by small doses of apomorphine seems exclusively mediated by dopaminergic systems in the nucleus accumbens

    NARCIS (Netherlands)

    Radhakishun, F.S.; Ree, J.M. van

    1987-01-01

    The reduction of motor activity elicited in rats by a subcutaneous injection of a small dose of apomorphine was reversed by pretreatment of the nucleus accumbens with haloperidol (10 pg), sulpride (10 pg) or desenkephalin-γ-endorphin (DEγE) (100 pg or 10 ng). These doses of the compounds did not

  5. The nucleus accumbens shell and the dorsolateral striatum mediate the reinforcing effects of cocaine through a serial connection

    NARCIS (Netherlands)

    Veeneman, Maartje M J; Damsteegt, Ruth; Vanderschuren, Louk J M J

    The reinforcing and addictive properties of cocaine are thought to rely on the dopaminergic innervation of the striatum. The ventromedial [i.e. nucleus accumbens shell (NAcc) shell] and dorsolateral [dorsolateral striatum (DLS)] regions of the striatum are serially connected, and it is thought that

  6. The Role of Nucleus Accumbens Shell in Learning about Neutral versus Excitatory Stimuli during Pavlovian Fear Conditioning

    Science.gov (United States)

    Bradfield, Laura A.; McNally, Gavan P.

    2010-01-01

    We studied the role of nucleus accumbens shell (AcbSh) in Pavlovian fear conditioning. Rats were trained to fear conditioned stimulus A (CSA) in Stage I, which was then presented in compound with a neutral stimulus and paired with shock in Stage II. AcbSh lesions had no effect on fear-learning to CSA in Stage I, but selectively prevented learning…

  7. Successful deep brain stimulation of the nucleus accumbens in severe alcohol dependence is associated with changed performance monitoring

    NARCIS (Netherlands)

    Kuhn, J.; Gründler, T.O.J.; Bauer, R.; Huff, W.; Fischer, A.G.; Lenartz, D.; Maarouf, M.; Bührle, C.; Klosterkötter, J.; Ullsperger, M.; Sturm, V.

    2011-01-01

    Following recent advances in neuromodulation therapy for mental disorders, we treated one patient with severe alcohol addiction with deep brain stimulation (DBS) of the nucleus accumbens (NAc). Before and one year following the surgery, we assessed the effects of DBS within the NAc on the addiction

  8. Interactions between Brainstem Noradrenergic Neurons and the Nucleus Accumbens Shell in Modulating Memory for Emotionally Arousing Events

    Science.gov (United States)

    Kerfoot, Erin C.; Williams, Cedric L.

    2011-01-01

    The nucleus accumbens shell (NAC) receives axons containing dopamine-[beta]-hydroxylase that originate from brainstem neurons in the nucleus of the solitary tract (NTS). Recent findings show that memory enhancement produced by stimulating NTS neurons after learning may involve interactions with the NAC. However, it is unclear whether these…

  9. Successful deep brain stimulation of the nucleus accumbens in severe alcohol dependence is associated with changed performance monitoring

    NARCIS (Netherlands)

    Kuhn, J.; Gründler, T.O.J.; Bauer, R.; Huff, W.; Fischer, A.G.; Lenartz, D.; Maarouf, M.; Bührle, C.; Klosterkötter, J.; Ullsperger, M.; Sturm, V.

    2011-01-01

    Following recent advances in neuromodulation therapy for mental disorders, we treated one patient with severe alcohol addiction with deep brain stimulation (DBS) of the nucleus accumbens (NAc). Before and one year following the surgery, we assessed the effects of DBS within the NAc on the addiction

  10. Dopamine D1 receptor modulation in nucleus accumbens lowers voluntary wheel running in rats bred to run high distances.

    Science.gov (United States)

    Roberts, Michael D; Gilpin, Leigh; Parker, Kyle E; Childs, Thomas E; Will, Matthew J; Booth, Frank W

    2012-02-01

    Dopamine signaling in the nucleus accumbens (NAc) has been postulated to influence reward development towards drugs of abuse and exercise. Herein, we used generation 4-5 rats that were selectively bred to voluntary run high (HVR) versus low (LVR) distances in order to examine if dopamine-like 1 (D1) receptor modulation in the NAc differentially affects nightly voluntary wheel running between these lines. A subset of generation 5-6 HVR and LVR rats were also used to study the mRNA expression of key genes related to reward and addiction in the NAc (i.e., DRD1, DRD5, DRD2, Nr4a2, FosB, and BDNF). In a crossover fashion, a D1-like agonist SKF 82958 (2 μg per side) or D1-like full antagonist SCH 23390 (4 μg per side) was bilaterally injected into the NAc of HVR and LVR female Wistar rats prior to their high running nights. Notably, during hours 2-4 (between 2000 and 2300) of the dark cycle there was a significant decrement in running distances in the HVR rats treated with the D1 agonist (p=0.025) and antagonist (p=0.017) whereas the running distances in LVR rats were not affected. Interestingly, HVR and LVR rats possessed similar NAc concentrations of the studied mRNAs. These data suggest that: a) animals predisposed to run high distances on a nightly basis may quickly develop a rewarding response to exercise due to an optimal D1-like receptor signaling pathway in the NAc that can be perturbed by either activation or blocking, b) D1-like agonist or antagonist injections do not increase running distances in rats that are bred to run low nightly distances, and c) running differences between HVR and LVR animals are seemingly not due to the expression of the studied mRNAs. Given the societal prevalence of obesity and extraneous physical inactivity, future studies should be performed in order to further determine the culprit for the low running phenotype observed in LVR animals.

  11. Rat nucleus accumbens core astrocytes modulate reward and the motivation to self-administer ethanol after abstinence.

    Science.gov (United States)

    Bull, Cecilia; Freitas, Kelen C C; Zou, Shiping; Poland, Ryan S; Syed, Wahab A; Urban, Daniel J; Minter, Sabrina C; Shelton, Keith L; Hauser, Kurt F; Negus, S Stevens; Knapp, Pamela E; Bowers, M Scott

    2014-11-01

    Our understanding of the active role that astrocytes play in modulating neuronal function and behavior is rapidly expanding, but little is known about the role that astrocytes may play in drug-seeking behavior for commonly abused substances. Given that the nucleus accumbens is critically involved in substance abuse and motivation, we sought to determine whether nucleus accumbens astrocytes influence the motivation to self-administer ethanol following abstinence. We found that the packing density of astrocytes that were expressing glial fibrillary acidic protein increased in the nucleus accumbens core (NAcore) during abstinence from EtOH self-administration. No change was observed in the nucleus accumbens shell. This increased NAcore astrocyte density positively correlated with the motivation for ethanol. Astrocytes can communicate with one another and influence neuronal activity through gap-junction hemichannels. Because of this, the effect of blocking gap-junction hemichannels on the motivation for ethanol was examined. The motivation to self-administer ethanol after 3 weeks abstinence was increased following microinjection of gap-junction hemichannel blockers into the NAcore at doses that block both neuronal and astrocytic channels. In contrast, no effect was observed following microinjection of doses that are not thought to block astrocytic channels or following microinjection of either dose into the nucleus accumbens shell. Additionally, the motivation for sucrose after 3 weeks abstinence was unaffected by NAcore gap-junction hemichannel blockers. Next, Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) were selectively expressed in NAcore astrocytes to test the effect of astrocyte stimulation. DREADD activation increased cytosolic calcium in primary astrocytes, facilitated responding for rewarding brain stimulation, and reduced the motivation for ethanol after 3 weeks abstinence. This is the first work to modulate drug-seeking behavior with

  12. The behavioral neurochemistry of motivation: methodological and conceptual issues in studies of the dynamic activity of nucleus accumbens dopamine.

    Science.gov (United States)

    Salamone, J D

    1996-02-01

    Considerable experimental and clinical evidence links forebrain dopamine (DA) systems to the performance of motor activities and to motivational processes. Much of the support for this conclusion was obtained from studies utilizing lesions or drugs to manipulate aspects of central dopaminergic function. Although such experiments yield important information concerning the behavioral consequences of interference with DA systems in brain, they do not demonstrate any relation between the dynamic activity of DA neurons and the level or type of motor function exhibited by the organism. This review discusses the emerging field of behavioral neurochemistry, and provides an overview of recent studies investigating the relation between nucleus accumbens DA release and behavior. Particular emphasis is placed upon current research involving microdialysis, voltammetry and electrophysiology. These different methods are viewed as complementary techniques for investigating the activity of DA systems in behaving animals. Evidence indicates that DA activity is most reliably activated by stimuli that trigger instrumental behavior and during the preparatory or instrumental phase of motivated behavior. The effects of consummatory reactions to positive reinforcers are somewhat equivocal; with food consumption, dialysis studies have yielded inconsistent results, while some voltammetric and electrophysiological studies have shown that DA activity in accumbens or ventral tegmental area actually decreases during consumption of food reinforcement. Moreover, the responsiveness of accumbens DA activity during behavioral stimulation is not unique to appetitive conditions, as several studies have shown that aversive or stressful conditions also stimulate accumbens DA release or metabolism. It is reasonable to suggest at this time that accumbens DA neurons are activated by a variety of different motivational conditions, but that the consequence of that activation is to modulate the behavioral

  13. Dual effects of limbic seizures on psychosis-relevant behaviors shown by nucleus accumbens kindling in rats

    Science.gov (United States)

    Ma, Jingyi; Leung, L. Stan

    2016-01-01

    Background A paradox in epilepsy and psychiatry is that temporal lobe epilepsy is often predisposed to schizophrenic-like psychosis, whereas convulsive therapy can relieve schizophrenic symptoms. We have previously demonstrated that the nucleus accumbens is a key structure in mediating postictal psychosis induced by a hippocampal electrographic seizure. Objective/Hypothesis The purpose of this study is to test a hypothesis that accumbens kindling cumulating in a single (1-time) or repeated (5-times) convulsive seizures have different effects on animal models of psychosis. Methods Electrical stimulation at 60 Hz was applied to nucleus accumbens to evoke afterdischarges until one, or five, convulsive seizures that involved the hind limbs (stage 5 seizures) were attained. Behavioral tests, performed at 3 days after the last seizure, included gating of hippocampal auditory evoked potentials (AEP) and prepulse inhibition to an acoustic startle response (PPI), tested without drug injection or after ketamine (3 mg/kg s.c.) injection, as well as locomotion induced by ketamine or methamphetamine (1 mg/kg i.p.). Results Compared to non-kindled control rats, 1-time, but not 5-times, convulsive seizures induced PPI deficit and decreased gating of hippocampal AEP, without drug injection. Compared to non-kindled rats, 5-times, but not 1-time, convulsive seizures antagonized ketamine-induced hyperlocomotion, ketamine-induced PPI deficit and AEP gating decrease. However, both 1- and 5-times convulsive seizures, significantly enhanced methamphetamine-induced locomotion as compared to non-kindled rats. Conclusions Accumbens kindling ending with 1 convulsive seizure may induce schizophrenic-like behaviors, while repeated (≥ 5) convulsive seizures induced by accumbens kindling may have therapeutic effects on dopamine independent psychosis. PMID:27267861

  14. Activin receptor signaling regulates cocaine-primed behavioral and morphological plasticity.

    Science.gov (United States)

    Gancarz, Amy M; Wang, Zi-Jun; Schroeder, Gabrielle L; Damez-Werno, Diane; Braunscheidel, Kevin M; Mueller, Lauren E; Humby, Monica S; Caccamise, Aaron; Martin, Jennifer A; Dietz, Karen C; Neve, Rachael L; Dietz, David M

    2015-07-01

    Activin receptor signaling, including the transcription factor Smad3, was upregulated in the rat nucleus accumbens (NAc) shell following withdrawal from cocaine. Direct genetic and pharmacological manipulations of this pathway bidirectionally altered cocaine seeking while governing morphological plasticity in NAc neurons. Thus, Activin/Smad3 signaling is induced following withdrawal from cocaine, and such regulation may be a key molecular mechanism underlying behavioral and cellular plasticity in the brain following cocaine self-administration.

  15. Cafeteria diet induces neuroplastic modifications in the nucleus accumbens mediated by microglia activation.

    Science.gov (United States)

    Gutiérrez-Martos, Miriam; Girard, Benoit; Mendonça-Netto, Sueli; Perroy, Julie; Valjent, Emmanuel; Maldonado, Rafael; Martin, Miquel

    2017-09-05

    High-palatable and caloric foods are widely overconsumed due to hedonic mechanisms that prevail over caloric necessities leading to overeating and overweight. The nucleus accumbens (NAc) is a key brain area modulating the reinforcing effects of palatable foods and is crucially involved in the development of eating disorders. We describe that prolonged exposure to high-caloric chocolate cafeteria diet leads to overeating and overweight in mice. NAc functionality was altered in these mice, presenting structural plasticity modifications in medium spiny neurons, increased expression of neuroinflammatory factors and activated microglia, and abnormal responses after amphetamine-induced hyperlocomotion. Chronic inactivation of microglia normalized these neurobiological and behavioural alterations exclusively in mice exposed to cafeteria diet. Our data suggest that prolonged exposure to cafeteria diet produces neuroplastic and functional changes in the NAc that can modify feeding behaviour. Microglia activation and neuroinflammation play an important role in the development of these neurobiological alterations. © 2017 Society for the Study of Addiction.

  16. Mefloquine in the nucleus accumbens promotes social avoidance and anxiety-like behavior in mice.

    Science.gov (United States)

    Heshmati, Mitra; Golden, Sam A; Pfau, Madeline L; Christoffel, Daniel J; Seeley, Elena L; Cahill, Michael E; Khibnik, Lena A; Russo, Scott J

    2016-02-01

    Mefloquine continues to be a key drug used for malaria chemoprophylaxis and treatment, despite reports of adverse events like depression and anxiety. It is unknown how mefloquine acts within the central nervous system to cause depression and anxiety or why some individuals are more vulnerable. We show that intraperitoneal injection of mefloquine in mice, when coupled to subthreshold social defeat stress, is sufficient to produce depression-like social avoidance behavior. Direct infusion of mefloquine into the nucleus accumbens (NAc), a key brain reward region, increased stress-induced social avoidance and anxiety behavior. In contrast, infusion into the ventral hippocampus had no effect. Whole cell recordings from NAc medium spiny neurons indicated that mefloquine application increases the frequency of spontaneous excitatory postsynaptic currents, a synaptic adaptation that we have previously shown to be associated with increased susceptibility to social defeat stress. Together, these data demonstrate a role for the NAc in mefloquine-induced depression and anxiety-like behaviors.

  17. Activation of D2 dopamine receptor-expressing neurons in the nucleus accumbens increases motivation.

    Science.gov (United States)

    Soares-Cunha, Carina; Coimbra, Barbara; David-Pereira, Ana; Borges, Sonia; Pinto, Luisa; Costa, Patricio; Sousa, Nuno; Rodrigues, Ana J

    2016-06-23

    Striatal dopamine receptor D1-expressing neurons have been classically associated with positive reinforcement and reward, whereas D2 neurons are associated with negative reinforcement and aversion. Here we demonstrate that the pattern of activation of D1 and D2 neurons in the nucleus accumbens (NAc) predicts motivational drive, and that optogenetic activation of either neuronal population enhances motivation in mice. Using a different approach in rats, we further show that activating NAc D2 neurons increases cue-induced motivational drive in control animals and in a model that presents anhedonia and motivational deficits; conversely, optogenetic inhibition of D2 neurons decreases motivation. Our results suggest that the classic view of D1-D2 functional antagonism does not hold true for all dimensions of reward-related behaviours, and that D2 neurons may play a more prominent pro-motivation role than originally anticipated.

  18. A Primary Role for Nucleus Accumbens and Related Limbic Network in Vocal Tics.

    Science.gov (United States)

    McCairn, Kevin W; Nagai, Yuji; Hori, Yukiko; Ninomiya, Taihei; Kikuchi, Erika; Lee, Ju-Young; Suhara, Tetsuya; Iriki, Atsushi; Minamimoto, Takafumi; Takada, Masahiko; Isoda, Masaki; Matsumoto, Masayuki

    2016-01-20

    Inappropriate vocal expressions, e.g., vocal tics in Tourette syndrome, severely impact quality of life. Neural mechanisms underlying vocal tics remain unexplored because no established animal model representing the condition exists. We report that unilateral disinhibition of the nucleus accumbens (NAc) generates vocal tics in monkeys. Whole-brain PET imaging identified prominent, bilateral limbic cortico-subcortical activation. Local field potentials (LFPs) developed abnormal spikes in the NAc and the anterior cingulate cortex (ACC). Vocalization could occur without obvious LFP spikes, however, when phase-phase coupling of alpha oscillations were accentuated between the NAc, ACC, and the primary motor cortex. These findings contrasted with myoclonic motor tics induced by disinhibition of the dorsolateral putamen, where PET activity was confined to the ipsilateral sensorimotor system and LFP spikes always preceded motor tics. We propose that vocal tics emerge as a consequence of dysrhythmic alpha coupling between critical nodes in the limbic and motor networks. VIDEO ABSTRACT.

  19. Cocaine exposure reorganizes cell type- and input-specific connectivity in the nucleus accumbens.

    Science.gov (United States)

    MacAskill, Andrew F; Cassel, John M; Carter, Adam G

    2014-09-01

    Repeated exposure to cocaine alters the structural and functional properties of medium spiny neurons (MSNs) in the nucleus accumbens (NAc). These changes suggest a rewiring of the NAc circuit, with an enhancement of excitatory synaptic connections onto MSNs. However, it is unknown how drug exposure alters the balance of long-range afferents onto different cell types in the NAc. Here we used whole-cell recordings, two-photon microscopy, optogenetics and pharmacogenetics to show how repeated cocaine exposure alters connectivity in the mouse NAc medial shell. Cocaine selectively enhanced amygdala innervation of MSNs expressing D1 dopamine receptors (D1-MSNs) relative to D2-MSNs. We also found that amygdala activity was required for cocaine-induced changes to behavior and connectivity. Finally, we established how heightened amygdala innervation can explain the structural and functional changes evoked by cocaine. Our findings reveal how exposure to drugs of abuse fundamentally reorganizes cell type- and input-specific connectivity in the NAc.

  20. Relief learning is dependent on NMDA receptor activation in the nucleus accumbens

    Science.gov (United States)

    Mohammadi, Milad; Fendt, Markus

    2015-01-01

    Background and Purpose Recently, we demonstrated that the nucleus accumbens (NAC) is required for the acquisition and expression of relief memory. The purpose of this study was to investigate the role of NMDA receptors within the NAC in relief learning. Experimental Approach The NMDA receptor antagonist 2-amino-5-phosphonopentanoic acid (AP-5) was injected into the NAC. The effects of these injections on the acquisition and expression of relief memory, as well as on the reactivity to aversive electric stimuli, were tested. Key Results Intra-accumbal AP-5 injections blocked the acquisition but not the expression of relief memory. Furthermore, reactivity to aversive electric stimuli was not affected by the AP-5 injections. Conclusion and Implication The present data indicate that NMDA-dependent plasticity within the NAC is crucial for the acquisition of relief memory. PMID:25572550

  1. Nitric oxide in the nucleus accumbens is involved in retrieval of inhibitory avoidance memory by nicotine.

    Science.gov (United States)

    Zarrindast, Mohammad Reza; Piri, Morteza; Nasehi, Mohammad; Ebrahimi-Ghiri, Mohaddeseh

    2012-03-01

    In the present study, the possible effect of nitric oxide agents injected into the nucleus accumbens (NAc) in the presence or absence of nicotine on morphine state-dependent memory in adult male Wistar rats was investigated. As a model of memory, a step-through type inhibitory avoidance task was used. Post-training injection of morphine (4 and 6mg/kg) dose dependently induced the impairment of memory retention. Administration of morphine (4 and 6mg/kg) before retention induced state-dependent retrieval of the memory acquired under post-training morphine (6mg/kg) influence. Injection of nicotine before retention (0.25 and 0.5mg/kg) alone and nicotine (0.1, 0.25 and 0.5mg/kg) plus an ineffective dose of morphine (2mg/kg) reversed the post-training morphine-induced memory impairment. The amnesia elicited by morphine (6mg/kg) was also prevented by pre-retention intra-NAc administration of a nitric oxide synthase (NOS) inhibitor, l-NAME (0.24μg/rat, intra-NAc). Interestingly, an ineffective dose of nicotine (0.1mg/kg) in combination with low doses of l-NAME (0.06 and 0.12μg/rat, intra-NAc) synergistically improved memory performance impaired by morphine given after training. It is important to note that intra-NAc administration of l-NAME before retention impaired memory retrieval by itself. In contrast, pre-retention administration of l-arginine, a nitric oxide (NO) precursor (0.25 and 0.5μg/rat, intra-NAc), which had no effect alone, prevented the nicotine reversal of morphine effect on memory. The results suggest a possible role for nitric oxide of nucleus accumbens in the improving effect of nicotine on the morphine-induced amnesia and morphine state-dependent memory.

  2. Task-related functional connectivity of nucleus accumbens in opiate drug addicts during physical detoxification: a cue-elicited task fMRI study%生理脱毒期阿片类药物依赖者线索诱发作业下伏隔核功能连接的fMRI研究

    Institute of Scientific and Technical Information of China (English)

    韩易; 傅先明; 钱若兵; 林彬; 袁季; 魏祥品; 牛朝诗; 汪业汉

    2014-01-01

    目的 探讨生理脱毒期阿片类药物依赖者线索诱发作业下与伏隔核存在异常功能连接的脑区及其在戒断复吸中的作用.方法 生理脱毒期阿片类药物依赖组和健康对照组各18例,在观看与阿片类药物依赖线索相关视频时进行功能磁共振成像扫描,分别选取左、右侧伏隔核为感兴趣区进行功能连接分析,确定与双侧伏隔核存在功能连接的脑区.结果 与健康对照组相比,生理脱毒期阿片类药物依赖组的伏隔核与前额叶(46,29,-9)、岛叶(31,25,-7)、后扣带回(4,-59,19)、楔前叶(4,-63,22)、枕叶(6,71,16)、舌回(11,-37,-8)和距状回(3,-45,7)的功能连接明显高于健康对照组,而与丘脑(-8,-13,2)、前扣带回(-2,44,20)功能连接明显低于健康对照组(P<0.05).结论 生理脱毒期阿片类药物依赖者线索诱导下的伏隔核存在功能异常,这可能是其容易复吸的重要原因之一.%Objective To explore the brain areas which have abnormal functional connectivity with nucleus accumbens in opiate drug addicts during physical detoxification nsing a cue-elicited task-related functional magnetic resonance imaging (fMRI),and to find out the role of nucleus accumbens dysfunction in the relapse of opiate drug dependence during physical detoxification.Methods Eighteen participants of opiate drug addicts during physical detoxification,and eighteen healthy controls performed a cue-elicited craving task in a MRI scanner while signal data were collected.The left and right nucleus accumbens were selected as regions of interest (ROIs) respectively,and calculated the linear correlation between the nucleus accumbens and the entire brain to find out the functional connectivity of the nucleus accumbens.Results Compared with the controls,the functional connectivity between the nucleus accumbens and the prefrontal cortex (46,29,-9),insula(3 1,25,-7),posterior cingutate (4,-59,19),precuneus(4,-63,22),occipital lobe(6,71,16),lingual

  3. The effects of GABAA and NMDA receptors in the shell-accumbens on spatial memory of METH-treated rats.

    Science.gov (United States)

    Heysieattalab, Soomaayeh; Naghdi, Nasser; Zarrindast, Mohammad-Reza; Haghparast, Abbas; Mehr, Shahram Ejtemaei; Khoshbouei, Habibeh

    2016-03-01

    Methamphetamine (METH) is a highly addictive and neurotoxic psychostimulant. Its use in humans is often associated with neurocognitive impairment and deficits in hippocampal plasticity. Striatal dopamine system is one of the main targets of METH. The dopamine neurons in the striatum directly or indirectly regulate the GABA and glutamatergic signaling in this region and thus their outputs. This is consistent with previous reports showing modification of neuronal activity in the striatum modulates the expression of hippocampal LTP and hippocampal-dependent memory tasks such as Morris water maze (MWM). Therefore, reversing or preventing METH-induced synaptic modifications via pharmacological manipulations of the shell-nucleus accumbens (shell-NAc) may introduce a viable therapeutic target to attenuate the METH-induced memory deficits. This study is designed to investigate the role of intra-shell NAc manipulation of GABAA and NMDA receptors and their interaction with METH on memory performance in MWM task. Pharmacological manipulations were performed in rats received METH or saline. We found systemic saline plus intra-shell NAc infusions of muscimol dose-dependently impaired performance, while bicuculline had no effect. Surprisingly, the intra-NAc infusions of 0.005μg/rat muscimol that has no effect on memory performance (ineffective dose) prevented METH-induced memory impairment. In the contrary, the intra-NAc infusions of bicuculline (0.2μg/rat) increased METH-induced memory impairment. However, pre-training intra-NAc infusions of D-AP5 dose-dependently impaired performance, while NMDA had no effect in rats received systemic saline (control group). The intra-NAc infusions with an ineffective dose of NMDA (0.1μg/rat) increased METH-induced memory impairment. Furthermore, intra-NAc infusions of D-AP5 with an ineffective dose (0.1μg/rat) prevented METH-induced memory impairment. Our result is consistent with the interpretation that METH-mediated learning deficit

  4. Prolonged nicotine exposure down-regulates presynaptic NMDA receptors in dopaminergic terminals of the rat nucleus accumbens.

    Science.gov (United States)

    Salamone, Alessia; Zappettini, Stefania; Grilli, Massimo; Olivero, Guendalina; Agostinho, Paula; Tomé, Angelo R; Chen, Jiayang; Pittaluga, Anna; Cunha, Rodrigo A; Marchi, Mario

    2014-04-01

    The presynaptic control of dopamine release in the nucleus accumbens (NAc) by glutamate and acetylcholine has a profound impact on reward signaling. Here we provide immunocytochemical and neurochemical evidence supporting the co-localization and functional interaction between nicotinic acetylcholine receptors (nAChRs) and N-methyl-D-aspartic acid (NMDA) receptors in dopaminergic terminals of the NAc. Most NAc dopaminergic terminals possessed the nAChR α4 subunit and the pre-exposure of synaptosomes to nicotine (30 μM) or to the α4β2-containing nAChR agonist 5IA85380 (10 nM) selectively inhibited the NMDA (100 μM)-evoked, but not the 4-aminopyridine (10 μM)-evoked, [(3)H] dopamine outflow; this inhibition was blunted by mecamylamine (10 μM). Nicotine and 5IA85380 pretreatment also inhibited the NMDA (100 μM)-evoked increase of calcium levels in single nerve terminals, an effect prevented by dihydro-β-erythroidine (1 μM). This supports a functional interaction between α4β2-containing nAChR and NMDA receptors within the same terminal, as supported by the immunocytochemical co-localization of α4 and GluN1 subunits in individual NAc dopaminergic terminals. The NMDA-evoked [(3)H]dopamine outflow was blocked by MK801 (1 μM) and inhibited by the selective GluN2B-selective antagonists ifenprodil (1 μM) and RO 25-6981 (1 μM), but not by the GluN2A-preferring antagonists CPP-19755 (1 μM) and ZnCl2 (1 nM). Notably, nicotine pretreatment significantly decreased the density of biotin-tagged GluN2B proteins in NAc synaptosomes. These results show that nAChRs dynamically and negatively regulate NMDA receptors in NAc dopaminergic terminals through the internalization of GluN2B receptors.

  5. Calcium-permeable AMPA receptors in the VTA and nucleus accumbens after cocaine exposure: When, how and why?

    Directory of Open Access Journals (Sweden)

    Marina E Wolf

    2012-06-01

    Full Text Available In animal models of drug addiction, cocaine exposure has been shown to increase levels of calcium-permeable AMPA receptors (CP-AMPARs in two brain regions that are critical for motivation and reward - the ventral tegmental area (VTA and the nucleus accumbens (NAc. This review compares CP-AMPAR plasticity in the two brain regions and addresses its functional significance. In VTA dopamine neurons, cocaine exposure results in synaptic insertion of high conductance CP-AMPARs in exchange for lower conductance calcium-impermeable AMPARs (CI-AMPARs. This plasticity is rapid (hours, GluA2-dependent, and can be observed with a single cocaine injection. In addition to strengthening synapses and altering Ca2+ signaling, CP-AMPAR insertion affects subsequent induction of plasticity at VTA synapses. However, CP-AMPAR insertion is unlikely to mediate the increased dopamine cell activity that occurs during early withdrawal from cocaine exposure. Within the VTA, the group I metabotropic glutamate receptor mGluR1 exerts a negative influence on CP-AMPAR accumulation. Acutely, mGluR1 stimulation elicits a form of LTD resulting from CP-AMPAR removal and CI-AMPAR insertion. In medium spiny neurons (MSNs of the NAc, extended access cocaine self-administration is required to increase CP-AMPAR levels. This is first detected after approximately a month of withdrawal and then persists. Once present in NAc synapses, CP-AMPARs mediate the expression of incubation of cue-induced cocaine craving. The mechanism of their accumulation may be GluA1-dependent, which differs from that observed in the VTA. However, similar to VTA, mGluR1 stimulation removes CP-AMPARs from MSN synapses. Loss of mGluR1 tone during cocaine withdrawal may contribute to CP-AMPAR accumulation in the NAc. Thus, results in both brain regions point to the possibility of using positive modulators of mGluR1 as a treatment for cocaine addiction.

  6. Selective serotonin receptor stimulation of the medial nucleus accumbens causes differential effects on food intake and locomotion.

    Science.gov (United States)

    Pratt, Wayne E; Blackstone, Kaitlin; Connolly, Megan E; Skelly, Mary Jane

    2009-10-01

    Substantial evidence suggests that pharmacological manipulations of neural serotonin pathways influence ingestive behaviors. Despite the known role of the nucleus accumbens in directing appetitive and consummatory behavior, there has been little examination of the influences that serotonin receptors may play in modulating feeding within nucleus accumbens circuitry. In these experiments, the authors examined the effects of bilateral nucleus accumbens infusions of the 5-HT1/7 receptor agonist 5-CT (at 0.0, 0.5, 1.0, or 4.0 microg/0.5 microl/side), the 5-HT receptor agonist EMD 386088 (at 0.0, 1.0, and 4.0 microg/0.5 microl/side), or the 5-HT2C preferential agonist RO 60-0175 (at 0.0, 2.0, or 5.0 microg/0.5 microl/side) on food intake and locomotor activity in the rat. Intra-accumbens infusions of 5-CT caused a dose-dependent reduction of food intake and rearing behavior, both in food-restricted animals given 2-hr free access to Purina Protab RMH 3000 Chow, as well as in nondeprived rats offered 2-hr access to a highly palatable fat/sucrose diet. In contrast, stimulation of 5-HT receptors with EMD 386088 caused a dose-dependent increase of intake under both feeding conditions, without affecting measures of locomotion. Infusions of the moderately selective 5-HT2C receptor agonist RO 60-0175 had no effects on feeding or locomotor measures in food-restricted animals, but did reduce intake of the fat/sucrose in nonrestricted animals at the 2.0 microg, but not the 5.0 microg dose. Intra-accumbens infusions of selective antagonists for the 5-HT (SB 269970), 5-HT (SB 252585), and 5-HT2C (RS 102221) receptors did not affect locomotion, and demonstrated no lasting changes in feeding for any of the groups tested. These data are the first to suggest that the activation of different serotonin receptor subtypes within the feeding circuitry of the medial nucleus accumbens differentially influence consummatory behavior.

  7. Nucleus accumbens dopamine and mu-opioid receptors modulate the reinstatement of food-seeking behavior by food-associated cues.

    Science.gov (United States)

    Guy, Elizabeth G; Choi, Eugene; Pratt, Wayne E

    2011-06-01

    The high attrition rates for dietary interventions aimed at promoting a healthier body mass may be caused, at least in part, by constant exposure to environmental stimuli that are associated with palatable foods. In both humans and animals, conditioned stimuli (CSs) that signal reward availability reliably reinstate food- and drug-seeking behaviors. The nucleus accumbens (NAcc) is critically involved in the cue-evoked reinstatement of food-seeking, but the role of individual neurotransmitter systems within the NAcc remains to be determined. These experiments tested the effects of intra-accumbal pharmacological manipulations of dopamine (DA) D(1) and D(2) receptors, mu-opioid receptors, or serotonin (5-HT) receptors on cue-evoked relapse to food-seeking. Rats were trained to lever press for sucrose pellets and the concurrent presentation of a light-tone CS. Once training was complete, lever-pressing was extinguished in the absence of either sucrose or CS presentation. Once each rat had reached extinction criterion, they received two reinstatement sessions in which lever pressing was renewed by response-contingent presentation of the CS. Prior to each reinstatement test, rats received NAcc microinfusions of saline or the selective D(1) receptor antagonist SCH 23390, the D(2) receptor antagonist raclopride, the mu-opioid receptor agonist [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO), or 5-HT hydrogen maleate. Compared to saline test days, intra-accumbens infusions of SCH 23390 (1 μg/0.5 μL), raclopride (1 μg/0.5 μL), or DAMGO (0.25 μg/0.5 μL) effectively blocked the cue-evoked reinstatement of food-seeking. In contrast, stimulation of serotonin (5-HT) receptors by 5-HT hydrogen maleate (5 μg/0.5 μL) had no effect on cue-induced reinstatement. These novel data support roles for NAcc DA D(1), D(2), and mu-opioid receptors in the cue-evoked reinstatement of food seeking.

  8. Galanin-induced decreases in nucleus accumbens/striatum excitatory postsynaptic potentials and morphine conditioned place preference require both galanin receptor 1 and galanin receptor 2.

    Science.gov (United States)

    Einstein, Emily B; Asaka, Yukiko; Yeckel, Mark F; Higley, Michael J; Picciotto, Marina R

    2013-05-01

    The neuropeptide galanin has been shown to alter the rewarding properties of morphine. To identify potential cellular mechanisms that might be involved in the ability of galanin to modulate opiate reward, we measured excitatory postsynaptic potentials (EPSPs), using both field and whole-cell recordings from striatal brain slices extracted from wild-type mice and mice lacking specific galanin receptor (GalR) subtypes. We found that galanin decreased the amplitude of EPSPs in both the dorsal striatum and nucleus accumbens. We then performed recordings in slices from knockout mice lacking either the GalR1 or GalR2 gene, and found that the ability of galanin to decrease EPSP amplitude was absent from both mouse lines, suggesting that both receptor subtypes are required for this effect. In order to determine whether behavioral responses to opiates were dependent on the same receptor subtypes, we tested GalR1 and GalR2 knockout mice for morphine conditioned place preference (CPP). Morphine CPP was significantly attenuated in both GalR1 and GalR2 knockout mice. These data suggest that mesolimbic excitatory signaling is significantly modulated by galanin in a GalR1-dependent and GalR2-dependent manner, and that morphine CPP is dependent on the same receptor subtypes.

  9. Galanin-induced decreases in nucleus accumbens/striatum EPSPs and morphine conditioned place preference require both GalR1 and GalR2

    Science.gov (United States)

    Einstein, Emily B.; Asaka, Yukiko; Yeckel, Mark F.; Higley, Michael J.; Picciotto, Marina R.

    2013-01-01

    The neuropeptide galanin has been shown to alter the rewarding properties of morphine. To identify potential cellular mechanisms that might be involved in the ability of galanin to modulate opiate reward, we measured excitatory post-synaptic potentials (EPSPs) using both field and whole-cell recordings from striatal brain slices extracted from wild type mice and mice lacking specific galanin receptor (GalR) subtypes. We found that galanin decreases the amplitude of EPSPs in both the dorsal striatum and nucleus accumbens. We then performed recordings in slices from knockout mice lacking either the GalR1 or GalR2 gene and found that the ability of galanin to decrease EPSP amplitude was absent from both mouse lines, suggesting that both receptor subtypes are required for this effect. In order to determine whether behavioral responses to opiates were dependent on the same receptor subtypes, we tested GalR1 and GalR2 mice for morphine conditioned place preference (CPP). Morphine CPP was significantly attenuated in both GalR1 and GalR2 knockout mice. These data suggest that mesolimbic excitatory signaling is significantly modulated by galanin in a GalR1- and GalR2-dependent manner and that morphine CPP is dependent on the same receptor subtypes. PMID:23387435

  10. Differential dopamine release dynamics in the nucleus accumbens core and shell track distinct aspects of goal-directed behavior for sucrose.

    Science.gov (United States)

    Cacciapaglia, Fabio; Saddoris, Michael P; Wightman, R Mark; Carelli, Regina M

    2012-04-01

    Mesolimbic dopamine projections to the nucleus accumbens (NAc) have been implicated in goal-directed behaviors for natural rewards and in learning processes involving cue-reward associations. The NAc has been traditionally subdivided into two anatomically distinct sub-regions with different functional properties: the shell and the core. The aim of the present study was to characterize rapid dopamine transmission across the two NAc sub-regions during cue-signaled operant behavior for a natural (sucrose) reward in rats. Using fast-scan cyclic voltammetry (FSCV) we observed differences in the magnitude and dynamics of dopamine release events between the shell and core. Specifically, although cue-evoked dopamine release was observed in both sub-regions, it was larger and longer lasting in the shell compared with the core. Further, secondary dopamine release events were observed following the lever press response for sucrose in the NAc shell, but not the core. These findings demonstrate that the NAc displays regional specificity in dopamine transmission patterns during cued operant behavior for natural reward.

  11. Moderate intensity treadmill exercise alters food preference via dopaminergic plasticity of ventral tegmental area-nucleus accumbens in obese mice.

    Science.gov (United States)

    Chen, Wei; Wang, Hai Jun; Shang, Ning Ning; Liu, Jun; Li, Juan; Tang, Dong Hui; Li, Qiong

    2017-02-22

    Obesity has been associated with the excessive intake of palatable food as well as physical inactivity. To investigate the neurobiological mechanism underlying the exercised-induced prevention and treatment of obesity, the present study examined the effect of treadmill exercise on the preference for palatable food in mice. Levels of tyrosine hydroxylase (TH) in the ventral tegmental area-nucleus accumbens system were also analysed, as well as levels of dopamine, dopamine transporter, and D2 receptors in the nucleus accumbens. Forty C57BL/6J mice were randomly divided into a control group (CG, n=10) and a high-fat diet group (HG, N=30). Mice of the HG group were fed a high-fat diet for 12 weeks in order to induce a model of obesity, following which the obese mice were randomly divided into an obese control group (OG, n=11) and an obese+exercise group (OEG, n=12). OEG mice received 8 weeks of treadmill exercise intervention. Our results indicate that, relative to animals in the OG group, OEG mice exhibited significant decreases in the preference for high-fat diets and insulin resistance, along with increases in the preference for sucrose and milk, TH and D2 receptor expression, and levels of dopamine in the ventral tegmental area-nucleus accumbens system. These results suggest that moderate-intensity treadmill exercise can alter food preference in obese mice, which may be mediated by dopaminergic plasticity of the ventral tegmental area-nucleus accumbens and enhanced insulin sensitivity. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Estudio de los Comportamientos Ingestivo, Locomotor, Reactivo y Muricida en Ratas con Lesión del Núcleo Accumbens.

    OpenAIRE

    Pérez Lucena, Esther

    2016-01-01

    Para delimitar la finalidad de la presente investigación se comenzará por presentar el objetivo general de la misma y a continuación sus objetivos concretos. - Objetivo General: Como se ha expuesto en los apartados anteriores, el núcleo accumbens ha sido estudiado desde muy diversos puntos de vista, no obstante, si se realiza una cuantificación de los trabajos publicados sobre el mismo para un conocimiento multidisciplinario e integral del núcle...

  13. Nucleus accumbens response to gains in reputation for the self relative to gains for others predicts social media use

    Directory of Open Access Journals (Sweden)

    Dar eMeshi

    2013-08-01

    Full Text Available Our reputation is important to us; we’ve experienced natural selection to care about our reputation. Recently, the neural processing of gains in reputation (positive social feedback concerning one’s character has been shown to occur in the human ventral striatum. It is still unclear, however, how individual differences in the processing of gains in reputation may lead to individual differences in real-world behavior. For example, in the real-world, one way that people currently maintain their reputation is by using social media websites, like Facebook. Furthermore, Facebook use consists of a social comparison component, where users observe others’ behavior and can compare it to their own. Therefore, we hypothesized a relationship between the way the brain processes specifically self-relevant gains in reputation and one’s degree of Facebook use. We recorded functional neuroimaging data while participants received gains in reputation, observed the gains in reputation of another person, or received monetary reward. We demonstrate that across participants, when responding to gains in reputation for the self, relative to observing gains for others, reward-related activity in the left nucleus accumbens predicts Facebook use. However, nucleus accumbens activity in response to monetary reward did not predict Facebook use. Finally, a control step-wise regression analysis showed that Facebook use primarily explains our results in the nucleus accumbens. Overall, our results demonstrate how individual sensitivity of the nucleus accumbens to the receipt of self-relevant social information leads to differences in real-world behavior.

  14. Optogenetic Stimulation of Accumbens Shell or Shell Projections to Lateral Hypothalamus Produce Differential Effects on the Motivation for Cocaine

    OpenAIRE

    Larson, Erin B.; Wissman, Anne M.; Loriaux, Amy L.; Kourrich, Saïd; Self, David W.

    2015-01-01

    Previous studies suggest that pharmacological or molecular activation of the nucleus accumbens shell (AcbSh) facilitates extinction of cocaine-seeking behavior. However, overexpression of CREB, which increases excitability of AcbSh neurons, enhances cocaine-seeking behavior while producing depression-like behavior in tests of mood. These discrepancies may reflect activity in differential AcbSh outputs, including those to the lateral hypothalamus (LH), a target region known to influence addict...

  15. The nucleus accumbens is involved in both the pursuit of social reward and the avoidance of social punishment

    OpenAIRE

    Kohls, Gregor; Perino, Michael T.; Taylor, James M.; Madva, Elizabeth N.; Cayless, Sarah J.; Troiani, Vanessa; Price, Elinora; Faja, Susan; Herrington, John D.; Schultz, Robert T.

    2013-01-01

    Human social motivation is characterized by the pursuit of social reward and the avoidance of social punishment. The ventral striatum/nucleus accumbens (VS/Nacc), in particular, has been implicated in the reward component of social motivation, i.e., the ‘wanting’ of social incentives like approval. However, it is unclear to what extent the VS/Nacc is involved in avoiding social punishment like disapproval, an intrinsically pleasant outcome. Thus, we conducted an event-related functional magne...

  16. Latent inhibition-related dopaminergic responses in the nucleus accumbens are disrupted following neonatal transient inactivation of the ventral subiculum.

    Science.gov (United States)

    Meyer, Francisca F; Louilot, Alain

    2011-06-01

    Schizophrenia would result from a defective connectivity between several integrative regions as a consequence of neurodevelopmental failure. Various anomalies reminiscent of early brain development disturbances have been observed in patients' left ventral subiculum of the hippocampus (SUB). Numerous data support the hypothesis of a functional dopaminergic dysregulation in schizophrenia. The common target structure for the action of antipsychotics appears to be a subregion of the ventral striatum, the dorsomedial shell part of the nucleus accumbens. Latent inhibition, a cognitive marker of interest for schizophrenia, has been found to be disrupted in acute patients. The present study set out to investigate the consequences of a neonatal functional inactivation of the left SUB by tetrodotoxin (TTX) in 8-day-old rats for the latent inhibition-related dopaminergic responses, as monitored by in vivo voltammetry in freely moving adult animals (11 weeks) in the left core and dorsomedial shell parts of the nucleus accumbens in an olfactory aversion procedure. Results obtained during the retention session of a three-stage latent inhibition protocol showed that the postnatal unilateral functional blockade of the SUB was followed in pre-exposed TTX-conditioned adult rats by a disruption of the behavioral expression of latent inhibition and induced a total and a partial reversal of the latent inhibition-related dopaminergic responses in the dorsomedial shell and core parts of the nucleus accumbens, respectively. The present data suggest that neonatal inactivation of the SUB has more marked consequences for the dopaminergic responses recorded in the dorsomedial shell part, than in the core part of the nucleus accumbens. These findings may provide new insight into the pathophysiology of schizophrenia.

  17. Intra-accumbens baclofen, but not muscimol, increases second order instrumental responding for food reward in rats.

    Directory of Open Access Journals (Sweden)

    Kim G T Pulman

    Full Text Available Stimulation of either GABA(A or GABA(B receptors within the nucleus accumbens shell strongly enhances food intake in rats. However the effects of subtype-selective stimulation of GABA receptors on instrumental responses for food reward are less well characterized. Here we contrast the effects of the GABA(A receptor agonist muscimol and GABA(B receptor agonist baclofen on instrumental responding for food using a second order reinforcement schedule. Bilateral intra-accumbens administration of baclofen (220-440 pmol stimulated responding but a higher dose (660 pmol induced stereotyped oral behaviour that interfered with responding. Baclofen (220-660 pmol also stimulated intake of freely available chow. Muscimol (220-660 pmol was without effect on responding for food on this schedule but did stimulate intake of freely available chow. Unilateral administration of either baclofen or muscimol (220 pmol induced similar patterns of c-fos immunoreactivity in several hypothalamic sites but differed in its induction in the central nucleus of the amygdala. We conclude that stimulation of GABA(A or GABA(B receptors in the nucleus accumbens shell of rats produces clearly distinguishable effects on operant responding for food.

  18. Acetylcholine in the accumbens is decreased by diazepam and increased by benzodiazepine withdrawal: a possible mechanism for dependency.

    Science.gov (United States)

    Rada, Pedro; Hoebel, Bartley G

    2005-01-31

    Diazepam is a benzodiazepine used in the treatment of anxiety, insomnia and seizures, but with the potential for abuse. Like the other benzodiazepine anxiolytics, diazepam does not increase dopamine in the nucleus accumbens. This raises the question as to which other neurotransmitter systems are involved in diazepam dependence. The goal was to monitor dopamine and acetylcholine simultaneously following acute and chronic diazepam treatment and after flumazenil-induced withdrawal. Rats were prepared with microdialysis probes in the nucleus accumbens and given diazepam (2, 5 and 7.5 mg/kg) acutely and again after chronic treatment. Accumbens dopamine and acetylcholine decreased, with signs of tolerance to the dopamine effect. When these animals were put into the withdrawal state with flumazenil, there was a significant rise in acetylcholine (145%, P<0.001) with a smaller significant rise in dopamine (124%, P<0.01). It is suggested that the increase in acetylcholine release, relative to dopamine, is a neural component of the withdrawal state that is aversive.

  19. Chronic cannabinoid treatment in adolescent attenuates c-Fos expression in nucleus accumbens of adult estrous rats

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    Samuel I. Brook

    2013-02-01

    Full Text Available Chronic cannabinoid exposure during adolescence may negatively impact brain development and alter adult motivation and behavior. We present evidence that treatment with a cannabinoid agonist during adolescence attenuates estrous-mediated expression of c-Fos within the nucleus accumbens of female rats exposed to a male conspecific. Thirty-two female Long-Evans rats were administered either 0.4 mg/kg of CP-55,940 or vehicle on a daily basis between the ages of 35-45 days. When subjects reached adulthood (days 71-76, they were tested within an exposure paradigm designed to invoke sexual motivation wihtout allowing for consummatory behavior. Female subjects were naturally-cyclins; half were tested when in behavioral estrus (as determined by vaginal cytology and half were tested outside of estrus. c-Fos expression was then quantified in multiple brain regions associated with female sexual motivation, in addition to two control regions. Analyses revealed that untreated females showed more c-Fos-positive neurons when estrous (versus non-estrous within the medial preoptic area of the hypothalamus, the ventromedial hypothalamus, and the nucleus accumbens core and shell. Significant attenuation of this estrous effect was observed within the nucleus accumbens core and shell of drug-treated females. This suggests that adolescent cannabinoid exposure may negatively impact research in our laboratory which indicated that chronic cannabinoid exposure during adolescence persistently attenuates the expression of sexual motivation in female rats and provide a potential neurobiological substrate for those behavioral deficits.

  20. Intra-accumbens injection of a dopamine aptamer abates MK-801-induced cognitive dysfunction in a model of schizophrenia.

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    Matthew R Holahan

    Full Text Available Systemic administration of the noncompetitive NMDA-receptor antagonist, MK-801, has been proposed to model cognitive deficits similar to those seen in patients with schizophrenia. The present work investigated the ability of a dopamine-binding DNA aptamer to regulate these MK-801-induced cognitive deficits when injected into the nucleus accumbens. Rats were trained to bar press for chocolate pellet rewards then randomly assigned to receive an intra-accumbens injection of a DNA aptamer (200 nM; n = 7, tris buffer (n = 6 or a randomized DNA oligonucleotide (n = 7. Animals were then treated systemically with MK-801 (0.1 mg/kg and tested for their ability to extinguish their bar pressing response. Two control groups were also included that did not receive MK-801. Data revealed that injection of Tris buffer or the random oligonucleotide sequence into the nucleus accumbens prior to treatment with MK-801 did not reduce the MK-801-induced extinction deficit. Animals continued to press at a high rate over the entire course of the extinction session. Injection of the dopamine aptamer reversed this MK-801-induced elevation in lever pressing to levels as seen in rats not treated with MK-801. Tests for activity showed that the aptamer did not impair locomotor activity. Results demonstrate the in vivo utility of DNA aptamers as tools to investigate neurobiological processes in preclinical animal models of mental health disease.

  1. Intra-accumbens injection of a dopamine aptamer abates MK-801-induced cognitive dysfunction in a model of schizophrenia.

    Science.gov (United States)

    Holahan, Matthew R; Madularu, Dan; McConnell, Erin M; Walsh, Ryan; DeRosa, Maria C

    2011-01-01

    Systemic administration of the noncompetitive NMDA-receptor antagonist, MK-801, has been proposed to model cognitive deficits similar to those seen in patients with schizophrenia. The present work investigated the ability of a dopamine-binding DNA aptamer to regulate these MK-801-induced cognitive deficits when injected into the nucleus accumbens. Rats were trained to bar press for chocolate pellet rewards then randomly assigned to receive an intra-accumbens injection of a DNA aptamer (200 nM; n = 7), tris buffer (n = 6) or a randomized DNA oligonucleotide (n = 7). Animals were then treated systemically with MK-801 (0.1 mg/kg) and tested for their ability to extinguish their bar pressing response. Two control groups were also included that did not receive MK-801. Data revealed that injection of Tris buffer or the random oligonucleotide sequence into the nucleus accumbens prior to treatment with MK-801 did not reduce the MK-801-induced extinction deficit. Animals continued to press at a high rate over the entire course of the extinction session. Injection of the dopamine aptamer reversed this MK-801-induced elevation in lever pressing to levels as seen in rats not treated with MK-801. Tests for activity showed that the aptamer did not impair locomotor activity. Results demonstrate the in vivo utility of DNA aptamers as tools to investigate neurobiological processes in preclinical animal models of mental health disease.

  2. Reduced Slc6a15 in Nucleus Accumbens D2-Neurons Underlies Stress Susceptibility.

    Science.gov (United States)

    Chandra, Ramesh; Francis, T Chase; Nam, Hyungwoo; Riggs, Lace M; Engeln, Michel; Rudzinskas, Sarah; Konkalmatt, Prasad; Russo, Scott J; Turecki, Gustavo; Iniguez, Sergio D; Lobo, Mary Kay

    2017-07-05

    Previous research demonstrates that Slc6a15, a neutral amino acid transporter, is associated with depression susceptibility. However, no study examined Slc6a15 in the ventral striatum [nucleus accumbens (NAc)] in depression. Given our previous characterization of Slc6a15 as a striatal dopamine receptor 2 (D2)-neuron-enriched gene, we examined the role of Slc6a15 in NAc D2-neurons in mediating susceptibility to stress in male mice. First, we showed that Slc6a15 mRNA was reduced in NAc of mice susceptible to chronic social defeat stress (CSDS), a paradigm that produces behavioral and molecular adaptations that resemble clinical depression. Consistent with our preclinical data, we observed Slc6a15 mRNA reduction in NAc of individuals with major depressive disorder (MDD). The Slc6a15 reduction in NAc occurred selectively in D2-neurons. Next, we used Cre-inducible viruses combined with D2-Cre mice to reduce or overexpress Slc6a15 in NAc D2-neurons. Slc6a15 reduction in D2-neurons caused enhanced susceptibility to a subthreshold social defeat stress (SSDS) as observed by reduced social interaction, while a reduction in social interaction following CSDS was not observed when Slc6a15 expression in D2-neurons was restored. Finally, since both D2-medium spiny neurons (MSNs) and D2-expressing choline acetyltransferase (ChAT) interneurons express Slc6a15, we examined Slc6a15 protein in these interneurons after CSDS. Slc6a15 protein was unaltered in ChAT interneurons. Consistent with this, reducing Slc5a15 selectively in NAc D2-MSNs, using A2A-Cre mice that express Cre selectively in D2-MSNs, caused enhanced susceptibility to SSDS. Collectively, our data demonstrate that reduced Slc6a15 in NAc occurs in MDD individuals and that Slc6a15 reduction in NAc D2-neurons underlies stress susceptibility.SIGNIFICANCE STATEMENT Our study demonstrates a role for reduced Slc6a15, a neutral amino acid transporter, in nucleus accumbens (NAc) in depression and stress susceptibility. The

  3. Altered gene expression and spine density in nucleus accumbens of adolescent and adult male mice exposed to emotional and physical stress.

    Science.gov (United States)

    Warren, Brandon L; Sial, Omar K; Alcantara, Lyonna F; Greenwood, Maria A; Brewer, Jacob S; Rozofsky, John P; Parise, Eric M; Bolaños-Guzmán, Carlos A

    2014-01-01

    Stressful early life experiences are implicated in lifelong health. However, little is known about the consequences of emotional stress (ES) or physical stress (PS) on neurobiology. Therefore, the following set of experiments was designed to assess changes in transcription and translation of key proteins within the nucleus accumbens (NAc). Male adolescent (postnatal day 35) or adult (8-week-old) mice were exposed to ES or PS using a witness social defeat paradigm. Then, 24 h after the last stress session, we measured levels of specific mRNAs and proteins within the NAc. Spine density was also assessed in separate groups of mice. Exposure to ES or PS disrupted extracellular signal-related kinase 2 (ERK2), reduced transcription of ΔFosB and had no effect on cAMP response element-binding protein (CREB) mRNA. Western blots revealed that exposure to ES or PS decreased ERK2 phosphorylation in adolescents, whereas the same stress regimen increased ERK2 phosphorylation in adults. Exposure to ES or PS had no effect on ΔFosB or CREB phosphorylation. ES and PS increased spine density in the NAc of adolescent exposed mice, but only exposure to PS increased spine density in adults. Together, these findings demonstrate that exposure to ES or PS is a potent stressor in adolescent and adult mice and can disturb the integrity of the NAc by altering transcription and translation of important signaling molecules in an age-dependent manner. Furthermore, exposure to ES and PS induces substantial synaptic plasticity of the NAc.

  4. Homer2 deletion alters dendritic spine morphology but not alcohol-associated adaptations in GluN2B-containing NMDA receptors in the nucleus accumbens

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    Natalie S McGuier

    2015-02-01

    Full Text Available Repeated exposure to ethanol followed by withdrawal leads to the alterations in glutamatergic signaling and impaired synaptic plasticity in the nucleus accumbens (NAc in both clinical and preclinical models of ethanol exposure. Homer2 is a member of a family of postsynaptic density (PSD scaffolding proteins that functions in part to cluster NMDA signaling complexes in the PSD, and has been shown to be critically important for plasticity in multiple models of drug and alcohol abuse. Here we used Homer2 KO mice and a chronic intermittent intraperitoneal (IP ethanol injection model to investigate a potential role for the protein in ethanol-induced adaptations in dendritic spine morphology and PSD protein expression. While deletion of Homer2 was associated with increased density of long spines on medium spiny neurons of the NAc core of saline treated mice, ethanol exposure had no effect on dendritic spine morphology in either wild-type (WT or Homer2 KO mice. Western blot analysis of tissue samples from the NAc enriched for PSD proteins revealed a main effect of ethanol treatment on the expression of GluN2B, but there was no effect of genotype or treatment on the expression other glutamate receptor subunits or PSD95. These data indicate that the global deletion of Homer2 leads to aberrant regulation of dendritic spine morphology in the NAc core that is associated with an increased density of long, thin spines. Unexpectedly, intermittent IP ethanol did not affect spine morphology in either WT or KO mice. Together these data implicate Homer2 in the formation of long, thin spines and further supports its role in neuronal structure.

  5. Resting-state functional connectivity of the nucleus accumbens in auditory and visual hallucinations in schizophrenia.

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    Rolland, Benjamin; Amad, Ali; Poulet, Emmanuel; Bordet, Régis; Vignaud, Alexandre; Bation, Rémy; Delmaire, Christine; Thomas, Pierre; Cottencin, Olivier; Jardri, Renaud

    2015-01-01

    Both auditory hallucinations (AH) and visual hallucinations may occur in schizophrenia. One of the main hypotheses underlying their occurrence involves the increased activity of the mesolimbic pathway, which links the ventral tegmental area (VTA) and the nucleus accumbens (NAcc). However, the precise contribution of the mesolimbic pathway in hallucinations across various sensory modalities has not yet been explored. We compared the resting-state functional connectivity (rs-FC) of the NAcc among 16 schizophrenia patients with pure AH, 15 with both visuoauditory hallucinations (VAH), and 14 without hallucinations (NoH). A between-group comparison was performed using random-effects ANCOVA (rs-FC of the bilateral NAcc as the dependent variable, groups as the between-subjects factor, age and Positive and Negative Syndrome Scale scores as covariates; q(false discovery rate [FDR]) hallucinations, but the NAcc FC patterns changed with the complexity of these experiences (ie, 0, 1, or 2 sensory modalities), rather than with severity. This might support the aberrant salience hypothesis of schizophrenia. Moreover, these findings suggest that future clinical and neurobiological studies of hallucinations should evaluate not only the global severity of symptoms but also their sensorial features.

  6. Features of compulsive checking behavior mediated by nucleus accumbens and orbital frontal cortex.

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    Dvorkin, Anna; Silva, Charmaine; McMurran, Thomas; Bisnaire, Liane; Foster, Jane; Szechtman, Henry

    2010-11-01

    The quinpirole sensitization model of obsessive-compulsive disorder was used to investigate the functional role that brain regions implicated in a neuroanatomical circuit of obsessive-compulsive disorder may play in compulsive checking behavior. Following repeated injections of saline or quinpirole (0.5mg/kg, twice per week, ×8 injections) to induce compulsive checking, rats received N-methyl-d-aspartate lesions of the nucleus accumbens core (NAc), orbital frontal cortex (OFC) and basolateral amygdala, or sham lesions. When retested at 17days post-surgery, the results showed effects of NAc and OFC but not basolateral amygdala lesion. NAc lesions affected measures indicative of the amount of checking behavior, whereas OFC lesions affected indices of staying away from checking. The pattern of results suggested that the functional roles of the NAc and OFC in checking behavior are to control the vigor of motor performance and focus on goal-directed activity, respectively. Furthermore, similarities in behavior between quinpirole sham rats and saline NAc lesion rats suggested that quinpirole may drive the vigor of checking by inhibition of NAc neurons, and that the NAc may be a site for the negative feedback control of checking.

  7. Dysfunction of nucleus accumbens-1 activates cellular senescence and inhibits tumor cell proliferation and oncogenesis.

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    Zhang, Yi; Cheng, Yan; Ren, Xingcong; Hori, Tsukasa; Huber-Keener, Kathryn J; Zhang, Li; Yap, Kai Lee; Liu, David; Shantz, Lisa; Qin, Zheng-Hong; Zhang, Suping; Wang, Jianrong; Wang, Hong-Gang; Shih, Ie-Ming; Yang, Jin-Ming

    2012-08-15

    Nucleus accumbens-1 (NAC1), a nuclear factor belonging to the BTB/POZ gene family, has emerging roles in cancer. We report here that NAC1 acts as a negative regulator of cellular senescence in transformed and nontransformed cells, and dysfunction of NAC1 induces senescence and inhibits its oncogenic potential. We show that NAC1 deficiency markedly activates senescence and inhibits proliferation in tumor cells treated with sublethal doses of γ-irradiation. In mouse embryonic fibroblasts from NAC1 knockout mice, following infection with a Ras virus, NAC1-/- cells undergo significantly more senescence and are either nontransformed or less transformed in vitro and less tumorigenic in vivo when compared with NAC1+/+ cells. Furthermore, we show that the NAC1-caused senescence blunting is mediated by ΔNp63, which exerts its effect on senescence through p21, and that NAC1 activates transcription of ΔNp63 under stressful conditions. Our results not only reveal a previously unrecognized function of NAC1, the molecular pathway involved and its impact on pathogenesis of tumor initiation and development, but also identify a novel senescence regulator that may be exploited as a potential target for cancer prevention and treatment.

  8. Nucleus accumbens core and shell are necessary for reinforcer devaluation effects on Pavlovian conditioned responding

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    Teghpal eSingh

    2010-10-01

    Full Text Available The nucleus accumbens (NA has been hypothesized to be part of a circuit in which cue-evoked information about expected outcomes is mobilized to guide behavior. Here we tested this hypothesis using a Pavlovian reinforcer devaluation task, previously applied to assess outcome-guided behavior after damage to regions such as the orbitofrontal cortex and amygdala that send projections to NA. Rats with sham lesions or neurotoxic lesions of either the core or shell subdivision of NA were trained to associate a 10 sec CS+ with delivery of three food pellets. After training, half of the rats in each lesion group received food paired with illness induced by LiCl injections; the remaining rats received food and illness unpaired. Subsequently, responding to the CS+ was assessed in an extinction probe test. Both sham and lesioned rats conditioned to the CS+ and formed a conditioned taste aversion. However only sham rats reduced their conditioned responding as a result of reinforcer devaluation; devalued rats with lesions of either core or shell showed levels of responding that were similar to lesioned, non-devalued rats. This impairment was not due to the loss of motivational salience conferred to the CS+ in lesioned rats as both groups responded similarly for the cue in conditioned reinforcement testing. These data suggest that NA core and shell are part of a circuit necessary for the use of cue-evoked information about expected outcomes to guide behavior.

  9. Discrete neurochemical coding of distinguishable motivational processes: insights from nucleus accumbens control of feeding.

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    Baldo, Brian A; Kelley, Ann E

    2007-04-01

    The idea that nucleus accumbens (Acb) dopamine transmission contributes to the neural mediation of reward, at least in a general sense, has achieved wide acceptance. Nevertheless, debate remains over the precise nature of dopamine's role in reward and even over the nature of reward itself. In the present article, evidence is reviewed from studies of food intake, feeding microstructure, instrumental responding for food reinforcement, and dopamine efflux associated with feeding, which suggests that reward processing in the Acb is best understood as an interaction among distinct processes coded by discrete neurotransmitter systems. In agreement with several theories of Acb dopamine function, it is proposed here that allocation of motor effort in seeking food or food-associated conditioned stimuli can be dissociated from computations relevant to the hedonic evaluation of food during the consummatory act. The former appears to depend upon Acb dopamine transmission and the latter upon striatal opioid peptide release. Moreover, dopamine transmission may play a role in 'stamping in' associations between motor acts and goal attainment and perhaps also neural representations corresponding to rewarding outcomes. Finally, evidence is reviewed that amino acid transmission specifically in the Acb shell acts as a central 'circuit breaker' to flexibly enable or terminate the consummatory act, via descending connections to hypothalamic feeding control systems. The heuristic framework outlined above may help explain why dopamine-compromising manipulations that strongly diminish instrumental goal-seeking behaviors leave consummatory activity relatively unaffected.

  10. Nucleus accumbens shell, but not core, tracks motivational value of salt.

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    Loriaux, Amy L; Roitman, Jamie D; Roitman, Mitchell F

    2011-09-01

    To appropriately respond to an affective stimulus, we must be able to track its value across changes in both the external and internal environment. The nucleus accumbens (NAc) is a critical component of reward circuitry, but recent work suggests that the NAc encodes aversion as well as reward. It remains unknown whether differential NAc activity reflects flexible changes in stimulus value when it is altered due to a change in physiological state. We measured the activity of individual NAc neurons when rats were given intraoral infusions of a hypertonic salt solution (0.45 M NaCl) across multiple sessions in which motivational state was manipulated. This normally nonpreferred taste was made rewarding via sodium depletion, which resulted in a strong motivation to seek out and consume salt. Recordings were made in three conditions: while sodium replete (REP), during acute sodium depletion (DEP), and following replenishment of salt to normal sodium balance (POST). We found that NAc neurons in the shell and core subregions responded differently across the three conditions. In the shell, we observed overall increases in NAc activity when the salt solution was nonpreferred (REP) but decreases when the salt solution was preferred (DEP). In the core, overall activity was significantly altered only after sodium balance was restored (POST). The results lend further support to the selective encoding of affective stimuli by the NAc and suggest that NAc shell is particularly involved in flexibly encoding stimulus value based on motivational state.

  11. Selective effects of perinatal ethanol exposure in medial prefrontal cortex and nucleus accumbens.

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    Lawrence, R Charles; Otero, Nicha K H; Kelly, Sandra J

    2012-01-01

    Ethanol exposure during development is the leading known cause of mental retardation and can result in characteristic physiological and cognitive deficits, often termed Fetal Alcohol Spectrum Disorders (FASD). Previous behavioral findings using rat models of FASD have suggested that there are changes in the nucleus accumbens (NAC) and medial prefrontal cortex (mPFC) following ethanol exposure during development. This study used a rat model of FASD to evaluate dendritic morphology in both the NAC and mPFC and cell number in the NAC. Dendritic morphology in mPFC and NAC was assessed using a modified Golgi stain and analyzed via three dimensional reconstructions with Neurolucida (MBF Bioscience). Cell counts in the NAC (shell and core) were determined using an unbiased stereology procedure (Stereo Investigator (MBF Bioscience)). Perinatal ethanol exposure did not affect neuronal or glial cell population numbers in the NAC. Ethanol exposure produced a sexually dimorphic effect on dendritic branching at one point along the NAC dendrites but was without effect on all other measures of dendritic morphology in the NAC. In contrast, spine density was reduced and distribution was significantly altered in layer II/III neurons of the mPFC following ethanol exposure. Ethanol exposure during development was also associated with an increase in soma size in the mPFC. These findings suggest that previously observed sexually dimorphic changes in activation of the NAC in a rat model of FASD may be due to altered input from the mPFC.

  12. Individual Variations in Nucleus Accumbens Responses Associated with Major Depressive Disorder Symptoms.

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    Misaki, Masaya; Suzuki, Hideo; Savitz, Jonathan; Drevets, Wayne C; Bodurka, Jerzy

    2016-02-16

    Abnormal reward-related responses in the nucleus accumbens (NAcc) have been reported for major depressive disorder (MDD) patients. However, variability exists in the reported results, which could be due to heterogeneity in neuropathology of depression. To parse the heterogeneity of MDD we investigated variation of NAcc responses to gain and loss anticipations using fMRI. We found NAcc responses to monetary gain and loss were significantly variable across subjects in both MDD and healthy control (HC) groups. The variations were seen as a hyperactive response subtype that showed elevated activation to the anticipation of both gain and loss, an intermediate response with greater activation to gain than loss, and a suppressed-activity with reduced activation to both gain and loss compared to a non-monetary condition. While these response variability were seen in both MDD and HC subjects, specific symptoms were significantly associated with the right NAcc variation in MDD. Both the hyper- and suppressed-activity subtypes of MDD patients had severe suicidal ideation and anhedonia symptoms. The intermediate subjects had less severity in these symptoms. These results suggest that differing propensities in reward responsiveness in the NAcc may affect the development of specific symptoms in MDD.

  13. Activin A is increased in the nucleus accumbens following a cocaine binge

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    Wang, Zi-Jun; Martin, Jennifer A.; Gancarz, Amy M.; Adank, Danielle N.; Sim, Fraser J.; Dietz, David M.

    2017-01-01

    Drug addiction is a long-lasting disease characterized by compulsive drug intake mediated in part by neuronal and biological adaptations in key brain areas, such as the nucleus accumbens (NAc). While we previously demonstrated involvement of the activin 2a receptor in drug taking, the role of its ligand, activin A, in cocaine relapse is unknown. Activin A levels in the NAc were assessed via ELISA and immunohistochemistry (in neurons, astrocytes, and microglia) following a cocaine binge paradigm. Cocaine exposure significantly increased the levels of activin A in the NAc of animals that had self-administered cocaine prior to the 14-day withdrawal compared with levels in saline controls. This was accompanied by an increase in the proportion of IBA1+ microglia in the NAc that were immunopositive for activin A. In contrast, the proportions of NeuN+ neurons and GFAP+ astrocytes that were immunopositive for activin A remained unaltered. In conclusion, these data suggest that increased secretion of activin A, particularly from microglia, in the NAc represents a novel potential target for the treatment of cocaine relapse. PMID:28272550

  14. Activation of nucleus accumbens NMDA receptors differentially affects appetitive or aversive taste learning and memory

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    Luis eNuñez-Jaramillo

    2012-04-01

    Full Text Available Taste memory depends on motivational and post-ingestional consequences; thus, it can be aversive (e.g., conditioned taste aversion, CTA if a novel, palatable taste is paired with visceral malaise, or it can be appetitive if no intoxication appears after novel taste consumption, and a taste preference is developed. The nucleus accumbens (NAc plays a role in hedonic reactivity to taste stimuli, and recent findings suggest that reward and aversion are differentially encoded by the activity of NAc neurons. The present study examined whether the requirement for NMDA receptors in the NAc core during rewarding appetitive taste learning differs from that during aversive taste conditioning, as well as during retrieval of appetitive versus aversive taste memory, using the taste preference or CTA model, respectively. Bilateral infusions of NMDA (1 μg/μl, 0.5 μl into the NAc core were performed before acquisition or before retrieval of taste preference or CTA. Activation of NMDA receptors before taste preference training or CTA acquisition did not alter memory formation. Furthermore, NMDA injections before aversive taste retrieval had no effect on taste memory; however, 24 h later, CTA extinction was significantly delayed. Also, NMDA injections, made before familiar appetitive memory retrieval, interrupted the development of taste preference and produced a preference delay 24 h later. These results suggest that memory formation for a novel taste produces neurochemical changes in the NAc core that have differential requirements for NMDA receptors during retrieval of appetitive or aversive memory.

  15. beta-Alanine elevates dopamine levels in the rat nucleus accumbens: antagonism by strychnine.

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    Ericson, Mia; Clarke, Rhona B C; Chau, PeiPei; Adermark, Louise; Söderpalm, Bo

    2010-04-01

    Glycine receptors (GlyRs) in the nucleus accumbens (nAc) have recently been suggested to be involved in the reinforcing and dopamine-elevating properties of ethanol via a neuronal circuitry involving the VTA. Apart from ethanol, both glycine and taurine have the ability to modulate dopamine output via GlyRs in the same brain region. In the present study, we wanted to explore whether yet another endogenous ligand for the GlyR, beta-alanine, had similar effects. To this end, we monitored dopamine in the nAc by means of in vivo microdialysis and found that local perfusion of beta-alanine increased dopamine output. In line with previous observations investigating ethanol, glycine and taurine, the competitive GlyR antagonist strychnine completely blocked the dopamine elevation. The present results suggest that beta-alanine has the ability to modulate dopamine levels in the nAc via strychnine-sensitive GlyRs, and are consistent with previous studies suggesting the importance of this receptor for modulating dopamine output.

  16. THC reduces the anticipatory nucleus accumbens response to reward in subjects with a nicotine addiction.

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    Jansma, J M; van Hell, H H; Vanderschuren, L J M J; Bossong, M G; Jager, G; Kahn, R S; Ramsey, N F

    2013-02-26

    Recent evidence has implicated the endocannabinoid (eCB) system in nicotine addiction. The eCB system also has an important role in reward mechanisms, and nicotine addiction has been associated with aberrant reward processing. Motivated by this evidence, we tested the hypothesis that eCB modulation of reward processing is altered in subjects with a nicotine addiction (NAD). For this purpose, we compared reward-related activity in NAD with healthy controls (HC) in a pharmacological magnetic resonance imaging (MRI) study using Δ(9)-tetrahydrocannabinol (THC) administration to challenge the eCB system. Eleven HC and 10 NAD participated in a 3-T functional MRI (fMRI) study with a double-blind, cross-over, placebo-controlled design, using a Monetary Incentive Delay (MID) paradigm with three reward levels. Reward activity in the nucleus accumbens (NAcc) and caudate putamen during anticipation and feedback of reward was compared after THC and placebo. fMRI results indicated a significant reduction of reward anticipation activity in the NAcc in NAD after THC administration, which was not present in HC. This is indicated by a significant group by drug by reward interaction. Our data show that THC significantly reduces the NAcc response to monetary reward anticipation in NAD. These results suggest that nicotine addiction is associated with altered eCB modulation of reward processing in the NAcc. This study adds important human data to existing evidence implicating the eCB system in nicotine addiction.

  17. PSMC5, a 19S Proteasomal ATPase, Regulates Cocaine Action in the Nucleus Accumbens.

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    Yoko H Ohnishi

    Full Text Available ΔFosB is a stable transcription factor which accumulates in the nucleus accumbens (NAc, a key part of the brain's reward circuitry, in response to chronic exposure to cocaine or other drugs of abuse. While ΔFosB is known to heterodimerize with a Jun family member to form an active transcription factor complex, there has not to date been an open-ended exploration of other possible binding partners for ΔFosB in the brain. Here, by use of yeast two-hybrid assays, we identify PSMC5-also known as SUG1, an ATPase-containing subunit of the 19S proteasomal complex-as a novel interacting protein with ΔFosB. We verify such interactions between endogenous ΔFosB and PSMC5 in the NAc and demonstrate that both proteins also form complexes with other chromatin regulatory proteins associated with gene activation. We go on to show that chronic cocaine increases nuclear, but not cytoplasmic, levels of PSMC5 in the NAc and that overexpression of PSMC5 in this brain region promotes the locomotor responses to cocaine. Together, these findings describe a novel mechanism that contributes to the actions of ΔFosB and, for the first time, implicates PSMC5 in cocaine-induced molecular and behavioral plasticity.

  18. Transfer of neuroplasticity from nucleus accumbens core to shell is required for cocaine reward.

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    Nicolas Marie

    Full Text Available It is well established that cocaine induces an increase of dendritic spines density in some brain regions. However, few studies have addressed the role of this neuroplastic changes in cocaine rewarding effects and have often led to contradictory results. So, we hypothesized that using a rigorous time- and subject-matched protocol would demonstrate the role of this spine increase in cocaine reward. We designed our experiments such as the same animals (rats were used for spine analysis and behavioral studies. Cocaine rewarding effects were assessed with the conditioned place preference paradigm. Spines densities were measured in the two subdivisions of the nucleus accumbens (NAcc, core and shell. We showed a correlation between the increase of spine density in NAcc core and shell and cocaine rewarding effects. Interestingly, when cocaine was administered in home cages, spine density was increase in NAcc core only. With anisomycin, a protein synthesis inhibitor, injected in the core we blocked spine increase in core and shell and also cocaine rewarding effects. Strikingly, whereas injection of this inhibitor in the shell immediately after conditioning had no effect on neuroplasticity or behavior, its injection 4 hours after conditioning was able to block neuroplasticity in shell only and cocaine-induced place preference. Thus, it clearly appears that the neuronal plasticity in the NAcc core is essential to induce plasticity in the shell, necessary for cocaine reward. Altogether, our data revealed a new mechanism in the NAcc functioning where a neuroplasticity transfer occurred from core to shell.

  19. Orexin mediates the expression of precipitated morphine withdrawal and concurrent activation of the nucleus accumbens shell.

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    Sharf, Ruth; Sarhan, Maysa; Dileone, Ralph J

    2008-08-01

    The lateral hypothalamic neuropeptide orexin (or hypocretin) is implicated in drug addiction. Although a role for orexin has been shown in reward and dependence, the molecular and neural mechanisms are unclear. We investigated the mechanism and neuroanatomic basis of orexin's role in morphine withdrawal. C57BL/6J mice received chronic morphine followed by naloxone (0 or 1 mg/kg, subcutaneous) to precipitate withdrawal. Before naloxone, mice received SB-334867 (0 or 20 mg/kg, intraperitoneal), an orexin 1 receptor (Ox1r) antagonist. Using immunohistochemistry, c-Fos, a marker of cell activation, was quantified in the nucleus accumbens (Acb), lateral hypothalamus (LH), ventral tegmental area (VTA), and locus coeruleus (LC). Retrograde tracing with fluorogold (FG) was performed to determine whether orexin neurons project directly to the Acb. SB-334867 before naloxone significantly attenuated withdrawal symptoms. Withdrawal was accompanied by an increase in c-Fos expression in the Acb shell (AcbSh), which was reduced by SB-334867 but had no effect on the VTA or the LC. Morphine withdrawal increased c-Fos expression in the dorsomedial (DMH) and perifornical (PFA) regions but not in the lateral region of the LH (LLH). Orexin neurons do not appear to form direct connections with Acb neurons. Altogether, these data demonstrate that orexin, acting via Ox1r, is critical for the expression of morphine withdrawal. AcbSh activation during withdrawal is dependent on Ox1r function and is likely mediated by indirect action of LH orexin neurons.

  20. Morphine conditioned place preference depends on glucocorticoid receptors in both hippocampus and nucleus accumbens.

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    Dong, Zhifang; Han, Huili; Wang, Meina; Xu, Lin; Hao, Wei; Cao, Jun

    2006-01-01

    Learned association between drugs of abuse and context is essential for the formation of drug conditioned place preference (CPP), which is believed to engage many brain regions including hippocampus and nucleus accumbens (NAc). The underlying mechanisms are not fully understood. Here, we examined whether glucocorticoid receptors (GRs) of hippocampus and NAc influenced the formation of morphine CPP in Sprague Dawley rats. We found that systemic or intrahippocampal infused DMSO vehicle (DMSO 20% in saline) 30 min before daily morphine (10 mg/kg, s.c.) conditioning did not affect the formation of morphine CPP. In contrast, systemic administration (5 mg/kg, s.c.) or intrahippocampal infusion (0, 0.1, 1.0, 10, 20 microg per side) of the GR antagonist RU38486 blocked or impaired the formation of CPP in a dose-dependent manner, respectively. Furthermore, intra-NAc infused RU38486 (10 microg per side) but not DMSO vehicle also prevented the formation of CPP. These results demonstrate that both the GRs of hippocampus and NAc are necessary for the formation of morphine CPP, suggesting a neural network function of the GRs in forming the opiate-associated memory.

  1. Nucleus accumbens deep brain stimulation in a rat model of binge eating.

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    Doucette, W T; Khokhar, J Y; Green, A I

    2015-12-15

    Binge eating (BE) is a difficult-to-treat behavior with high relapse rates, thus complicating several disorders including obesity. In this study, we tested the effects of high-frequency deep brain stimulation (DBS) in a rodent model of BE. We hypothesized that BE rats receiving high-frequency DBS in the nucleus accumbens (NAc) core would have reduced binge sizes compared with sham stimulation in both a 'chronic BE' model as well as in a 'relapse to chronic BE' model. Male Sprague-Dawley rats (N=18) were implanted with stimulating electrodes in bilateral NAc core, and they received either active stimulation (N=12) or sham stimulation (N=6) for the initial chronic BE experiments. After testing in the chronic BE state, rats did not engage in binge sessions for 1 month, and then resumed binge sessions (relapse to chronic BE) with active or sham stimulation (N=5-7 per group). A significant effect of intervention group was observed on binge size in the chronic BE state, but no significant difference between intervention groups was observed in the relapse to chronic BE experiments. This research, making use of both a chronic BE model as well as a relapse to chronic BE model, provides data supporting the hypothesis that DBS of the NAc core can decrease BE. Further research will be needed to learn how to increase the effect size and decrease deep brain stimulation-treatment outcome variability across the continuum of BE behavior.

  2. Repeated toluene exposure increases c-Fos in catecholaminergic cells of the nucleus accumbens shell.

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    Tomaszycki, Michelle L; Aulerich, Kelsey E; Bowen, Scott E

    2013-01-01

    Toluene is a frequently abused solvent. Previous studies have suggested that toluene acts like other drugs of abuse, specifically on the dopaminergic system in the nucleus accumbens (NAc) and ventral tegmental area (VTA) of the mesolimbic pathway. Although changes in dopamine (DA) levels and c-Fos have been observed in both acute and repeated exposure paradigms, the extent to which c-Fos is localized to catecholaminergic cells is unknown. The present study tested the effects of repeated toluene exposure (1000-4000ppm) on locomotor activity and cells containing c-Fos, tyrosine hydroxylase (TH), or both in the core and shell of the NAc, as well as the anterior and posterior VTA. We focused our study on adolescents, since adolescence is a time of great neural change and a time when individuals tend to be more susceptible to drug abuse. In early tests, toluene dose-dependently increased locomotor activity. Repeated exposure to the highest concentration of toluene resulted in sensitization to toluene's effects on locomotor activity. Although the number of cells immunopositive for c-Fos or TH did not significantly differ across groups, cells immunopositive for TH+c-Fos were higher in the NAc shell of animals exposed to 4000ppm than in animals exposed to air (control) or 1000ppm. Taken together, these findings demonstrate that repeated high dose toluene exposure increases locomotor activity as well as activation of catecholaminergic cells in the shell of the NAc. © 2013 Elsevier Inc. All rights reserved.

  3. Biological substrates of reward and aversion: a nucleus accumbens activity hypothesis.

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    Carlezon, William A; Thomas, Mark J

    2009-01-01

    The nucleus accumbens (NAc) is a critical element of the mesocorticolimbic system, a brain circuit implicated in reward and motivation. This basal forebrain structure receives dopamine (DA) input from the ventral tegmental area (VTA) and glutamate (GLU) input from regions including the prefrontal cortex (PFC), amygdala (AMG), and hippocampus (HIP). As such, it integrates inputs from limbic and cortical regions, linking motivation with action. The NAc has a well-established role in mediating the rewarding effects of drugs of abuse and natural rewards such as food and sexual behavior. However, accumulating pharmacological, molecular, and electrophysiological evidence has raised the possibility that it also plays an important (and sometimes underappreciated) role in mediating aversive states. Here we review evidence that rewarding and aversive states are encoded in the activity of NAc medium spiny GABAergic neurons, which account for the vast majority of the neurons in this region. While admittedly simple, this working hypothesis is testable using combinations of available and emerging technologies, including electrophysiology, genetic engineering, and functional brain imaging. A deeper understanding of the basic neurobiology of mood states will facilitate the development of well-tolerated medications that treat and prevent addiction and other conditions (e.g., mood disorders) associated with dysregulation of brain motivation systems.

  4. Stress during development alters dendritic morphology in the nucleus accumbens and prefrontal cortex.

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    Muhammad, A; Carroll, C; Kolb, B

    2012-08-02

    The long-term effects of stress during development have been well characterized. However, the effects of developmental stress on the underlying neurological mechanisms related to the reward system are not well understood. The present report studied the long term effects of stress during development on the structural plasticity in the cortical and subcortical regions. Rats exposed to stress during embryonic development (prenatal stress; PS) or soon after birth (maternal separation; MS) were studied for structural alteration at the neuronal level in the nucleus accumbens (NAc), orbital frontal cortex (OFC), and medial prefrontal cortex (mPFC). The findings show that stress during development increased dendritic branching, length, and spine density in the NAc, and subregions of the PFC. PS experience increased dendritic branching and length in the mPFC apical and basilar dendrites. In contrast, a PS-associated decrease in dendritic branching and length was observed in the basilar branches of the OFC. MS resulted in an increase in dendritic growth and spine density in the subregions of the PFC. The effect of PS on neuroanatomy was more robust than MS despite the shorter duration and intensity. The altered dendritic growth and spine density associated with stress during development could have potential impact on NAc and PFC related behaviors.

  5. Gene expression changes in the nucleus accumbens of alcohol-preferring rats following chronic ethanol consumption.

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    Bell, Richard L; Kimpel, Mark W; McClintick, Jeanette N; Strother, Wendy N; Carr, Lucinda G; Liang, Tiebing; Rodd, Zachary A; Mayfield, R Dayne; Edenberg, Howard J; McBride, William J

    2009-11-01

    The objective of this study was to determine the effects of binge-like alcohol drinking on gene expression changes in the nucleus accumbens (ACB) of alcohol-preferring (P) rats. Adult male P rats were given ethanol under multiple scheduled access (MSA; three 1-h dark cycle sessions/day) conditions for 8 weeks. For comparison purposes, a second ethanol drinking group was given continuous/daily alcohol access (CA; 24h/day). A third group was ethanol-naïve (W group). Average ethanol intakes for the CA and MSA groups were approximately 9.5 and 6.5 g/kg/day, respectively. Fifteen hours after the last drinking episode, rats were euthanized, the brains extracted, and the ACB dissected. RNA was extracted and purified for microarray analysis. The only significant differences were between the CA and W groups (palcohol consumption and preference; 4 of these genes (Tgfa, Hspa5, Mtus1 and Creb3l2) are involved in anti-apoptosis and increased transcription, suggesting that they may be contributing to cellular protection and maintaining high alcohol intakes. Overall, these findings suggest that chronic CA drinking results in genomic changes that can be observed during the early acute phase of ethanol withdrawal. Conversely, chronic MSA drinking, with its associated protracted withdrawal periods, results in genomic changes that may be masked by tight regulation of these genes following repeated experiences of ethanol withdrawal.

  6. Dopamine in nucleus accumbens: salience modulation in latent inhibition and overshadowing.

    Science.gov (United States)

    Nelson, A J D; Thur, K E; Marsden, C A; Cassaday, H J

    2011-12-01

    Latent inhibition (LI) is demonstrated when non-reinforced pre-exposure to a to-be-conditioned stimulus retards later learning. Learning is similarly retarded in overshadowing, in this case using the relative intensity of competing cues to manipulate associability. Electrolytic/excitotoxic lesions to shell accumbens (NAc) and systemic amphetamine both reliably abolish LI. Here a conditioned emotional response procedure was used to demonstrate LI and overshadowing and to examine the role of dopamine (DA) within NAc. Experiment 1 showed that LI but not overshadowing was abolished by systemic amphetamine (1.0 mg/kg i.p.). In Experiment 2, 6-hydroxydopamine (6-OHDA) was used to lesion DA terminals within NAc: both shell- and core- (plus shell-)lesioned rats showed normal LI and overshadowing. Experiment 3 compared the effects of amphetamine microinjected at shell and core coordinates prior to conditioning: LI, but not overshadowing, was abolished by 10.0 but not 5.0 µg/side amphetamine injected in core but not shell NAc. These results suggest that the abolition of LI produced by NAc shell lesions is not readily reproduced by regionally restricted DA depletion within NAc; core rather than shell NAc mediates amphetamine-induced abolition of LI; overshadowing is modulated by different neural substrates.

  7. Effects of bilateral reversible inactivation of Accumbens Nucleus on acquisition and consolidation of memory in rats

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    Abbas Ali Vafaee

    2003-09-01

    Full Text Available Extensive evidence indicates that the Accumbens Nucleus (AN probably involved in emotional memory. The present work investigated possible of AN involvement on acquisition and consolidation memory in passive avoidance learning (PAL task. This is experimental research and during that Albino male Wistar rats (n=80 were surgically implanted bilaterally with cannulae aimed at the AN were trained to PAL task. They received one trial PAL (1 ma 1.5 s footshock. Retention was tested 2 days after training. Lidocaine 2% (0.6 µl/side 20 min before of training for assessment of acquisition and Tetrodotoxine (5ng/0.6ml/side immediately, 60 and 120 min after training for assessment of consolidation were used to temporarily inactivate the AN. Control rats were injected with the same volume of saline. The data indicate that bilateral inactivation of AN immediately and 60 min after training significantly impaired consolidation of memory (P0.05. These results suggest that AN make contribution and involvement of long term memory and may be more important to the consolidation (time dependent of memory for the PAL.

  8. Nucleus Accumbens Core and Shell are Necessary for Reinforcer Devaluation Effects on Pavlovian Conditioned Responding.

    Science.gov (United States)

    Singh, Teghpal; McDannald, Michael A; Haney, Richard Z; Cerri, Domenic H; Schoenbaum, Geoffrey

    2010-01-01

    The nucleus accumbens (NA) has been hypothesized to be part of a circuit in which cue-evoked information about expected outcomes is mobilized to guide behavior. Here we tested this hypothesis using a Pavlovian reinforcer devaluation task, previously applied to assess outcome-guided behavior after damage to regions such as the orbitofrontal cortex and amygdala that send projections to NA. Rats with sham lesions or neurotoxic lesions of either the core or shell subdivision of NA were trained to associate a 10-s CS+ with delivery of three food pellets. After training, half of the rats in each lesion group received food paired with illness induced by LiCl injections; the remaining rats received food and illness unpaired. Subsequently, responding to the CS+ was assessed in an extinction probe test. Both sham and lesioned rats conditioned to the CS+ and formed a conditioned taste aversion. However only sham rats reduced their conditioned responding as a result of reinforcer devaluation; devalued rats with lesions of either core or shell showed levels of responding that were similar to lesioned, non-devalued rats. This impairment was not due to the loss of motivational salience conferred to the CS+ in lesioned rats as both groups responded similarly for the cue in conditioned reinforcement testing. These data suggest that NA core and shell are part of a circuit necessary for the use of cue-evoked information about expected outcomes to guide behavior.

  9. Long-term Effects of Maternal Deprivation on the Volume, Number and Size of Neurons in the Amygdala and Nucleus Accumbens of Rats.

    Science.gov (United States)

    Aleksić, Dubravka; Aksić, Milan; Radonjić, Nevena V; Jovanović, Aleksandar; Marković, Branka; Petronijević, Nataša; Radonjić, Vidosava; Mališ, Miloš; Filipović, Branislav

    2016-09-01

    Maternal deprivation (MD) in rodents is an important neurodevelopmental model for studying a variety of behavioral changes which closely resemble the symptoms of schizophrenia in humans. To determine whether early-life stress leads to changes in the limbic system structures: the amygdala and the nucleus accumbens, 9-day-old Wistar rats were exposed to 24 hour MD. On P60 the rats were sacrificed for morphometric analysis and their brains were compared to the control group. Results show that MD affected important limbic system structures: the amygdala and the nucleus accumbens, whose volume was decreased (17% of the control value for the amygdala and 9% of the control value for the nucleus accumbens ), as well as the number of neurons (41% of the control value for the amygdala and 43% of the control value for the nucleus accumbens ) and the size of their cells soma (12% of the control value for the amygdala and 33% of the control value for the nucleus accumbens ). This study indicates that early stress in life leads to changes in the morphology of the limbic areas of the brain, most probably due to the loss of neurons during postnatal development, and it further contributes to our understanding of the effects of maternal deprivation on brain development.

  10. NPY mediates reward activity of morphine, via NPY Y1 receptors, in the nucleus accumbens shell.

    Science.gov (United States)

    Desai, Sagar J; Upadhya, Manoj A; Subhedar, Nishikant K; Kokare, Dadasaheb M

    2013-06-15

    Although the interaction between endogenous neuropeptide Y (NPY) and opioidergic systems in processing of reward has been speculated, experimental evidence is lacking. We investigated the role of NPY, and its Y1 receptors, in the nucleus accumbens shell (AcbSh) in morphine induced reward and reinforcement behavior. Rats were implanted with cannulae targeted at AcbSh for drug administration, and with stimulating electrode in the medial forebrain bundle (MFB). The rats were then conditioned in an operant conditioning chamber for electrical self-stimulation of the MFB. Increased rate of lever pressings was evaluated against the frequency of the stimulating current. Increase in rate of lever presses was considered as a measure of reward and reinforcement. About 30-70% increase in self-stimulation was observed following bilateral intra-AcbSh treatment with morphine, NPY or [Leu(31), Pro(34)]-NPY (NPY Y1/Y5 receptors agonist), however, BIBP3226 (selective NPY Y1 receptors antagonist) produced opposite effect. The reward effect of morphine was significantly potentiated by NPY or [Leu(31), Pro(34)]-NPY, but antagonized by BIBP3226. NPY-immunoreactivity in the AcbSh, arcuate nucleus (ARC) and lateral part of bed nucleus of stria terminalis (BNSTl) was significantly more in the operant conditioned rats than in naïve control. However, morphine administration to the conditioned rats resulted in significant decrease in the NPY-immunoreactivity in all these anatomical regions. Since the role of morphine in modulation of mesolimbic-dopaminergic pathway is well established, we suggest that NPY system in AcbSh, ARC and BNSTl, perhaps acting via Y1-receptor system, may be an important component of the mesolimbic-AcbSh reward circuitry triggered by endogenous opioids.

  11. Addiction and Reward-related Genes Show Altered Expression in the Postpartum Nucleus Accumbens

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    Changjiu eZhao

    2014-11-01

    Full Text Available Motherhood involves a switch in natural rewards, whereby offspring become highly rewarding. Nucleus accumbens (NAC is a key CNS region for natural rewards and addictions, but to date no study has evaluated on a large scale the events in NAC that underlie the maternal change in natural rewards. In this study we utilized microarray and bioinformatics approaches to evaluate postpartum NAC gene expression changes in mice. Modular Single-set Enrichment Test (MSET indicated that postpartum (relative to virgin NAC gene expression profile was significantly enriched for genes related to addiction and reward in 5 of 5 independently curated databases (e.g., Malacards, Phenopedia. Over 100 addiction/reward related genes were identified and these included: Per1, Per2, Arc, Homer2, Creb1, Grm3, Fosb, Gabrb3, Adra2a, Ntrk2, Cry1, Penk, Cartpt, Adcy1, Npy1r, Htr1a, Drd1a, Gria1, and Pdyn. ToppCluster analysis found maternal NAC expression profile to be significantly enriched for genes related to the drug action of nicotine, ketamine, and dronabinol. Pathway analysis indicated postpartum NAC as enriched for RNA processing, CNS development/differentiation, and transcriptional regulation. Weighted Gene Coexpression Network Analysis identified possible networks for transcription factors, including Nr1d1, Per2, Fosb, Egr1, and Nr4a1. The postpartum state involves increased risk for mental health disorders and MSET analysis indicated postpartum NAC to be enriched for genes related to depression, bipolar disorder, and schizophrenia. Mental health related genes included: Fabp7, Grm3, Penk, and Nr1d1. We confirmed via quantitative PCR Nr1d1, Per2, Grm3, Penk, Drd1a, and Pdyn. This study indicates for the first time that postpartum NAC involves large scale gene expression alterations linked to addiction and reward. Because the postpartum state also involves decreased response to drugs, the findings could provide insights into how to mitigate addictions.

  12. The nucleus accumbens 5-HTR₄-CART pathway ties anorexia to hyperactivity.

    Science.gov (United States)

    Jean, A; Laurent, L; Bockaert, J; Charnay, Y; Dusticier, N; Nieoullon, A; Barrot, M; Neve, R; Compan, V

    2012-12-11

    In mental diseases, the brain does not systematically adjust motor activity to feeding. Probably, the most outlined example is the association between hyperactivity and anorexia in Anorexia nervosa. The neural underpinnings of this 'paradox', however, are poorly elucidated. Although anorexia and hyperactivity prevail over self-preservation, both symptoms rarely exist independently, suggesting commonalities in neural pathways, most likely in the reward system. We previously discovered an addictive molecular facet of anorexia, involving production, in the nucleus accumbens (NAc), of the same transcripts stimulated in response to cocaine and amphetamine (CART) upon stimulation of the 5-HT(4) receptors (5-HTR(4)) or MDMA (ecstasy). Here, we tested whether this pathway predisposes not only to anorexia but also to hyperactivity. Following food restriction, mice are expected to overeat. However, selecting hyperactive and addiction-related animal models, we observed that mice lacking 5-HTR(1B) self-imposed food restriction after deprivation and still displayed anorexia and hyperactivity after ecstasy. Decryption of the mechanisms showed a gain-of-function of 5-HTR(4) in the absence of 5-HTR(1B), associated with CART surplus in the NAc and not in other brain areas. NAc-5-HTR(4) overexpression upregulated NAc-CART, provoked anorexia and hyperactivity. NAc-5-HTR(4) knockdown or blockade reduced ecstasy-induced hyperactivity. Finally, NAc-CART knockdown suppressed hyperactivity upon stimulation of the NAc-5-HTR(4). Additionally, inactivating NAc-5-HTR(4) suppressed ecstasy's preference, strengthening the rewarding facet of anorexia. In conclusion, the NAc-5-HTR(4)/CART pathway establishes a 'tight-junction' between anorexia and hyperactivity, suggesting the existence of a primary functional unit susceptible to limit overeating associated with resting following homeostasis rules.

  13. Activation of dopamine receptors in the nucleus accumbens promotes sucrose-reinforced cued approach behavior

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    Saleem M. Nicola

    2016-07-01

    Full Text Available Dopamine receptor activation in the nucleus accumbens (NAc promotes vigorous environmentally-cued food-seeking in hungry rats. Rats fed ad libitum, however, respond to fewer food-predictive cues, particularly when the value of food reward is low. Here, we investigated whether this difference could be due to differences in the degree of dopamine receptor activation in the NAc. First, we observed that although rats given ad libitum access to chow in their home cages approached a food receptacle in response to reward-predictive cues, the number of such approaches declined as animals accumulated food rewards. Intriguingly, cued approach to food occurred in clusters, with several cued responses followed by successive non-responses. This pattern suggested that behavior was dictated by transitions between two states, responsive and non-responsive. Injection of D1 or D2 dopamine receptor agonists into the NAc dose-dependently increased cue responding by promoting transitions to the responsive state and by preventing transitions to the non-responsive state. In contrast, antagonists of either D1 or D2 receptors promoted long bouts of non-responding by inducing transitions to the non-responsive state and by preventing transitions to the responsive state. Moreover, locomotor behavior during the inter-trial interval was correlated with the responsive state, and was also increased by dopamine receptor agonists. These results suggest that activation of NAc dopamine receptors plays an important role in regulating the probability of approach to food under conditions of normative satiety.

  14. Nucleus accumbens core neurons encode value-independent associations necessary for sensory preconditioning.

    Science.gov (United States)

    Cerri, Domenic H; Saddoris, Michael P; Carelli, Regina M

    2014-10-01

    Reinforcement-based learning models predict that the strength of association between cues and outcomes is driven by aspects of outcome value. However, animals routinely make associations between contingent stimuli in the world, even if those associations hold no value to the organism. At the neural level, the nucleus accumbens (NAc) is known to encode associative information, but it is not known whether this encoding is specific for value-based information (consistent with reinforcement-based models) or if the NAc additionally plays a more general role in forming predictive associations, independent of outcome value. To test this, we employed a sensory preconditioning (SPC) task where rats initially (Preconditioning) received either contingent pairings of 2 neutral stimuli (e.g., tone [A] and light [X]; "Paired"), or random noncontingent presentations ("Unpaired"). After cue X was subsequently conditioned with food (First-Order Conditioning), the effect of preconditioning was assessed in Phase 3 (Test) by presentations of cue A alone. Electrophysiological recordings from the NAc core showed significant increases in phasic encoding for the stimuli in the Paired (but not Unpaired) condition as well as during test. Further, these effects were only seen in Paired rats that showed successful behavior during test (Good Learners), but not those who did not (Poor Learners) or Unpaired controls. These findings reveal a role for the NAc in the encoding of associative contingencies independent of value, and suggest that this structure also plays a more general role in forming associations necessary for predictive behavior. PsycINFO Database Record (c) 2014 APA, all rights reserved.

  15. Distribution and compartmental organization of GABAergic medium-sized spiny neurons in the mouse Nucleus Accumbens

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    Giuseppe eGangarossa

    2013-02-01

    Full Text Available The nucleus accumbens (NAc is a critical brain region involved in many reward-related behaviors. The NAc comprises major compartments the core and the shell, which encompass several subterritories. GABAergic medium-sized spiny neurons (MSNs constitute the output neurons of the NAc core and shell. While the functional organization of the NAc core outputs resembles the one described for the dorsal striatum, a simple classification of the NAc shell neurons has been difficult to define due to the complexity of the compartmental segregation of cells. We used a variety of BAC transgenic mice expressing enhanced green fluorescence (EGFP or the Cre-recombinase (Cre under the control of the promoter of dopamine D1, D2, and D3 receptors and of adenosine A2a receptor to dissect the microanatomy of the NAc. Moreover, using various immunological markers we characterized in detail the distribution of MSNs in the mouse NAc. In addition, cell-type specific ERK phosphorylation in the NAc subterritories was analyzed following acute administration of SKF81297 (a D1R-like agonist, quinpirole (a D2R-like agonist, apomorphine (a non-selective DA receptor agonist, raclopride (a D2R-like antagonist, and psychostimulant drugs, including cocaine and d-amphetamine. Each drug generated a unique topography and cell-type specific activation of ERK in the NAc. Our results show the existence of marked differences in the receptor expression pattern and functional activation of MSNs within the shell subterritories. This study emphasizes the anatomical and functional heterogeneity of the NAc, which will have to be considered in its further study.

  16. Antipsychotic treatment leading to dopamine supersensitivity persistently alters nucleus accumbens function.

    Science.gov (United States)

    El Hage, Cynthia; Bédard, Anne-Marie; Samaha, Anne-Noël

    2015-12-01

    Chronic exposure to some antipsychotic medications can induce supersensitivity to dopamine receptor stimulation. This is linked to a worsening of clinical outcome and to antipsychotic treatment failure. Here we investigated the role of striatal subregions [nucleus accumbens (NAc) and caudate-putamen (CPu)] in the expression of antipsychotic-induced dopamine supersensitivity. We treated rats with haloperidol (HAL) or olanzapine (OLZ), using regimens that achieve clinically relevant kinetics of striatal D2 receptor occupancy. Under these conditions, HAL produces dopamine supersensitivity whereas OLZ does not. We then assessed behaviors evoked by the dopamine agonist amphetamine (AMPH). We either injected AMPH into the striatum or inhibited striatal function with microinjections of GABA receptor agonists prior to injecting AMPH systemically. HAL-treated rats were dopamine supersensitive, as indicated by sensitization to systemic AMPH-induced potentiation of both locomotor activity and operant responding for a conditioned reward (CR). Intra-CPu injections of AMPH had no effect on these behaviors, in any group. Intra-NAc injections of AMPH enhanced operant responding for CR in OLZ-treated and control rats, but not in HAL-treated rats. In HAL-treated rats, inhibition of the NAc also failed to disrupt systemic AMPH-induced potentiation of operant responding for CR. Furthermore, while intra-NAc AMPH enhanced locomotion in both HAL-treated and control animals, inhibition of the NAc disrupted systemic AMPH-induced locomotion only in control rats. Thus, antipsychotic-induced dopamine supersensitivity persistently disrupts NAc function, such that some behaviors that normally depend upon NAc dopamine no longer do so. This has implications for understanding dysfunctions in dopamine-mediated behaviors in patients undergoing chronic antipsychotic treatment. Copyright © 2015 Elsevier Ltd. All rights reserved.

  17. Cholinergic depletion in nucleus accumbens impairs mesocortical dopamine activation and cognitive function in rats.

    Science.gov (United States)

    Laplante, François; Zhang, Zi-Wei; Huppé-Gourgues, Frédéric; Dufresne, Marc M; Vaucher, Elvire; Sullivan, Ron M

    2012-11-01

    In rats, selective depletion of the cholinergic interneurons in the ventral striatum (nucleus accumbens or N.Acc.) results in heightened behavioural sensitivity to amphetamine and impaired sensorimotor gating processes, suggesting a hyper-responsiveness to dopamine (DA) activity in the N.Acc. We hypothesized that local cholinergic depletion may also trigger distal functional alterations, particularly in prefrontal cortex (PFC). Adult male Sprague-Dawley rats were injected bilaterally in the N.Acc. with an immunotoxin targeting choline acetyltransferase. Two weeks later, cognitive function was assessed using the delayed alternation paradigm in the T-maze. The rats were then implanted with voltammetric recording electrodes in the ventromedial PFC to measure in vivo extracellular DA release in response to mild tail pinch stress. The PFC was also examined for density of tyrosine hydroxylase (TH)-labelled varicosities. In another cohort of control and lesioned rats, we measured post mortem tissue content of DA. Depletion of cholinergic neurons (restricted to N.Acc.) significantly impaired delayed alternation performance across delay intervals. While (basal) post mortem indices of PFC DA function were unaffected by N.Acc. lesions, in vivo mesocortical DA activation was markedly reduced; this deficit correlated significantly with cognitive impairments. TH-labelled varicosities however, were unaffected in cortical layer V relative to controls. These data suggest that selective depletion of cholinergic interneurons in N.Acc. triggers widespread functional impairments in mesocorticolimbic DA function and cognition. The possible relevance of these findings is also discussed in relation to schizophrenia, where reduced density of cholinergic neurons in ventral striatum has been reported. Copyright © 2012 Elsevier Ltd. All rights reserved.

  18. Central and peripheral contributions to dynamic changes in nucleus accumbens glucose induced by intravenous cocaine

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    Ken Taro Wakabayashi

    2015-02-01

    Full Text Available The pattern of neural, physiological and behavioral effects induced by cocaine is consistent with metabolic neural activation, yet direct attempts to evaluate central metabolic effects of this drug have produced controversial results. Here, we used enzyme-based glucose sensors coupled with high-speed amperometry in freely moving rats to examine how intravenous cocaine at a behaviorally active dose affects extracellular glucose levels in the nucleus accumbens (NAc, a critical structure within the motivation-reinforcement circuit. In drug-naive rats, cocaine induced a bimodal increase in glucose, with the first, ultra-fast phasic rise appearing during the injection (latency 6-8 s; ~50 µM or ~5% of baseline followed by a larger, more prolonged tonic elevation (~100 µM or 10% of baseline, peak ~15 min. While the rapid, phasic component of the glucose response remained stable following subsequent cocaine injections, the tonic component progressively decreased. Cocaine-methiodide, cocaine’s peripherally acting analog, induced an equally rapid and strong initial glucose rise, indicating cocaine’s action on peripheral neural substrates as its cause. However, this analog did not induce increases in either locomotion or tonic glucose, suggesting direct central mediation of these cocaine effects. Under systemic pharmacological blockade of dopamine transmission, both phasic and tonic components of the cocaine-induced glucose response were only slightly reduced, suggesting a significant role of non-dopamine mechanisms in cocaine-induced accumbal glucose influx. Hence, intravenous cocaine induces rapid, strong inflow of glucose into NAc extracellular space by involving both peripheral and central, non-dopamine drug actions, thus preventing a possible deficit resulting from enhanced glucose use by brain cells.

  19. Overexpression of CREB in the nucleus accumbens shell increases cocaine reinforcement in self-administering rats.

    Science.gov (United States)

    Larson, Erin B; Graham, Danielle L; Arzaga, Rose R; Buzin, Nicole; Webb, Joseph; Green, Thomas A; Bass, Caroline E; Neve, Rachael L; Terwilliger, Ernest F; Nestler, Eric J; Self, David W

    2011-11-09

    Chronic exposure to addictive drugs enhances cAMP response element binding protein (CREB)-regulated gene expression in nucleus accumbens (NAc), and these effects are thought to reduce the positive hedonic effects of passive cocaine administration. Here, we used viral-mediated gene transfer to produce short- and long-term regulation of CREB activity in NAc shell of rats engaging in volitional cocaine self-administration. Increasing CREB expression in NAc shell markedly enhanced cocaine reinforcement of self-administration behavior, as indicated by leftward (long-term) and upward (short-term) shifts in fixed ratio dose-response curves. CREB also increased the effort exerted by rats to obtain cocaine on more demanding progressive ratio schedules, an effect highly correlated with viral-induced modulation of BDNF protein in the NAc shell. CREB enhanced cocaine reinforcement when expressed either throughout acquisition of self-administration or when expression was limited to postacquisition tests, indicating a direct effect of CREB independent of reinforcement-related learning. Downregulating endogenous CREB in NAc shell by expressing a short hairpin RNA reduced cocaine reinforcement in similar tests, while overexpression of a dominant-negative CREB(S133A) mutant had no significant effect on cocaine self-administration. Finally, increasing CREB expression after withdrawal from self-administration enhanced cocaine-primed relapse, while reducing CREB levels facilitated extinction of cocaine seeking, but neither altered relapse induced by cocaine cues or footshock stress. Together, these findings indicate that CREB activity in NAc shell increases the motivation for cocaine during active self-administration or after withdrawal from cocaine. Our results also highlight that volitional and passive drug administration can lead to substantially different behavioral outcomes.

  20. The nucleus accumbens 5-HTR4-CART pathway ties anorexia to hyperactivity

    Science.gov (United States)

    Jean, A; Laurent, L; Bockaert, J; Charnay, Y; Dusticier, N; Nieoullon, A; Barrot, M; Neve, R; Compan, V

    2012-01-01

    In mental diseases, the brain does not systematically adjust motor activity to feeding. Probably, the most outlined example is the association between hyperactivity and anorexia in Anorexia nervosa. The neural underpinnings of this ‘paradox', however, are poorly elucidated. Although anorexia and hyperactivity prevail over self-preservation, both symptoms rarely exist independently, suggesting commonalities in neural pathways, most likely in the reward system. We previously discovered an addictive molecular facet of anorexia, involving production, in the nucleus accumbens (NAc), of the same transcripts stimulated in response to cocaine and amphetamine (CART) upon stimulation of the 5-HT4 receptors (5-HTR4) or MDMA (ecstasy). Here, we tested whether this pathway predisposes not only to anorexia but also to hyperactivity. Following food restriction, mice are expected to overeat. However, selecting hyperactive and addiction-related animal models, we observed that mice lacking 5-HTR1B self-imposed food restriction after deprivation and still displayed anorexia and hyperactivity after ecstasy. Decryption of the mechanisms showed a gain-of-function of 5-HTR4 in the absence of 5-HTR1B, associated with CART surplus in the NAc and not in other brain areas. NAc-5-HTR4 overexpression upregulated NAc-CART, provoked anorexia and hyperactivity. NAc-5-HTR4 knockdown or blockade reduced ecstasy-induced hyperactivity. Finally, NAc-CART knockdown suppressed hyperactivity upon stimulation of the NAc-5-HTR4. Additionally, inactivating NAc-5-HTR4 suppressed ecstasy's preference, strengthening the rewarding facet of anorexia. In conclusion, the NAc-5-HTR4/CART pathway establishes a ‘tight-junction' between anorexia and hyperactivity, suggesting the existence of a primary functional unit susceptible to limit overeating associated with resting following homeostasis rules. PMID:23233022

  1. Increases in cytoplasmic dopamine compromise the normal resistance of the nucleus accumbens to methamphetamine neurotoxicity.

    Science.gov (United States)

    Thomas, David M; Francescutti-Verbeem, Dina M; Kuhn, Donald M

    2009-06-01

    Methamphetamine (METH) is a neurotoxic drug of abuse that damages the dopamine (DA) neuronal system in a highly delimited manner. The brain structure most affected by METH is the caudate-putamen (CPu) where long-term DA depletion and microglial activation are most evident. Even damage within the CPu is remarkably heterogenous with lateral and ventral aspects showing the greatest deficits. The nucleus accumbens (NAc) is largely spared of the damage that accompanies binge METH intoxication. Increases in cytoplasmic DA produced by reserpine, L-DOPA or clorgyline prior to METH uncover damage in the NAc as evidenced by microglial activation and depletion of DA, tyrosine hydroxylase (TH), and the DA transporter. These effects do not occur in the NAc after treatment with METH alone. In contrast to the CPu where DA, TH, and DA transporter levels remain depleted chronically, DA nerve ending alterations in the NAc show a partial recovery over time. None of the treatments that enhance METH toxicity in the NAc and CPu lead to losses of TH protein or DA cell bodies in the substantia nigra or the ventral tegmentum. These data show that increases in cytoplasmic DA dramatically broaden the neurotoxic profile of METH to include brain structures not normally targeted for damage by METH alone. The resistance of the NAc to METH-induced neurotoxicity and its ability to recover reveal a fundamentally different neuroplasticity by comparison to the CPu. Recruitment of the NAc as a target of METH neurotoxicity by alterations in DA homeostasis is significant in light of the important roles played by this brain structure.

  2. MCH and apomorphine in combination enhance action potential firing of nucleus accumbens shell neurons in vitro

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    F Woodward Hopf

    2013-04-01

    Full Text Available The MCH and dopamine receptor systems have been shown to modulate a number of behaviors related to reward processing, addiction, and neuropsychiatric conditions such as schizophrenia and depression. In addition, MCH and dopamine receptors can interact in a positive manner, for example in the expression of cocaine self-administration. A recent report (Chung et al., 2011a showed that the DA1/DA2 dopamine receptor activator apomorphine suppresses pre-pulse inhibition, a preclinical model for some aspects of schizophrenia. Importantly, MCH can enhance the effects of lower doses of apomorphine, suggesting that co-modulation of dopamine and MCH receptors might alleviate some symptoms of schizophrenia with a lower dose of dopamine receptor modulator and thus fewer potential side effects. Here, we investigated whether MCH and apomorphine could enhance action potential firing in vitro in the nucleus accumbens shell (NAshell, a region which has previously been shown to mediate some behavioral effects of MCH. Using whole-cell patch-clamp electrophysiology, we found that MCH, which has no effect on firing on its own, was able to increase NAshell firing when combined with a subthreshold dose of apomorphine. Further, this MCH/apomorphine increase in firing was prevented by an antagonist of either a DA1 or a DA2 receptor, suggesting that apomorphine acts through both receptor types to enhance NAshell firing. The MCH/apomorphine-mediated firing increase was also prevented by an MCH receptor antagonist or a PKA inhibitor. Taken together, our results suggest that MCH can interact with lower doses of apomorphine to enhance NAshell firing, and thus that MCH and apomorphine might interact in vivo within the NAshell to suppress pre-pulse inhibition.

  3. SIRT1-FOXO3a regulate cocaine actions in the nucleus accumbens.

    Science.gov (United States)

    Ferguson, Deveroux; Shao, Ningyi; Heller, Elizabeth; Feng, Jian; Neve, Rachael; Kim, Hee-Dae; Call, Tanessa; Magazu, Samantha; Shen, Li; Nestler, Eric J

    2015-02-18

    Previous studies have shown that chronic cocaine administration induces SIRT1, a Class III histone deacetylase, in the nucleus accumbens (NAc), a key brain reward region, and that such induction influences the gene regulation and place conditioning effects of cocaine. To determine the mechanisms by which SIRT1 mediates cocaine-induced plasticity in NAc, we used chromatin immunoprecipitation followed by massively parallel sequencing (ChIP-seq), 1 d after 7 daily cocaine (20 mg/kg) or saline injections, to map SIRT1 binding genome-wide in mouse NAc. Our unbiased results revealed two modes of SIRT1 action. First, despite its induction in NAc, chronic cocaine causes depletion of SIRT1 from most affected gene promoters in concert with enrichment of H4K16ac (itself a deacetylation target of SIRT1), which is associated with increased expression of these genes. Second, we deduced the forkhead transcription factor (FOXO) family to be a downstream mechanism through which SIRT1 regulates cocaine action. We proceeded to demonstrate that SIRT1 induction causes the deacetylation and activation of FOXO3a in NAc, which leads to the induction of several known FOXO3a gene targets in other systems. Finally, we directly establish a role for FOXO3a in promoting cocaine-elicited behavioral responses by use of viral-mediated gene transfer: we show that overexpressing FOXO3a in NAc enhances cocaine place conditioning. The discovery of these two actions of SIRT1 in NAc in the context of behavioral adaptations to cocaine represents an important step forward in advancing our understanding of the molecular adaptations underlying cocaine action.

  4. Ceftriaxone attenuates cocaine relapse after abstinence through modulation of nucleus accumbens AMPA subunit expression.

    Science.gov (United States)

    LaCrosse, Amber L; Hill, Kristine; Knackstedt, Lori A

    2016-02-01

    Using the extinction-reinstatement model of cocaine relapse, we and others have demonstrated that the antibiotic ceftriaxone attenuates cue- and cocaine-primed reinstatement of cocaine-seeking. Reinstatement is contingent on the release of glutamate in the nucleus accumbens core (NAc) and manipulations that reduce glutamate efflux or block post-synaptic glutamate receptors attenuate reinstatement. We have demonstrated that the mechanism of action by which ceftriaxone attenuates reinstatement involves increased NAc GLT-1 expression and a reduction in NAc glutamate efflux during reinstatement. Here we investigated the effects of ceftriaxone (100 and 200 mg/kg) on context-primed relapse following abstinence without extinction training and examined the effects of ceftriaxone on GluA1, GluA2 and GLT-1 expression. We conducted microdialysis during relapse to determine if an increase in NAc glutamate accompanies relapse after abstinence and whether ceftriaxone blunts glutamate efflux. We found that both doses of ceftriaxone attenuated relapse. While relapse was accompanied by an increase in NAc glutamate, ceftriaxone (200 mg/kg) was unable to significantly reduce NAc glutamate efflux during relapse despite its ability to upregulate GLT-1. GluA1 was reduced in the NAc by both doses of ceftriaxone while GluA2 expression was unchanged, indicating that ceftriaxone altered AMPA subunit composition following cocaine. Finally, GLT-1 was not altered in the PFC by ceftriaxone. These results indicate that it is possible to attenuate context-primed relapse to cocaine-seeking through modification of post-synaptic receptor properties without attenuating glutamate efflux during relapse. Furthermore, increasing NAc GLT-1 protein expression is not sufficient to attenuate glutamate efflux.

  5. Reduced Caudate and Nucleus Accumbens Response to Rewards in Unmedicated Subjects with Major Depressive Disorder

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    Pizzagalli, Diego A.; Holmes, Avram J.; Dillon, Daniel G.; Goetz, Elena L.; Birk, Jeffrey L.; Bogdan, Ryan; Dougherty, Darin D.; Iosifescu, Dan V.; Rauch, Scott L.; Fava, Maurizio

    2009-01-01

    Objective Major depressive disorder (MDD) is characterized by impaired reward processing, possibly due to dysfunction in the basal ganglia. However, few neuroimaging studies of depression have distinguished between anticipatory and consummatory phases of reward processing. Using functional magnetic resonance imaging (fMRI) and a task that dissociates anticipatory and consummatory phases of reward processing, the authors tested the hypothesis that MDD participants would show reduced reward-related responses in basal ganglia structures. Method A monetary incentive delay task was presented to 30 unmedicated MDD subjects and 31 healthy comparison subjects during fMRI scanning. Whole-brain analyses focused on neural responses to reward-predicting cues and rewarding outcomes (i.e., monetary gains). Secondary analyses focused on the relationship between anhedonic symptoms and basal ganglia volumes. Results Relative to comparison subjects, MDD participants showed significantly weaker responses to gains in the left nucleus accumbens and bilateral caudate. Group differences in these regions were specific to rewarding outcomes and did not generalize to neutral or negative outcomes, although relatively reduced responses to monetary penalties in MDD emerged in other caudate regions. By contrast, evidence for group differences during reward anticipation was weaker, although MDD subjects showed reduced activation to reward cues in a small sector of the left posterior putamen. Among MDD subjects, anhedonic symptoms and depression severity were associated with reduced bilateral caudate volume. Conclusions These results indicate that basal ganglia dysfunction in MDD may affect the consummatory phase of reward processing. Additionally, morphometric results suggest that anhedonia in MDD is related to caudate volume. PMID:19411368

  6. Beer self-administration provokes lateralized nucleus accumbens dopamine release in male heavy drinkers.

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    Oberlin, Brandon G; Dzemidzic, Mario; Tran, Stella M; Soeurt, Christina M; O'Connor, Sean J; Yoder, Karmen K; Kareken, David A

    2015-03-01

    Although striatal dopamine (DA) is important in alcohol abuse, the nature of DA release during actual alcohol drinking is unclear, since drinking includes self-administration of both conditioned flavor stimuli (CS) of the alcoholic beverage and subsequent intoxication, the unconditioned stimulus (US). Here, we used a novel self-administration analog to distinguish nucleus accumbens (NAcc) DA responses specific to the CS and US. Right-handed male heavy drinkers (n = 26) received three positron emission tomography (PET) scans with the D2/D3 radioligand [(11)C]raclopride (RAC) and performed a pseudo self-administration task that separately administered a flavor CS of either a habitually consumed beer or the appetitive control Gatorade®, concomitant with the US of ethanol intoxication (0.06 g/dL intravenous (IV) administration) or IV saline. Scan conditions were Gatorade flavor + saline (Gat&Sal), Gatorade flavor + ethanol (Gat&Eth), and beer flavor + ethanol (Beer&Eth). Ethanol (US) reduced RAC binding (inferring DA release) in the left (L) NAcc [Gat&Sal > Gat&Eth]. Beer flavor (CS) increased DA in the right (R) NAcc [Gat&Eth > Beer&Eth]. The combination of beer flavor and ethanol (CS + US), [Gat&Sal > Beer&Eth], induced DA release in bilateral NAcc. Self-reported intoxication during scanning correlated with L NAcc DA release. Relative to saline, infusion of ethanol increased alcoholic drink wanting. Our findings suggest lateralized DA function in the NAcc, with L NAcc DA release most reflecting intoxication, R NAcc DA release most reflecting the flavor CS, and the conjoint CS + US producing a bilateral NAcc response.

  7. Central and peripheral contributions to dynamic changes in nucleus accumbens glucose induced by intravenous cocaine

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    Wakabayashi, Ken T.; Kiyatkin, Eugene A.

    2015-01-01

    The pattern of neural, physiological and behavioral effects induced by cocaine is consistent with metabolic neural activation, yet direct attempts to evaluate central metabolic effects of this drug have produced controversial results. Here, we used enzyme-based glucose sensors coupled with high-speed amperometry in freely moving rats to examine how intravenous cocaine at a behaviorally active dose affects extracellular glucose levels in the nucleus accumbens (NAc), a critical structure within the motivation-reinforcement circuit. In drug-naive rats, cocaine induced a bimodal increase in glucose, with the first, ultra-fast phasic rise appearing during the injection (latency 6–8 s; ~50 μM or ~5% of baseline) followed by a larger, more prolonged tonic elevation (~100 μM or 10% of baseline, peak ~15 min). While the rapid, phasic component of the glucose response remained stable following subsequent cocaine injections, the tonic component progressively decreased. Cocaine-methiodide, cocaine's peripherally acting analog, induced an equally rapid and strong initial glucose rise, indicating cocaine's action on peripheral neural substrates as its cause. However, this analog did not induce increases in either locomotion or tonic glucose, suggesting direct central mediation of these cocaine effects. Under systemic pharmacological blockade of dopamine transmission, both phasic and tonic components of the cocaine-induced glucose response were only slightly reduced, suggesting a significant role of non-dopamine mechanisms in cocaine-induced accumbal glucose influx. Hence, intravenous cocaine induces rapid, strong inflow of glucose into NAc extracellular space by involving both peripheral and central, non-dopamine drug actions, thus preventing a possible deficit resulting from enhanced glucose use by brain cells. PMID:25729349

  8. Interacting Cannabinoid and Opioid Receptors in the Nucleus Accumbens Core Control Adolescent Social Play.

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    Manduca, Antonia; Lassalle, Olivier; Sepers, Marja; Campolongo, Patrizia; Cuomo, Vincenzo; Marsicano, Giovanni; Kieffer, Brigitte; Vanderschuren, Louk J M J; Trezza, Viviana; Manzoni, Olivier J J

    2016-01-01

    Social play behavior is a highly rewarding, developmentally important form of social interaction in young mammals. However, its neurobiological underpinnings remain incompletely understood. Previous work has suggested that opioid and endocannabinoid neurotransmission interact in the modulation of social play. Therefore, we combined behavioral, pharmacological, electrophysiological, and genetic approaches to elucidate the role of the endocannabinoid 2-arachidonoylglycerol (2-AG) in social play, and how cannabinoid and opioid neurotransmission interact to control social behavior in adolescent rodents. Systemic administration of the 2-AG hydrolysis inhibitor JZL184 or the opioid receptor agonist morphine increased social play behavior in adolescent rats. These effects were blocked by systemic pretreatment with either CB1 cannabinoid receptor (CB1R) or mu-opioid receptor (MOR) antagonists. The social play-enhancing effects of systemic morphine or JZL184 treatment were also prevented by direct infusion of the CB1R antagonist SR141716 and the MOR antagonist naloxone into the nucleus accumbens core (NAcC). Searching for synaptic correlates of these effects in adolescent NAcC excitatory synapses, we observed that CB1R antagonism blocked the effect of the MOR agonist DAMGO and, conversely, that naloxone reduced the effect of a cannabinoid agonist. These results were recapitulated in mice, and completely abolished in CB1R and MOR knockout mice, suggesting that the functional interaction between CB1R and MOR in the NAcC in the modulation of social behavior is widespread in rodents. The data shed new light on the mechanism by which endocannabinoid lipids and opioid peptides interact to orchestrate rodent socioemotional behaviors.

  9. Interacting cannabinoid and opioid receptors in the nucleus accumbens core control adolescent social play

    Directory of Open Access Journals (Sweden)

    Antonia Manduca

    2016-11-01

    Full Text Available Social play behavior is a highly rewarding, developmentally important form of social interaction in young mammals. However, its neurobiological underpinnings remain incompletely understood. Previous work has suggested that opioid and endocannabinoid neurotransmission interact in the modulation of social play. Therefore, we combined behavioral, pharmacological, electrophysiological and genetic approaches to elucidate the role of the endocannabinoid 2-arachidonoylglycerol (2-AG in social play, and how cannabinoid and opioid neurotransmission interact to control social behavior in adolescent rodents. Systemic administration of the 2-AG hydrolysis inhibitor JZL184 or the opioid receptor agonist morphine increased social play behavior in adolescent rats. These effects were blocked by systemic pretreatment with either CB1 cannabinoid receptor (CB1R or mu-opioid receptor (MOR antagonists. The social play-enhancing effects of systemic morphine or JZL184 treatment were also prevented by direct infusion of the CB1R antagonist SR141716 and the MOR antagonist naloxone into the nucleus accumbens core (NAcC. Searching for synaptic correlates of these effects in adolescent NAcC excitatory synapses, we observed that CB1R antagonism blocked the effect of the MOR agonist DAMGO and, conversely, that naloxone reduced the effect of a cannabinoid agonist. These results were recapitulated in mice, and completely abolished in CB1R and MOR knockout mice, suggesting that the functional interaction between CB1R and MOR in the NAcC in the modulation of mediates social behavior is widespread in rodents. The data shed new light on the mechanism by which endocannabinoid lipids and opioid peptides interact to orchestrate rodent socioemotional behaviors.

  10. Oxytocin in the nucleus accumbens core reduces reinstatement of methamphetamine-seeking behaviour in rats.

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    Baracz, Sarah J; Everett, Nicholas A; McGregor, Iain S; Cornish, Jennifer L

    2016-03-01

    The psychostimulant methamphetamine (METH) is an addictive illicit drug. Systemic administration of the neuropeptide oxytocin modulates METH-related reward and METH-seeking behaviour. Recent findings demonstrated a reduction in METH-induced reward by oxytocin administration into the nucleus accumbens (NAc) core. It is not known, however, if oxytocin acts in this region to reduce relapse to METH-seeking behaviour. Using the drug reinstatement paradigm in rats experienced at METH self-administration, we aimed to determine whether oxytocin pre-treatment within the NAc core would reduce relapse to METH use and if this could be reversed by the co-administration of the oxytocin receptor (OTR) antagonist desGly-NH2,d(CH2)5[D-Tyr2,Thr4]OVT. Male Sprague-Dawley rats underwent surgery to implant an intravenous jugular vein catheter and bilateral microinjection cannulae in the NAc core. Rats were then trained to self-administer intravenous METH (0.1 mg/kg/infusion) by lever press during 2-hour fixed ratio 1 scheduled sessions for 20 days. Following extinction of lever press activity, the effect of microinjecting saline, oxytocin (0.5 pmol, 1.5 pmol, 4.5 pmol) or co-administration of oxytocin (1.5 pmol) and desGly-NH2,d(CH2)5[D-Tyr2,Thr4]OVT (1 nmol, 3 nmol) in the NAc core (500 nl/side) was examined on METH-primed (1 mg/kg, i.p.) reinstatement of drug-seeking behaviour. Our results showed oxytocin directly administered into the NAc core decreased METH-primed reinstatement in a dose-dependent manner. Co-administration of the selective OTR antagonist did not specifically reverse the inhibitory effects of oxytocin on METH priming, suggesting mediation by receptors other than the OTR. These findings highlight an important modulatory effect of oxytocin in the NAc core on relapse to METH seeking.

  11. Dynamics of neural coding in the accumbens during extinction and reinstatement of rewarded behavior.

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    Janak, Patricia H; Chen, Ming-Teh; Caulder, Tara

    2004-09-23

    Neural correlates of reward-seeking behavior are observed in the nucleus accumbens (NAC). The dependence of these correlates upon the presence of a reward was studied by comparing the behavioral correlates observed when the presence of the reward was manipulated within a single behavioral session. Rats were well-trained on a continuous reinforcement instrumental task reinforced by 0.1 ml drops of 5% sucrose. Extracellular single-unit neural activity was recorded from electrode arrays implanted into the NAC when instrumental behavior was and then was not reinforced with sucrose (within-session extinction). A variable delay between the instrumental response and the sucrose delivery allowed for separation of neural activity related to these task events. A spike activity increase around the time of the instrumental response was the most common behavioral correlate, while a decrease in spike activity upon sucrose delivery was the second most common behavioral correlate. Following removal of the reinforcer, subjects continued to perform the instrumental response, allowing for the examination of response-related spike activity under extinction conditions in which the response was no longer reinforced by sucrose. A majority of the response-related neural activity patterns were lost when sucrose was no longer available. New neural responses also were detected during this period. For some subjects, the reinforcer was again made available during the same session. Encoding of the primary behavioral events during this period of reinstated reinforcer was similar, but not identical, to that observed during the first period of reinforced responding. These findings reveal that instrumental task-associated spike activity within the NAC is partially dependent upon the presence of the reinforcer, and that encoding across the population is distinct under reinforced and extinction conditions.

  12. Associations between personality changes and nucleus accumbens ablation in opioid addicts

    Institute of Scientific and Technical Information of China (English)

    Hai-kang ZHAO; Chong-wang CHANG; Ning GENG; Li GAO; Jing WANG; Xin WANG; Ya-rong WANG; Xue-lian WANG; Guo-dong GAO

    2012-01-01

    It has been reported that nucleus accumbens (NAc) lesions can help to prevent relapse in opioid addicts.This article aimed to investigate associations between personality changes and NAc lesions.Methods:The surgery group consisted of 78 patients who had received bilateral stereotactic lesions of the NAc to treat opioid addiction.Seventy two non-surgery opioid addicts were appropriately paired with the patients of the surgery group as the non-surgery group.All participants were interviewed in person and received urine tests,naloxone provocative tests and hair tests to determine the prevalence of relapse.Eysenck personality questionnaire (EPQ) and the health survey questionnaire (SF-36) were employed to assess personality and functional health,respectively.Results:In the surgery group,30 participants relapsed,and the non-relapse rate was 61.5% (48/78).Compared with the Chinese normative data,the neuroticism (N) and psychoticism (P) dimensions of the EPQ in the non-surgery group were significantly higher,whereas the lie (L) dimension was significantly lower.There was no significant difference in all dimensions of the EPQ between the surgery group and the Chinese normative data.The N dimension in the relapse group and the L dimension in the surgery group were significantly lower than those of the non-surgery group.The P dimension in the relapse group was significantly higher than that of the non-relapse group.The extraversion (E) dimension was relatively stable between these groups.Conclusion:Although the influence of other factors cannot be excluded,it is apparent that surgically induced NAc lesions are associated with lower P and N dimensions for opioid addicts,and a higher P dimension is associated with a tendency to relapse.

  13. Ketamine and imipramine in the nucleus accumbens regulate histone deacetylation induced by maternal deprivation and are critical for associated behaviors.

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    Réus, Gislaine Z; Abelaira, Helena M; dos Santos, Maria Augusta B; Carlessi, Anelise S; Tomaz, Débora B; Neotti, Morgana V; Liranço, João Lucas G; Gubert, Carolina; Barth, Maurício; Kapczinski, Flávio; Quevedo, João

    2013-11-01

    Studies indicate that histone deacetylation is important for long term changes related to stress and antidepressant treatment. The present study aimed to evaluate the effects of the classic antidepressant imipramine, and of an antagonist of the N-methyl-d-asparte (NMDA) receptor, ketamine, on behavior and histone deacetylase (HDAC) activity in the brains of maternally deprived adult rats. To this aim, deprived and non-deprived (control) male Wistar rats were divided into the following groups: non-deprived+saline; non-deprived+imipramine (30 mg/kg); non-deprived+ketamine (15 mg/kg); deprived+saline; deprived+imipramine (30 mg/kg); and deprived+ketamine (15 mg/kg). The drugs were administrated once a day for 14 days during their adult phase. Their behavior were then assessed using the forced swimming and open field tests. In addition, the HDAC activity was evaluated in the prefrontal cortex, hippocampus, amygdala and nucleus accumbens using the kit ELISA-sandwich test. In deprived rats treated with saline, we observed an increase in the immobility time, but treatments with imipramine and ketamine were able to reverse this alteration, decreasing the immobility time. Also, there was a decrease on number of crossings with imipramine treatment in non-deprived rats, and an increase on number of crossings with ketamine treatment in deprived rats. The HDAC activity did not alter in the prefrontal cortex, hippocampus and amygdala by deprivation or via treatment with imipramine or ketamine. However, in the nucleus accumbens we observed an increase of HDAC activity in the deprived rats, and interestingly, imipramine and ketamine treatments were able to decrease HDAC activity in this brain area. These findings provide a novel insight into the epigenetic regulation of histone deacetylase in the nucleus accumbens caused by imipramine and ketamine, and indicate that molecular events are necessary to reverse specific stress-induced behavior.

  14. Role of Dopamine Receptors Subtypes, D1-Like and D2-Like, within the Nucleus Accumbens Subregions, Core and Shell, on Memory Consolidation in the One-Trial Inhibitory Avoidance Task

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    Manago, Francesca; Castellano, Claudio; Oliverio, Alberto; Mele, Andrea; De Leonibus, Elvira

    2009-01-01

    Recent evidence demonstrated that dopamine within the nucleus accumbens mediates consolidation of both associative and nonassociative memories. However, the specific contribution of the nucleus accumbens subregions, core and shell, and of D1 and D2 receptors subtypes has not been yet clarified. The aim of this study was, therefore, to directly…

  15. Role of Dopamine Receptors Subtypes, D1-Like and D2-Like, within the Nucleus Accumbens Subregions, Core and Shell, on Memory Consolidation in the One-Trial Inhibitory Avoidance Task

    Science.gov (United States)

    Manago, Francesca; Castellano, Claudio; Oliverio, Alberto; Mele, Andrea; De Leonibus, Elvira

    2009-01-01

    Recent evidence demonstrated that dopamine within the nucleus accumbens mediates consolidation of both associative and nonassociative memories. However, the specific contribution of the nucleus accumbens subregions, core and shell, and of D1 and D2 receptors subtypes has not been yet clarified. The aim of this study was, therefore, to directly…

  16. Orexin in Rostral Hotspot of Nucleus Accumbens Enhances Sucrose 'Liking' and Intake but Scopolamine in Caudal Shell Shifts 'Liking' Toward 'Disgust' and 'Fear'.

    Science.gov (United States)

    Castro, Daniel C; Terry, Rachel A; Berridge, Kent C

    2016-07-01

    The nucleus accumbens (NAc) contains a hedonic hotspot in the rostral half of medial shell, where opioid agonist microinjections are known to enhance positive hedonic orofacial reactions to the taste of sucrose ('liking' reactions). Within NAc shell, orexin/hypocretin also has been reported to stimulate food intake and is implicated in reward, whereas blockade of muscarinic acetylcholine receptors by scopolamine suppresses intake and may have anti-reward effects. Here, we show that NAc microinjection of orexin-A in medial shell amplifies the hedonic impact of sucrose taste, but only within the same anatomically rostral site, identical to the opioid hotspot. By comparison, at all sites throughout medial shell, orexin microinjections stimulated 'wanting' to eat, as reflected by increases in intake of palatable sweet chocolates. At NAc shell sites outside the hotspot, orexin selectively enhanced 'wanting' to eat without enhancing sweetness 'liking' reactions. In contrast, microinjections of the antagonist scopolamine at all sites in NAc shell suppressed sucrose 'liking' reactions as well as suppressing intake of palatable food. Conversely, scopolamine increased aversive 'disgust' reactions elicited by bitter quinine at all NAc shell sites. Finally, scopolamine microinjections localized to the caudal half of medial shell additionally generated a fear-related anti-predator reaction of defensive treading and burying directed toward the corners of the transparent chamber. Together, these results confirm a rostral hotspot in NAc medial shell as a unique site for orexin induction of hedonic 'liking' enhancement, similar to opioid enhancement. They also reveal distinct roles for orexin and acetylcholine signals in NAc shell for hedonic reactions and motivated behaviors.

  17. Chronic ethanol intake-induced changes in open-field behavior and calcium/calmodulin-dependent protein kinase Ⅳ expression in nucleus accumbens of rats: naloxone reversal

    Institute of Scientific and Technical Information of China (English)

    Jing LI; Wei-liang BIAN; Gui-qin XIE; Sheng-zhong CUI; Mei-ling WU; Yue-hua LI; Ling-li QUE; Xiao-ru YUAN

    2008-01-01

    Aim: To investigate the effects of chronic ethanol intake on the locomotor activity and the levels of calcium/calmodulin-dependent protein kinase Ⅳ (CaM kinase Ⅳ) in the nucleus accumbens (NAc) of rats. Simultaneously, the effects of non-selective opioid antagonist (naloxone) on the CaM kinase Ⅳ expression in the NAc and ethanol consumption of rats were also observed. Methods: Ethanol was administered in drinking water at the concentrations of 6% (v/v), for 28 d. The locomotor activity of rats was investigated in the open-field apparatus. CaM kinase Ⅳ levels in the NAc were analyzed using Western blotting. Results: Rats consuming ethanol solution exhibited a significant decrease of ambulation activity, accompanied by a reduced frequency of explorative rearing in an open-field task on d 7 and d 14 of chronic ethanol ingestion, whereas presumed adaptation to the neurological effects of ethanol was observed on d 28. Chronic ethanol intake elicited a significant decrease of the CaM kinase Ⅳ expression in the nuclei, but not in the cytoplasm of the NAc on d 28. Naloxone treatment significantly attenu-ated ethanol intake of rats and antagonized the decrease of CaM kinase Ⅳ in the nuclei of NAc neurons. The cytosolic CaM kinase Ⅳ protein levels of the NAc also increased in rats exposed to ethanol plus naloxone. Conclusion: Chronic ethanol intake-induced changes in explorative behavior is mediated at least partly by changes in CaM kinase Ⅳ signaling in the nuclei of the NAc, and naloxone attenuates ethanol consumption through antagonizing the downregulation of CaM kinase Ⅳ in the NAc.

  18. Role of dopamine in the plasticity of glutamic acid decarboxylase messenger RNA in the rat frontal cortex and the nucleus accumbens.

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    Rétaux, S; Trovero, F; Besson, M J

    1994-12-01

    The modulatory role of dopamine (DA) on the expression of mRNA encoding the large isoform of glutamic acid decarboxylase (GAD67), the biosynthesis enzyme of gamma aminobutyric acid (GABA), was examined in GABA neurons of two structures innervated by DA neurons originating from the ventral tegmental area (VTA): the medial frontal cortex (MFC) and the nucleus accumbens (NAcc). A bilateral electrolytic lesion of VTA was performed in rats to produce a DA denervation of both the MFC and NAcc. The efficacy of VTA lesions was verified by measurement of locomotor activity and by immunohistochemical detection of tyrosine hydroxylase in the mesencephalon. GAD67 mRNA was detected by in situ hybridization histochemistry using a 35S-labelled cDNA probe. Densitometric analysis of GAD67 mRNA hybridization signals revealed in VTA-lesioned rats a significant decrease (-24%) in GAD67 mRNA levels in the prelimbic area of the MFC and no significant effect in the anterior cingulate area or the frontoparietal cortex. Single cell analyses by computer-assisted grain counting showed that the decrease in GAD67 mRNA levels in prelimbic MFC was due to a change in GAD67 mRNA expression in a subpopulation of GABA interneurons located in the deep cortical layers (V-VI). By contrast, in the NAcc of VTA-lesioned rats, GAD67 mRNA levels were significantly increased in the anterior part and in the core but were unchanged in the shell part. These results suggest that in two target structures of VTA DA neurons, GAD67 mRNA expression is, in normal conditions, under a tonic stimulatory and a tonic inhibitory DA control in the MFC and the NAcc respectively. A schematic diagram is proposed for functional interactions between these structures.

  19. Comparison of the MK-801-induced appetitive extinction deficit with pressing for reward and associated pERK1/2 staining in prefrontal cortex and nucleus accumbens.

    Science.gov (United States)

    Holahan, Matthew R; Westby, Erin P; Albert, Katrina

    2012-03-01

    Administration of the noncompetitive N-methyl-d-aspartate (NMDA)-receptor antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801) has been shown to produce extinction deficits on appetitive operant tasks. The present study sought to further explore this by comparing extinction pressing to pressing for the primary reward and examining associated neural correlates to determine if the MK-801 extinction profile resembled the behavioral and neural profile associated with pressing for primary reward. Immunohistochemical labeling of phosphorylated extracellular signal-regulated kinase-1 and -2(pERK1/2) in the prelimbic (PrL) and infralimbic (IL) cortices and nucleus accumbens shell (AcbSh) and core (AcbC) was examined after rewarded or extinction lever pressing conditions. A dose-response curve revealed a within-day extinction deficit following administration of 0.05 mg/kg MK-801. All doses of MK-801 were associated with reduced IL pERK1/2 staining but only the 0.05 mg/kg dose was associated with elevated AcbSh pERK1/2 labeling. Extinction pressing under the influence of MK-801 was elevated compared to that seen during rewarded pressing-whether on MK-801 or saline. Rewarded pressing following saline or MK-801 was associated with elevated pERK1/2 in the PrL with no similar patterns in the MK-801/extinction group. There was more pERK1/2 labeling in the AcbSh of the MK-801 extinction group than any other condition. These data suggest that the MK-801-induced extinction deficit may be due to the combination of an underactive cortical behavioral inhibition system and an overactive AcbSh reward system.

  20. Repeated cocaine enhances ventral hippocampal-stimulated dopamine efflux in the nucleus accumbens and alters ventral hippocampal NMDA receptor subunit expression.

    Science.gov (United States)

    Barr, Jeffrey L; Forster, Gina L; Unterwald, Ellen M

    2014-08-01

    Dopaminergic neurotransmission in the nucleus accumbens is important for various reward-related cognitive processes including reinforcement learning. Repeated cocaine enhances hippocampal synaptic plasticity, and phasic elevations of accumbal dopamine evoked by unconditioned stimuli are dependent on impulse flow from the ventral hippocampus. Therefore, sensitized hippocampal activity may be one mechanism by which drugs of abuse enhance limbic dopaminergic activity. In this study, in vivo microdialysis in freely moving adult male Sprague-Dawley rats was used to investigate the effect of repeated cocaine on ventral hippocampus-mediated dopaminergic transmission within the medial shell of the nucleus accumbens. Following seven daily injections of saline or cocaine (20 mg/kg, ip), unilateral infusion of N-methyl-d-aspartate (NMDA, 0.5 μg) into the ventral hippocampus transiently increased both motoric activity and ipsilateral dopamine efflux in the medial shell of the nucleus accumbens, and this effect was greater in rats that received repeated cocaine compared to controls that received repeated saline. In addition, repeated cocaine altered NMDA receptor subunit expression in the ventral hippocampus, reducing the NR2A : NR2B subunit ratio. Together, these results suggest that repeated exposure to cocaine produces maladaptive ventral hippocampal-nucleus accumbens communication, in part through changes in glutamate receptor composition. A behaviorally sensitizing regimen of cocaine (20 mg/kg, ip 7 days) also sensitized ventral hippocampus (hipp)-mediated dopaminergic transmission within the nucleus accumbens (Nac) to NMDA stimulation (bolts). This was associated with reduced ventral hippocampal NR2A:NR2B subunit ratio, suggesting that repeated exposure to cocaine produces changes in hippocampal NMDA receptor composition that lead to enhanced ventral hippocampus-nucleus accumbens communication.

  1. Integrating mRNA and miRNA Weighted Gene Co-Expression Networks with eQTLs in the Nucleus Accumbens of Subjects with Alcohol Dependence.

    Directory of Open Access Journals (Sweden)

    Mohammed Mamdani

    Full Text Available Alcohol consumption is known to lead to gene expression changes in the brain. After performing weighted gene co-expression network analyses (WGCNA on genome-wide mRNA and microRNA (miRNA expression in Nucleus Accumbens (NAc of subjects with alcohol dependence (AD; N = 18 and of matched controls (N = 18, six mRNA and three miRNA modules significantly correlated with AD were identified (Bonferoni-adj. p≤ 0.05. Cell-type-specific transcriptome analyses revealed two of the mRNA modules to be enriched for neuronal specific marker genes and downregulated in AD, whereas the remaining four mRNA modules were enriched for astrocyte and microglial specific marker genes and upregulated in AD. Gene set enrichment analysis demonstrated that neuronal specific modules were enriched for genes involved in oxidative phosphorylation, mitochondrial dysfunction and MAPK signaling. Glial-specific modules were predominantly enriched for genes involved in processes related to immune functions, i.e. cytokine signaling (all adj. p≤ 0.05. In mRNA and miRNA modules, 461 and 25 candidate hub genes were identified, respectively. In contrast to the expected biological functions of miRNAs, correlation analyses between mRNA and miRNA hub genes revealed a higher number of positive than negative correlations (χ2 test p≤ 0.0001. Integration of hub gene expression with genome-wide genotypic data resulted in 591 mRNA cis-eQTLs and 62 miRNA cis-eQTLs. mRNA cis-eQTLs were significantly enriched for AD diagnosis and AD symptom counts (adj. p = 0.014 and p = 0.024, respectively in AD GWAS signals in a large, independent genetic sample from the Collaborative Study on Genetics of Alcohol (COGA. In conclusion, our study identified putative gene network hubs coordinating mRNA and miRNA co-expression changes in the NAc of AD subjects, and our genetic (cis-eQTL analysis provides novel insights into the etiological mechanisms of AD.

  2. Activation of muscarinic and nicotinic acetylcholine receptors in the nucleus accumbens core is necessary for the acquisition of drug reinforcement.

    Science.gov (United States)

    Crespo, Jose A; Sturm, Katja; Saria, Alois; Zernig, Gerald

    2006-05-31

    Neurotransmitter release in the nucleus accumbens core (NACore) during the acquisition of remifentanil or cocaine reinforcement was determined in an operant runway procedure by simultaneous tandem mass spectrometric analysis of dopamine, acetylcholine, and remifentanil or cocaine itself. Run times for remifentanil or cocaine continually decreased over the five consecutive runs of the experiment. Intra-NACore dopamine, acetylcholine, and drug peaked with each intravenous remifentanil or cocaine self-administration and decreased to pre-run baseline with half-lives of approximately 10 min. As expected, remifentanil or cocaine peaks did not vary between the five runs. Surprisingly, however, drug-contingent dopamine peaks also did not change over the five runs, whereas acetylcholine peaks did. Thus, the acquisition of drug reinforcement was paralleled by a continuous increase in acetylcholine overflow in the NACore, whereas the overflow of dopamine, the expected prime neurotransmitter candidate for conditioning in drug reinforcement, did not increase. Local intra-accumbens administration by reverse microdialysis of either atropine or mecamylamine completely and reversibly blocked the acquisition of remifentanil reinforcement. Our findings suggest that activation of muscarinic and nicotinic acetylcholine receptors in the NACore by acetylcholine volume transmission is necessary during the acquisition phase of drug reinforcement conditioning.

  3. The Effects of Histaminergic Agents in the Nucleus Accumbens of Rats in the Elevated Plus-Maze Test of Anxiety

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    Mohammad-Reza Zarrindast

    2010-11-01

    Full Text Available ABSTRACTIntroduction/Aims: The nucleus accumbens (NAc receives histaminergic neurons from tuberomammillary nuclei. There are also reports indicating that central histamine systems are involved in many physiological behavioral processes, including anxiety. The aim of the present study was to assess whether the histaminergic system of the NAc is involved in the anxiety-related behaviors. Methods: As a model of anxiety the elevated plus maze which is a useful test to investigate the effects of anxiogenic or anxiolytic drugs in rodents was used in male Wistar rats. Results:Intra-NAc administration of histamine (0.01, 0.1 and 1 μg/rat increased the percentage of open arm time (%OAT and open arm entries (%OAE but not locomotor activity, indicating an anxiolytic response. Furthermore, bilateral microinjections of different doses of the H1 receptor antagonist pyrilamine (0.001, 0.01, 0.1 and 1 μg/rat or the H2 receptor antagonist ranitidine (0.001, 0.01, 0.1 and 1 μg/rat into the NAc increased %OAT and %OAE but not locomotor activity. However, both histamine and histamine receptor antagonists showed an anxiolytic-like effect, the antagonists (1 μg/rat also decreased the histamine response. Discussion: The results may indicate a modulatory effect for the H1 and H2 histamine receptors of nucleus accumbens in the anxiety behavior of rats.

  4. Biphasic firing response of nucleus accumbens neurons elicited by THPB-18 and its correlation with DA receptor subtypes

    Institute of Scientific and Technical Information of China (English)

    Yu FU; Zi-tao ZHU; Xing-zu ZHU; Guo-zhang JIN

    2004-01-01

    AIM: To investigate the possibility whether THPB-18 (l-12-shloroscoulerine) possesses the D1 agonist-D2 antagonist action on meso-accumbens-mPFC DA system. METHODS: Single unit spontaneous firing activity was recorded in the nucleus accumbens (Nac) neurons of naive and unilateral-6-hydroxydopamine (6-OHDA)-lesioned Sprague-Dawley rats. The effects of drugs applied intravenously or iontophoretically were determined by the change of firing rates. RESULTS: Under normal conditions, the systemic administration of THPB-18 produced a decrease-increase biphasic firing pattern in the Nac neurons during cumulative doses. High dose of THPB- 18 was capable of reversing the inhibition induced by both D2 agonist LY171555 and D1/D2 agonist APO on Nac firing activity. Spiperone pretreatment could not block the high dose of THPB-18-induced firing rate increase, which was reversed by the D1 selective antagonist SCH23390. The tested Nac neurons were effectively inhibited by iontophoretically applied THPB-18 in 90% of 6-OHDA-lesioned rats, while THPB-18 caused variable effects on the firing of Nac neurons in the neurons of unlesioned rats. The inhibitory effect of THPB-18 was blocked by iontophoretic application of SCH23390, but not D2 antagonist spiperone. CONCLUSION: Similar to l-stepholidine,THPB-18 also possesses the "D1 agonistic-D2 antagonistic" dual action on the VTA-Nac DA system.

  5. Investigating the dynamics of the brain response to music: A central role of the ventral striatum/nucleus accumbens.

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    Mueller, Karsten; Fritz, Thomas; Mildner, Toralf; Richter, Maxi; Schulze, Katrin; Lepsien, Jöran; Schroeter, Matthias L; Möller, Harald E

    2015-08-01

    Ventral striatal activity has been previously shown to correspond well to reward value mediated by music. Here, we investigate the dynamic brain response to music and manipulated counterparts using functional magnetic resonance imaging (fMRI). Counterparts of musical excerpts were produced by either manipulating the consonance/dissonance of the musical fragments or playing them backwards (or both). Results show a greater involvement of the ventral striatum/nucleus accumbens both when contrasting listening to music that is perceived as pleasant and listening to a manipulated version perceived as unpleasant (backward dissonant), as well as in a parametric analysis for increasing pleasantness. Notably, both analyses yielded a ventral striatal response that was strongest during an early phase of stimulus presentation. A hippocampal response to the musical stimuli was also observed, and was largely mediated by processing differences between listening to forward and backward music. This hippocampal involvement was again strongest during the early response to the music. Auditory cortex activity was more strongly evoked by the original (pleasant) music compared to its manipulated counterparts, but did not display a similar decline of activation over time as subcortical activity. These findings rather suggest that the ventral striatal/nucleus accumbens response during music listening is strongest in the first seconds and then declines.

  6. Differential activation of accumbens shell and core dopamine by sucrose reinforcement with nose poking and with lever pressing.

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    Bassareo, V; Cucca, F; Frau, R; Di Chiara, G

    2015-11-01

    In order to investigate the role of modus operandi in the changes of nucleus accumbens (NAc) dopamine (DA) transmission in sucrose reinforcement, extracellular DA was monitored by microdialysis in the NAc shell and core of rats trained on a fixed-ratio 1 schedule to respond for sucrose pellets by nose poking and lever pressing respectively. After training, rats were tested on three different sessions: sucrose reinforcement, extinction and passive sucrose presentation. In rats responding by nose poking dialysate DA increased in the shell but not in the core under reinforced as well as under extinction sessions. In contrast, in rats responding by lever pressing dialysate DA increased both in the accumbens shell and core under reinforced and extinction sessions. Response non-contingent sucrose presentation increased dialysate DA in the shell and core of rats trained to respond for sucrose by nose poking as well as in those trained by lever pressing. In rats trained to respond for sucrose by nose poking on a FR5 schedule dialysate DA also increased selectively in the NAc shell during reinforced responding and in both the shell and core under passive sucrose presentation. These findings, while provide an explanation for the discrepancies existing in the literature over the responsiveness of shell and core DA in rats responding for food, are consistent with the notion that NAc shell and core DA encode different aspects of reinforcement.

  7. Maternal deprivation enhances behavioral vulnerability to stress associated with miR-504 expression in nucleus accumbens of rats.

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    Yi Zhang

    Full Text Available OBJECTIVE: In this study, the effect of maternal deprivation (MD and chronic unpredictable stress (CUS in inducing depressive behaviors and associated molecular mechanism were investigated in rats. METHODS: Maternal deprivation was established by separating pups from their mothers for 6 hours daily from postnatal day 1 to day 14. Chronic unpredictable stress was established by water deprivation, elevated open platform, food deprivation, restraint stress and electric foot shock. The depressive behaviors were determined by use of sucrose preference test and forced swim test. RESULTS: Rats in MD/CUS group exhibited lower sucrose preference rate, longer immobility time, and lighter body weights than rats in other groups (MD/control, non-MD/CUS and non-MD/control group. Meanwhile, higher miR-504 expression and lower dopamine receptor D1 (DRD1 and D2 (DRD2 expression were observed in the nucleus accumbens of rats in the MD/CUS group than in the other three groups. MiR-504 expression correlated negatively with DRD1 gene expression and sucrose preference rate in the sucrose preference test, but correlated positively with immobility time in forced swim test. Both DRD2 mRNA and protein expression correlated negatively with immobility time in forced swim test. CONCLUSION: These results suggest that MD enhances behavioral vulnerability to stress during adulthood, which is associated with the upregulation of miR-504 and downregulation of DRD2 expression in the nucleus accumbens.

  8. A High-Fat Meal, or Intraperitoneal Administration of a Fat Emulsion, Increases Extracellular Dopamine in the Nucleus Accumbens

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    Bartley G. Hoebel

    2012-06-01

    Full Text Available Evidence links dopamine (DA in the nucleus accumbens (NAc shell to the ingestion of palatable diets. Less is known, however, about the specific relation of DA to dietary fat and circulating triglycerides (TG, which are stimulated by fat intake and promote overeating. The present experiments tested in Sprague-Dawley rats whether extracellular levels of NAc DA increase in response to acute access to fat-rich food or peripheral injection of a fat emulsion and, if so, whether this is related to caloric intake or elevated circulating lipids. When rats consumed more calories of a high-fat meal compared with a low-fat meal, there was a significant increase in extracellular accumbens DA (155% vs. 119%. Systemic injection of a fat emulsion, which like a high-fat diet raises circulating TG but eliminates the factor of taste and allows for the control of caloric intake, also significantly increased extracellular levels of DA (127% compared to an equicaloric glucose solution (70% and saline (85%. Together, this suggests that a rise in circulating TG may contribute to the stimulatory effect of a high-fat diet on NAc DA.

  9. Lesions of the nucleus accumbens core modulate development of matching behavior.

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    Kai, Nobuyuki; Tsutsui, Yuji; Kobayashi, Kazuto

    2014-04-30

    The development of choice is a crucial determinant in the performance of appetitive responses. Given two options with different reinforcement rates, animals match their relative rate of responding to the relative rates of reinforcement (i.e., matching behavior). A previous study has shown that the nucleus accumbens core (AcbC) is involved in the performance of matching behavior in trained animals. However, the role of the AcbC in the acquisition of matching behavior has not been addressed. We conducted a series of experimental sessions to examine the role of the AcbC on the development of matching behavior. Instrumental responding was measured in rats with excitotoxic lesions of the AcbC. Rats were given two options that differed in the relative rate of reinforcement under concurrent variable-interval schedules. The locations of the more frequently reinforced option and the alternative option were randomly switched between sessions. Lesions of the AcbC accelerated the development of matching behavior compared to the sham-operated group. The AcbC-lesioned rats exhibited closer conformity to the matching law than shams when the options were in the same positions as in the previous session (the same condition), but not when the option locations had been switched (the different condition). The AcbC rats showed smaller probabilities of switching behavior between alternatives than shams. Post-reinforcement pausing was not affected by the AcbC lesion. Neither numbers of rewards obtained nor number of lever presses were different between the AcbC-lesioned rats and shams over session blocks. Our results suggest that the AcbC plays a regulatory role in the development of matching behavior through switching probabilities rather than perception of reward magnitude. The differential effect of AcbC lesions on the matching behavior between the same and different conditions suggests influence of the spontaneous recovery, that is, reversion to a previously reinforced choice at the

  10. Natural reward experience alters AMPA and NMDA receptor distribution and function in the nucleus accumbens.

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    Kyle K Pitchers

    Full Text Available Natural reward and drugs of abuse converge upon the mesolimbic system which mediates motivation and reward behaviors. Drugs induce neural adaptations in this system, including transcriptional, morphological, and synaptic changes, which contribute to the development and expression of drug-related memories and addiction. Previously, it has been reported that sexual experience in male rats, a natural reward behavior, induces similar neuroplasticity in the mesolimbic system and affects natural reward and drug-related behavior. The current study determined whether sexual experience causes long-lasting changes in mating, or ionotropic glutamate receptor trafficking or function in the nucleus accumbens (NAc, following 3 different reward abstinence periods: 1 day, 1 week, or 1 month after final mating session. Male Sprague Dawley rats mated during 5 consecutive days (sexual experience or remained sexually naïve to serve as controls. Sexually experienced males displayed facilitation of initiation and performance of mating at each time point. Next, intracellular and membrane surface expression of N-methyl-D-aspartate (NMDA: NR1 subunit and α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA: GluA1, GluA2 subunits receptors in the NAc was determined using a bis(sulfosuccinimidylsuberate (BS(3 protein cross-linking assay followed by Western Blot analysis. NR1 expression was increased at 1 day abstinence both at surface and intracellular, but decreased at surface at 1 week of abstinence. GluA2 was increased intracellularly at 1 week and increased at the surface after 1 month of abstinence. Finally, whole-cell patch clamp electrophysiological recordings determined reduced AMPA/NMDA ratio of synaptic currents in NAc shell neurons following stimulation of cortical afferents in sexually experienced males after all reward abstinence periods. Together, these data show that sexual experience causes long-term alterations in glutamate receptor expression and

  11. Loss of Plasticity in the D2-Accumbens Pallidal Pathway Promotes Cocaine Seeking.

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    Heinsbroek, Jasper A; Neuhofer, Daniela N; Griffin, William C; Siegel, Griffin S; Bobadilla, Ana-Clara; Kupchik, Yonatan M; Kalivas, Peter W

    2017-01-25

    Distinct populations of D1- and D2-dopamine receptor-expressing medium spiny neurons (D1-/D2-MSNs) comprise the nucleus accumbens, and activity in D1-MSNs promotes, whereas activity in D2-MSNs inhibits, motivated behaviors. We used chemogenetics to extend D1-/D2-MSN cell specific regulation to cue-reinstated cocaine seeking in a mouse model of self-administration and relapse, and found that either increasing activity in D1-MSNs or decreasing activity in D2-MSNs augmented cue-induced reinstatement. Both D1- and D2-MSNs provide substantial GABAergic innervation to the ventral pallidum, and chemogenetic inhibition of ventral pallidal neurons blocked the augmented reinstatement elicited by chemogenetic regulation of either D1- or D2-MSNs. Because D1- and D2-MSNs innervate overlapping populations of ventral pallidal neurons, we next used optogenetics to examine whether changes in synaptic plasticity in D1- versus D2-MSN GABAergic synapses in the ventral pallidum could explain the differential regulation of VP activity. In mice trained to self-administer cocaine, GABAergic LTD was abolished in D2-, but not in D1-MSN synapses. A μ opioid receptor antagonist restored GABA currents in D2-, but not D1-MSN synapses of cocaine-trained mice, indicating that increased enkephalin tone on presynaptic μ opioid receptors was responsible for occluding the LTD. These results identify a behavioral function for D1-MSN innervation of the ventral pallidum, and suggest that losing LTDGABA in D2-MSN, but not D1-MSN input to ventral pallidum may promote cue-induced reinstatement of cocaine-seeking. More than 90% of ventral striatum is composed of two cell types, those expressing dopamine D1 or D2 receptors, which exert opposing roles on motivated behavior. Both cell types send GABAergic projections to the ventral pallidum and were found to differentially promote cue-induced reinstatement of cocaine seeking via the ventral pallidum. Furthermore, after cocaine self-administration, synaptic

  12. Dynamic shaping of dopamine signals during probabilistic Pavlovian conditioning.

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    Hart, Andrew S; Clark, Jeremy J; Phillips, Paul E M

    2015-01-01

    Cue- and reward-evoked phasic dopamine activity during Pavlovian and operant conditioning paradigms is well correlated with reward-prediction errors from formal reinforcement learning models, which feature teaching signals in the form of discrepancies between actual and expected reward outcomes. Additionally, in learning tasks where conditioned cues probabilistically predict rewards, dopamine neurons show sustained cue-evoked responses that are correlated with the variance of reward and are maximal to cues predicting rewards with a probability of 0.5. Therefore, it has been suggested that sustained dopamine activity after cue presentation encodes the uncertainty of impending reward delivery. In the current study we examined the acquisition and maintenance of these neural correlates using fast-scan cyclic voltammetry in rats implanted with carbon fiber electrodes in the nucleus accumbens core during probabilistic Pavlovian conditioning. The advantage of this technique is that we can sample from the same animal and recording location throughout learning with single trial resolution. We report that dopamine release in the nucleus accumbens core contains correlates of both expected value and variance. A quantitative analysis of these signals throughout learning, and during the ongoing updating process after learning in probabilistic conditions, demonstrates that these correlates are dynamically encoded during these phases. Peak CS-evoked responses are correlated with expected value and predominate during early learning while a variance-correlated sustained CS signal develops during the post-asymptotic updating phase.

  13. Intermittent-access binge consumption of sweet high-fat liquid does not require opioid or dopamine receptors in the nucleus accumbens.

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    Lardeux, Sylvie; Kim, James J; Nicola, Saleem M

    2015-10-01

    Binge eating disorders are characterized by episodes of intense consumption of high-calorie food. In recently developed animal models of binge eating, rats given intermittent access to such food escalate their consumption over time. Consumption of calorie-dense food is associated with neurochemical changes in the nucleus accumbens, including dopamine release and alterations in dopamine and opioid receptor expression. Therefore, we hypothesized that binge-like consumption on intermittent access schedules is dependent on opioid and/or dopamine neurotransmission in the accumbens. To test this hypothesis, we asked whether injection of dopamine and opioid receptor antagonists into the core and shell of the accumbens reduced consumption of a sweet high-fat liquid in rats with and without a history of intermittent binge access to the liquid. Although injection of a μ opioid agonist increased consumption, none of the antagonists (including μ opioid, δ opioid, κ opioid, D1 dopamine and D2 dopamine receptor antagonists, as well as the broad-spectrum opioid receptor antagonist naltrexone) reduced consumption, and this was the case whether or not the animals had a prior history of intermittent access. These results suggest that consumption of sweet, fatty food does not require opioid or dopamine receptor activation in the accumbens even under intermittent access conditions that resemble human binge episodes.

  14. Interactions among mu- and delta-opioid receptors, especially putative delta1- and delta2-opioid receptors, promote dopamine release in the nucleus accumbens.

    NARCIS (Netherlands)

    Hirose, N.; Murakawa, K.; Takada, K.; Oi, Y.; Suzuki, T.; Nagase, H.; Cools, A.R.; Koshikawa, N.

    2005-01-01

    The effect of interactions among mu- and delta-opioid receptors, especially the putative delta(1)- and delta(2)-opioid receptors, in the nucleus accumbens on accumbal dopamine release was investigated in awake rats by in vivo brain microdialysis. In agreement with previous studies, perfusion of the

  15. Interactions among mu- and delta-opioid receptors, especially putative delta1- and delta2-opioid receptors, promote dopamine release in the nucleus accumbens.

    NARCIS (Netherlands)

    Hirose, N.; Murakawa, K.; Takada, K.; Oi, Y.; Suzuki, T.; Nagase, H.; Cools, A.R.; Koshikawa, N.

    2005-01-01

    The effect of interactions among mu- and delta-opioid receptors, especially the putative delta(1)- and delta(2)-opioid receptors, in the nucleus accumbens on accumbal dopamine release was investigated in awake rats by in vivo brain microdialysis. In agreement with previous studies, perfusion of the

  16. γ-endorphin and Nα-acetyl-γ-endorphin interfere with distinct dopaminergic systems in the nucleus accumbens via opioid and non-opioid mechanisms

    NARCIS (Netherlands)

    Ree, J.M. van; Gaffori, O.; Kiraly, I.

    1984-01-01

    Low doses (10 ng) of the dopamine agonist apomorphine induced hypolocomotion when injected into the nucleus accumbens of rats. This behavioral response was antagonized by local treatment with either the opioid peptide γ-endorphin (γE) or the non-opioid peptide Nα-acetyl-γ-endorphin (AcγE) in a dose

  17. Nucleus Accumbens Dopamine D2-Receptor Expressing Neurons Control Behavioral Flexibility in a Place Discrimination Task in the IntelliCage

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    Macpherson, Tom; Morita, Makiko; Wang, Yanyan; Sasaoka, Toshikuni; Sawa, Akira; Hikida, Takatoshi

    2016-01-01

    Considerable evidence has demonstrated a critical role for the nucleus accumbens (NAc) in the acquisition and flexibility of behavioral strategies. These processes are guided by the activity of two discrete neuron types, dopamine D1- or D2-receptor expressing medium spiny neurons (D1-/D2-MSNs). Here we used the IntelliCage, an automated…

  18. Role of alpha adrenoceptors in the nucleus accumbens in the control of accumbal noradrenaline efflux: a microdialysis study with freely moving rats.

    NARCIS (Netherlands)

    Aono, Y.; Saigusa, T.; Watanabe, S.; Iwakami, T.; Mizoguchi, N.; Ikeda, H.; Ishige, K.; Tomiyama, K.; Oi, Y.; Ueda, K.; Rausch, W.D.; Waddington, J.L.; Ito, Y.; Koshikawa, N.; Cools, A.R.

    2007-01-01

    Microdialysis technique was used to study the effects of the locally applied alpha adrenoceptor agonist phenylephrine and antagonist phentolamine on the basal noradrenaline efflux as well as on the noradrenaline uptake inhibitor desipramine-elicited noradrenaline efflux in the nucleus accumbens (NAc

  19. Dopaminergic responses in the core part of the nucleus accumbens to subcutaneous MK801 administration are increased following postnatal transient blockade of the prefrontal cortex.

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    Tagliabue, Emmanuelle; Pouvreau, Tiphaine; Eybrard, Séverine; Meyer, Francisca; Louilot, Alain

    2017-09-29

    Schizophrenia is a complex and devastating neuropsychiatric disease thought to result from impaired connectivity between several integrative regions, stemming from developmental failures. In particular, the left prefrontal cortex of schizophrenia patients seems to be targeted by such early developmental disturbances. Data obtained over the last three decades support the hypothesis of a dopaminergic dysfunction in schizophrenia. Striatal dopaminergic dysregulation in schizophrenia may result from a dysconnection between the prefrontal cortex and the striatum (dorsal and ventral) involving glutamatergic N-methyl-d-aspartate (NMDA) receptors. In the context of animal modeling of the pathophysiology of schizophrenia, the present study was designed to investigate the effects of MK 801 (dizocilpine) on locomotor activity and dopaminergic responses in the left core part of the nucleus accumbens (ventral striatum) in adult rats following neonatal tetrodotoxin inactivation of the left prefrontal cortex (infralimbic/prelimbic region) at postnatal day 8. Dopaminergic variations were recorded in the nucleus accumbens by means of in vivo voltammetry in freely moving adult animals. Following MK 801 administration, and in comparison to control (PBS) animals, animals microinjected with tetrodotoxin display locomotor hyperactivity and increased extracellular dopamine levels in the core part of the nucleus accumbens. These findings suggest neonatal functional inactivation of the prefrontal cortex may lead to a dysregulation of dopamine release in the core part of the nucleus accumbens involving NMDA receptors. The results obtained may provide new insight into the involvement of NMDA receptors in the pathophysiology of schizophrenia and suggest that future studies should look carefully at the core of the nucleus accumbens. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Electrical resistance increases at the tissue-electrode interface as an early response to nucleus accumbens deep brain stimulation.

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    Kale, Rajas P; Kouzani, Abbas Z; Berk, Julian; Walder, Ken; Berk, Michael; Tye, Susannah J

    2016-08-01

    The therapeutic actions of deep brain stimulation are not fully understood. The early inflammatory response of electrode implantation is associated with symptom relief without electrical stimulation, but is negated by anti-inflammatory drugs. Early excitotoxic necrosis and subsequent glial scarring modulate the conductivity of the tissue-electrode interface, which can provide some detail into the inflammatory response of individual patients. The feasibility of this was demonstrated by measuring resistance values across a bipolar electrode which was unilaterally implanted into the nucleus accumbens of a rat while receiving continuous deep brain stimulation with a portable back-mounted device using clinical parameters (130Hz, 200μA, 90μs) for 3 days. Daily resistance values rose significantly (pstimulation.

  1. Electrical resistance increases at the tissue-electrode interface as an early response to nucleus accumbens deep brain stimulation.

    Science.gov (United States)

    Kale, Rajas P; Kouzani, Abbas Z; Berk, Julian; Walder, Ken; Berk, Michael; Tye, Susannah J; Kale, Rajas P; Kouzani, Abbas Z; Berk, Julian; Walder, Ken; Berk, Michael; Tye, Susannah J; Berk, Julian; Berk, Michael; Tye, Susannah J; Kouzani, Abbas Z; Kale, Rajas P; Walder, Ken

    2016-08-01

    The therapeutic actions of deep brain stimulation are not fully understood. The early inflammatory response of electrode implantation is associated with symptom relief without electrical stimulation, but is negated by anti-inflammatory drugs. Early excitotoxic necrosis and subsequent glial scarring modulate the conductivity of the tissue-electrode interface, which can provide some detail into the inflammatory response of individual patients. The feasibility of this was demonstrated by measuring resistance values across a bipolar electrode which was unilaterally implanted into the nucleus accumbens of a rat while receiving continuous deep brain stimulation with a portable back-mounted device using clinical parameters (130Hz, 200μA, 90μs) for 3 days. Daily resistance values rose significantly (pstimulation.

  2. Blockade of Cannabinoid CB1 receptor attenuates the acquisition of morphine-induced conditioned place preference along with a downregulation of ERK, CREB phosphorylation, and BDNF expression in the nucleus accumbens and hippocampus.

    Science.gov (United States)

    Zhang, Jianbo; Wang, Na; Chen, Bo; Wang, Yi'nan; He, Jing; Cai, Xintong; Zhang, Hongbo; Wei, Shuguang; Li, Shengbin

    2016-09-06

    Cannabinoid CB1 receptor (CB1R) is highly expressed in the mesocorticolimbic system and associated with drug craving and relapse. Clinical trials suggest that CB1R antagonists may represent new therapies for drug addiction. However, the downstream signaling of CB1R is not fully elucidated. In the present study, we investigated the relationship between CB1R and the extracellular signal-regulated kinase (ERK), cAMP response element-binding protein (CREB), brain-derived neurotrophic factor (BDNF) signaling in the nucleus accumbens (NAc) and hippocampus in morphine-induced conditioned place preference (CPP), which is used to assess the morphine-induced reward memory. The protein level of CB1R, ERK, CREB, and BDNF were detected by western blotting. Additionally, a CB1R antagonist, AM251, was used to study whether blockade of CB1R altered the CPP and above-mentioned molecules. We found an increase of CB1R expression in the NAc and hippocampus of the mice following morphine CPP, but not those after repeated morphine in home cage without context exposure (NO-CPP). Both morphine CPP and NO-CPP induced an upregulation of ERK, CREB phosphorylation and BDNF expression. Furthermore, pretreatment with AM251 before morphine attenuated the CPP acquisition and CB1R expression as well as the activation of ERK-CREB-BDNF cascade. Collectively, these findings demonstrate that (1) Repeated morphine with context exposures but not merely the pharmacological effects of morphine increased CB1R expression both in the NAc and hippocampus. (2) CB1R antagonist mediated blockade of ERK-CREB-BDNF signaling activation in the NAc and hippocampus may be an important mechanism underlying the attenuation of morphine CPP.

  3. Repeated methamphetamine administration differentially alters fos expression in caudate-putamen patch and matrix compartments and nucleus accumbens.

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    Jakub P Jedynak

    Full Text Available BACKGROUND: The repeated administration of psychostimulant drugs produces a persistent and long-lasting increase ("sensitization" in their psychomotor effects, which is thought to be due to changes in the neural circuitry that mediate these behaviors. One index of neuronal activation used to identify brain regions altered by repeated exposure to drugs involves their ability to induce immediate early genes, such as c-fos. Numerous reports have demonstrated that past drug experience alters the ability of drugs to induce c-fos in the striatum, but very few have examined Fos protein expression in the two major compartments in the striatum--the so-called patch/striosome and matrix. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, we used immunohistochemistry to investigate the effects of pretreatment with methamphetamine on the ability of a subsequent methamphetamine challenge to induce Fos protein expression in the patch and matrix compartments of the dorsolateral and dorsomedial caudate-putamen and in the ventral striatum (nucleus accumbens. Animals pretreated with methamphetamine developed robust psychomotor sensitization. A methamphetamine challenge increased the number of Fos-positive cells in all areas of the dorsal and ventral striatum. However, methamphetamine challenge induced Fos expression in more cells in the patch than in the matrix compartment in the dorsolateral and dorsomedial caudate-putamen. Furthermore, past experience with methamphetamine increased the number of methamphetamine-induced Fos positive cells in the patch compartment of the dorsal caudate putamen, but not in the matrix or in the core or shell of the nucleus accumbens. CONCLUSIONS/SIGNIFICANCE: These data suggest that drug-induced alterations in the patch compartment of the dorsal caudate-putamen may preferentially contribute to some of the enduring changes in brain activity and behavior produced by repeated treatment with methamphetamine.

  4. Increased impulsive behavior and risk proneness following lentivirus-mediated dopamine transporter over-expression in rats' nucleus accumbens.

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    Adriani, W; Boyer, F; Gioiosa, L; Macrì, S; Dreyer, J-L; Laviola, G

    2009-03-03

    Multiple theories have been proposed for sensation seeking and vulnerability to impulse-control disorders [Zuckerman M, Kuhlman DM (2000) Personality and risk-taking: Common biosocial factors. J Pers 68:999-1029], and many of these rely on a dopamine system deficit. Available animal models reproduce only some behavioral symptoms and seem devoid of construct validity. We used lentivirus tools for over-expressing or silencing the dopamine transporter (DAT) and we evaluated the resulting behavioral profiles in terms of motivation and self-control. Wistar adult rats received stereotaxic inoculation of a lentivirus that allowed localized intra-accumbens delivery of a DAT gene enhancer/silencer, or the green fluorescent protein, GFP. These animals were studied for intolerance to delay, risk proneness and novelty seeking. As expected, controls shifted their demanding from a large reward toward a small one when the delivery of the former was increasingly delayed (or uncertain). Interestingly, in the absence of general locomotor effects, DAT over-expressing rats showed increased impulsivity (i.e. a more marked shift of demanding from the large/delayed toward the small/soon reward), and increased risk proneness (i.e. a less marked shift from the large/uncertain toward the small/sure reward), compared with controls. Rats with enhanced or silenced DAT expression did not show any significant preference for a novel environment. In summary, consistent with literature on comorbidity between attention-deficit/hyperactivity disorder and pathological gambling, we demonstrate that DAT over-expression in rats' nucleus accumbens leads to impulsive and risk prone phenotype. Thus, a reduced dopaminergic tone following altered accumbal DAT function may subserve a sensation-seeker phenotype and the vulnerability to impulse-control disorders.

  5. Ethanol up-regulates nucleus accumbens neuronal activity dependent pentraxin (Narp): implications for alcohol-induced behavioral plasticity.

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    Ary, Alexis W; Cozzoli, Debra K; Finn, Deborah A; Crabbe, John C; Dehoff, Marlin H; Worley, Paul F; Szumlinski, Karen K

    2012-06-01

    Neuronal activity dependent pentraxin (Narp) interacts with α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) glutamate receptors to facilitate excitatory synapse formation by aggregating them at established synapses. Alcohol is well-characterized to influence central glutamatergic transmission, including AMPA receptor function. Herein, we examined the influence of injected and ingested alcohol upon Narp protein expression, as well as basal Narp expression in mouse lines selectively bred for high blood alcohol concentrations under limited access conditions. Alcohol up-regulated accumbens Narp levels, concomitant with increases in levels of the GluR1 AMPA receptor subunit. However, accumbens Narp or GluR1 levels did not vary as a function of selectively bred genotype. We next employed a Narp knock-out (KO) strategy to begin to understand the behavioral relevance of alcohol-induced changes in protein expression in several assays of alcohol reward. Compared to wild-type mice, Narp KO animals: fail to escalate daily intake of high alcohol concentrations under free-access conditions; shift their preference away from high alcohol concentrations with repeated alcohol experience; exhibit a conditioned place-aversion in response to the repeated pairing of 3 g/kg alcohol with a distinct environment and fail to exhibit alcohol-induced locomotor hyperactivity following repeated alcohol treatment. Narp deletion did not influence the daily intake of either food or water, nor did it alter any aspect of spontaneous or alcohol-induced motor activity, including the development of tolerance to its motor-impairing effects with repeated treatment. Taken together, these data indicate that Narp induction, and presumably subsequent aggregation of AMPA receptors, may be important for neuroplasticity within limbic subcircuits mediating or maintaining the rewarding properties of alcohol.

  6. Repeated Cycles of Chronic Intermittent Ethanol Exposure Increases Basal Glutamate in the Nucleus Accumbens of Mice without affecting glutamate transport

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    William C. Griffin

    2015-02-01

    Full Text Available Repeated cycles of chronic intermittent ethanol (CIE exposure increase voluntary consumption of ethanol in mice. Previous work has shown that extracellular glutamate in the nucleus accumbens (NAc is significantly elevated in ethanol dependent mice and that pharmacologically manipulating glutamate concentrations in the NAc will alter ethanol drinking, indicating that glutamate homeostasis plays a crucial role in ethanol drinking in this model. The present studies were designed to measure extracellular glutamate at a time point in which mice would ordinarily be allowed voluntary access to ethanol in the CIE model and, additionally, to measure glutamate transport capacity in the NAc at the same time point. Extracellular glutamate was measured using quantitative microdialysis procedures. Glutamate transport capacity was measured under Na+ dependent and Na+ independent conditions to determine whether the function of excitatory amino acid transporters (EAATs; also known as system XAG or of system Xc- (Glial cysteine-glutamate exchanger was influenced by CIE exposure. The results of the quantitative microdialysis experiment confirm increased extracellular glutamate (~2 –fold in the NAc of CIE exposed mice (i.e. ethanol-dependent compared to non-dependent mice in the NAc, consistent with earlier work. However, the increase in extracellular glutamate was not due to altered transporter function in the NAc of ethanol-dependent mice, because neither Na+ dependent nor Na+ independent glutamate transport was significantly altered by CIE exposure. These findings point to the possibility that hyperexcitability of cortical-striatal pathways underlies the increases in extracellular glutamate found in the nucleus accumbens of ethanol-dependent mice.

  7. Dorsal Periaqueductal gray simultaneously modulates ventral Subiculum induced-plasticity in the Basolateral Amygdala and the Nucleus Accumbens

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    Omer eHorovitz

    2015-03-01

    Full Text Available The ventral subiculum of the hippocampus projects both to the basolateral amygdala, which is typically, associated with a response to aversive stimuli, as well as to the nucleus accumbens, which is typically associated with a response to appetitive stimuli. Traditionally, studies of the responses to emotional events focus on either negative or positive affect-related processes, however, emotional experiences often affect both. The ability of high-level processing brain regions (e.g. medial prefrontal cortex to modulate the balance between negative and positive affect-related regions was examined extensively. In contrast, the ability of low-level processing areas (e.g. periaqueductal grey - PAG to do so, has not been sufficiently studied. To address whether midbrain structures have the ability to modulate limbic regions, we first examined the ventral subiculum stimulation’s (vSub ability to induce plasticity in the basolateral amygdala (BLA and nucleus accumbens (NAcc simultaneously in rats. Further, dorsal PAG (dPAG priming ability to differentially modulate vSub stimulation induced plasticity in the BLA and the NAcc was subsequently examined. vSub stimulation resulted in plasticity in both the BLA and the NAcc simultaneously. Moreover, depending on stimulus intensity, differential dPAG priming effects on LTP in these two regions were observed. The results demonstrate that negative and positive affect-related processes may be simultaneously modulated. Furthermore, under some conditions lower-level processing areas, such as the dPAG, may differentially modulate plasticity in these regions and thus affect the long-term emotional outcome of the experience.

  8. Episodic sucrose intake during food restriction increases synaptic abundance of AMPA receptors in nucleus accumbens and augments intake of sucrose following restoration of ad libitum feeding.

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    Peng, X-X; Lister, A; Rabinowitsch, A; Kolaric, R; Cabeza de Vaca, S; Ziff, E B; Carr, K D

    2015-06-01

    Weight-loss dieting often leads to loss of control, rebound weight gain, and is a risk factor for binge pathology. Based on findings that food restriction (FR) upregulates sucrose-induced trafficking of glutamatergic AMPA receptors to the nucleus accumbens (NAc) postsynaptic density (PSD), this study was an initial test of the hypothesis that episodic "breakthrough" intake of forbidden food during dieting interacts with upregulated mechanisms of synaptic plasticity to increase reward-driven feeding. Ad libitum (AL) fed and FR subjects consumed a limited amount of 10% sucrose, or had access to water, every other day for 10 occasions. Beginning three weeks after return of FR rats to AL feeding, when 24-h chow intake and rate of body weight gain had normalized, subjects with a history of sucrose intake during FR consumed more sucrose during a four week intermittent access protocol than the two AL groups and the group that had access to water during FR. In an experiment that substituted noncontingent administration of d-amphetamine for sucrose, FR subjects displayed an enhanced locomotor response during active FR but a blunted response, relative to AL subjects, during recovery from FR. This result suggests that the enduring increase in sucrose consumption is unlikely to be explained by residual enhancing effects of FR on dopamine signaling. In a biochemical experiment which paralleled the sucrose behavioral experiment, rats with a history of sucrose intake during FR displayed increased abundance of pSer845-GluA1, GluA2, and GluA3 in the NAc PSD relative to rats with a history of FR without sucrose access and rats that had been AL throughout, whether they had a history of episodic sucrose intake or not. A history of FR, with or without a history of sucrose intake, was associated with increased abundance of GluA1. A terminal 15-min bout of sucrose intake produced a further increase in pSer845-GluA1 and GluA2 in subjects with a history of sucrose intake during FR

  9. Subregion-specific role of glutamate receptors in the nucleus accumbens on drug context-induced reinstatement of cocaine-seeking behavior in rats.

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    Xie, Xiaohu; Lasseter, Heather C; Ramirez, Donna R; Ponds, KaiCee L; Wells, Audrey M; Fuchs, Rita A

    2012-03-01

    The functional integrity of the nucleus accumbens (NAC) core and shell is necessary for contextual cocaine-seeking behavior in the reinstatement animal model of drug relapse; however, the neuropharmacological mechanisms underlying this phenomenon are poorly understood. The present study evaluated the contribution of metabotropic glutamate receptor subtype 1 (mGluR1) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptor populations to drug context-induced reinstatement of cocaine-seeking behavior. Rats were trained to lever press for un-signaled cocaine infusions in a distinct context followed by extinction training in a different context. Cocaine-seeking behavior (non-reinforced active lever pressing) was then assessed in the previously cocaine-paired and extinction contexts after JNJ16259685 (mGluR1 antagonist: 0.0, 0.6, or 30 pg/0.3 µl/hemisphere) or CNQX (AMPA/kainate receptor antagonist: 0.0, 0.03, or 0.3 µg/0.3 µl /hemisphere) administration into the NAC core, medial or lateral NAC shell, or the ventral caudate-putamen (vCPu, anatomical control). JNJ16259685 or CNQX in the NAC core dose-dependently impaired contextual cocaine-seeking behavior relative to vehicle. Conversely, CNQX, but not JNJ16259685, in the lateral or medial NAC shell attenuated, whereas CNQX or JNJ16259685 in vCPu failed to inhibit, this behavior. The manipulations failed to alter instrumental behavior in the extinction context, general motor activity or food-reinforced instrumental behavior in control experiments. Thus, glutamate-mediated changes in drug context-induced motivation for cocaine involve distinct neuropharmacological mechanisms within the core and shell subregions of the NAC, with the stimulation of mGlu1 and AMPA/kainate receptors in the NAC core and the stimulation of AMPA/kainate, but not mGlu1, receptors in the NAC shell being necessary for this phenomenon.

  10. Signal Words

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    SIGNAL WORDS TOPIC FACT SHEET NPIC fact sheets are designed to answer questions that are commonly asked by the ... making decisions about pesticide use. What are Signal Words? Signal words are found on pesticide product labels, ...

  11. Expression of 5-HT2A receptors in prefrontal cortex pyramidal neurons projecting to nucleus accumbens. Potential relevance for atypical antipsychotic action

    OpenAIRE

    Mocci, Giuseppe; Jiménez-Sánchez, Laura; Adell, Albert; Cortés, Roser; Artigas, Francesc

    2013-01-01

    The prefrontal cortex (PFC) is involved in higher brain functions altered in schizophrenia. Classical antipsychotic drugs modulate information processing in cortico-limbic circuits via dopamine D2 receptor blockade in nucleus accumbens (NAc) whereas atypical antipsychotic drugs preferentially target cortical serotonin (5-HT) receptors. The brain networks involved in the therapeutic action of atypical drugs are not fully understood. Previous work indicated that medial PFC (mPFC) pyramidal neur...

  12. Increasing oxytocin receptor expression in the nucleus accumbens of pre-pubertal female prairie voles enhances alloparental responsiveness and partner preference formation as adults

    OpenAIRE

    Keebaugh, Alaine C.; Young, Larry J.

    2011-01-01

    Oxytocin receptors (OXTR) in the nucleus accumbens (NAcc) promote alloparental behavior and partner preference formation in female prairie voles. Within the NAcc there is significant individual variation in OXTR binding and virgin juvenile and adult females with a high density of OXTR in the NAcc display an elevated propensity to engage in alloparental behavior toward novel pups. Over-expression of OXTR in the NAcc of adult female prairie voles using viral vector gene transfer facilitates par...

  13. Overexpression of 5-HT1B mRNA in nucleus accumbens shell projection neurons differentially affects microarchitecture of initiation and maintenance of ethanol consumption

    OpenAIRE

    Furay, AR; Neumaier, JF; Mullenix, AT; Kaiyala, KK; Sandygren, N; Hoplight, BJ

    2010-01-01

    Serotonin 1B (5-HT1B) heteroreceptors on nucleus accumbens shell (NAcSh) projection neurons have been shown to enhance the voluntary consumption of alcohol by rats, presumably by modulating the activity of the mesolimbic reward pathway. The present study examined whether increasing 5-HT1B receptors expressed on NAcSh projection neurons via viral mediated gene transfer enhances ethanol consumption during the initiation or maintenance phase of drinking and alters the temporal pattern of drinkin...

  14. Lipopolysaccharide increases degradation of central monoamines: an in vivo microdialysis study in the nucleus accumbens and medial prefrontal cortex of mice.

    Science.gov (United States)

    van Heesch, Floor; Prins, Jolanda; Konsman, Jan Pieter; Korte-Bouws, Gerdien A H; Westphal, Koen G C; Rybka, Joanna; Olivier, Berend; Kraneveld, Aletta D; Korte, S Mechiel

    2014-02-15

    Peripheral administration of lipopolysaccharide (LPS) in rodents induces anhedonia, i.e. the inability to experience pleasure. Recently, we reported that serotonin transporter (SERT) function is required for LPS-induced anhedonia. Less is known about the effect of LPS on the biological activity of dopamine transporters (DAT) and norepinephrine transporters (NET). Therefore, in vivo microdialysis was performed in the nucleus accumbens and medial prefrontal cortex of C57BL6/J mice exposed to saline or LPS (133 µg/kg i.p.). To investigate the possible involvement of different monoamine transporters, the triple reuptake inhibitor DOV 216,303 or saline was i.p. injected 30 min before the saline/LPS injection. The dose of LPS, shown to decrease responding for brain stimulation reward in mice, significantly increased extracellular levels of monoamine metabolites (5-HIAA, DOPAC and HVA) in the nucleus accumbens and medial prefrontal cortex. Remarkably, DOV 216,303 abolished LPS-induced DOPAC and HVA formation in the nucleus accumbens, suggesting that LPS increases DAT activity in this brain area. DOV 216,303 also inhibited LPS-induced DOPAC and HVA formation in the medial prefrontal cortex. Since DAT density is very low in this brain structure, reuptake of DA predominantly takes place via NET, suggesting that LPS increases DAT and NET activity in the medial prefrontal cortex. Furthermore, DOV 216,303 pretreatment prevented LPS-induced 5-HIAA formation only in the medial prefrontal cortex, indicating that LPS increases prefrontal SERT activity. In conclusion, the present findings suggest that peripheral LPS increases DAT activity in the nucleus accumbens and increases NET and SERT activity in the medial prefrontal cortex of mice.

  15. Effects of bupropion on the forced swim test and release of dopamine in the nucleus accumbens in ACTH-treated rats.

    Science.gov (United States)

    Kitamura, Yoshihisa; Yagi, Takahiko; Kitagawa, Kouhei; Shinomiya, Kazuaki; Kawasaki, Hiromu; Asanuma, Masato; Gomita, Yutaka

    2010-08-01

    The dopamine reuptake inhibitor bupropion has clinically been proven to improve depression and treatment-resistant depression. We examined its influence on the duration of immobility during the forced swim test in adrenocorticotropic hormone (ACTH)-treated rats and further analyzed the possible role of dopamine receptors in this effect. Additionally, the mechanism by which bupropion acts in this model was explored specifically in relation to the site of action through the use of microinjections into the medial prefrontal cortex and nucleus accumbens. Bupropion significantly decreased the duration of immobility in normal and ACTH-treated rats. This effect was blocked by D2 and D3 receptor antagonists in normal rats. Furthermore, infusions of bupropion into the nucleus accumbens, but not medial prefrontal cortex, decreased the immobility of normal and ACTH-treated rats during the forced swim test. Bupropion treatment plus repeated ACTH treatment significantly increased the extracellular dopamine concentration. These findings suggest the antidepressant-like effect of bupropion to be related to levels of dopamine in the rat nucleus accumbens.

  16. Nucleus accumbens corticotropin-releasing factor increases cue-triggered motivation for sucrose reward: paradoxical positive incentive effects in stress?

    Science.gov (United States)

    Peciña, Susana; Schulkin, Jay; Berridge, Kent C

    2006-01-01

    Background Corticotropin-releasing factor (CRF) is typically considered to mediate aversive aspects of stress, fear and anxiety. However, CRF release in the brain is also elicited by natural rewards and incentive cues, raising the possibility that some CRF systems in the brain mediate an independent function of positive incentive motivation, such as amplifying incentive salience. Here we asked whether activation of a limbic CRF subsystem magnifies the increase in positive motivation for reward elicited by incentive cues previously associated with that reward, in a way that might exacerbate cue-triggered binge pursuit of food or other incentives? We assessed the impact of CRF microinjections into the medial shell of nucleus accumbens using a pure incentive version of Pavlovian-Instrumental transfer, a measure specifically sensitive to the incentive salience of reward cues (which it separates from influences of aversive stress, stress reduction, frustration and other traditional explanations for stress-increased behavior). Rats were first trained to press one of two levers to obtain sucrose pellets, and then separately conditioned to associate a Pavlovian cue with free sucrose pellets. On test days, rats received microinjections of vehicle, CRF (250 or 500 ng/0.2 μl) or amphetamine (20 μg/0.2 μl). Lever pressing was assessed in the presence or absence of the Pavlovian cues during a half-hour test. Results Microinjections of the highest dose of CRF (500 ng) or amphetamine (20 μg) selectively enhanced the ability of Pavlovian reward cues to trigger phasic peaks of increased instrumental performance for a sucrose reward, each peak lasting a minute or so before decaying after the cue. Lever pressing was not enhanced by CRF microinjections in the baseline absence of the Pavlovian cue or during the presentation without a cue, showing that the CRF enhancement could not be explained as a result of generalized motor arousal, frustration or stress, or by persistent

  17. Nucleus accumbens corticotropin-releasing factor increases cue-triggered motivation for sucrose reward: paradoxical positive incentive effects in stress?

    Directory of Open Access Journals (Sweden)

    Schulkin Jay

    2006-04-01

    Full Text Available Abstract Background Corticotropin-releasing factor (CRF is typically considered to mediate aversive aspects of stress, fear and anxiety. However, CRF release in the brain is also elicited by natural rewards and incentive cues, raising the possibility that some CRF systems in the brain mediate an independent function of positive incentive motivation, such as amplifying incentive salience. Here we asked whether activation of a limbic CRF subsystem magnifies the increase in positive motivation for reward elicited by incentive cues previously associated with that reward, in a way that might exacerbate cue-triggered binge pursuit of food or other incentives? We assessed the impact of CRF microinjections into the medial shell of nucleus accumbens using a pure incentive version of Pavlovian-Instrumental transfer, a measure specifically sensitive to the incentive salience of reward cues (which it separates from influences of aversive stress, stress reduction, frustration and other traditional explanations for stress-increased behavior. Rats were first trained to press one of two levers to obtain sucrose pellets, and then separately conditioned to associate a Pavlovian cue with free sucrose pellets. On test days, rats received microinjections of vehicle, CRF (250 or 500 ng/0.2 μl or amphetamine (20 μg/0.2 μl. Lever pressing was assessed in the presence or absence of the Pavlovian cues during a half-hour test. Results Microinjections of the highest dose of CRF (500 ng or amphetamine (20 μg selectively enhanced the ability of Pavlovian reward cues to trigger phasic peaks of increased instrumental performance for a sucrose reward, each peak lasting a minute or so before decaying after the cue. Lever pressing was not enhanced by CRF microinjections in the baseline absence of the Pavlovian cue or during the presentation without a cue, showing that the CRF enhancement could not be explained as a result of generalized motor arousal, frustration or stress

  18. Low expression of nucleus accumbens-associated protein 1 predicts poor prognosis for patients with pancreatic ductal adenocarcinoma.

    Science.gov (United States)

    Nishi, Takeshi; Maruyama, Riruke; Urano, Takeshi; Nakayama, Naomi; Kawabata, Yasunari; Yano, Seiji; Yoshida, Manabu; Nakayama, Kentaro; Miyazaki, Kohji; Takenaga, Keizo; Tanaka, Tsuneo; Tajima, Yoshitsugu

    2012-12-01

    Nucleus accumbens-associated protein 1 (NAC1) is overexpressed in various carcinomas including ovarian, cervical, breast, and pancreatic carcinomas. High expression of NAC1 is considered to have adverse effects on prognosis through negative regulation of growth arrest and DNA-damage-inducible 45-γ interacting protein 1 (GADD45GIP1) in ovarian and cervical carcinomas. In the present study, the expression of NAC1 in pancreatic ductal adenocarcinoma (PDA) was measured using immunohistochemistry and computer-assisted image analysis in order to investigate its correlation with various clinicopathological parameters and prognosis. Patients with low-NAC1 PDA had worse overall survival (P = 0.0010) and a shorter disease-free survival (P = 0.0036) than patients with high-NAC1 PDA. This was a clinical effect opposite to that reported in ovarian and cervical carcinomas. Furthermore, knockdown of NAC1 in pancreatic carcinoma cell lines did not increase expression of the GADD45GIP1 protein. These results indicate that the gene(s) regulated by NAC1 vary depending on the types of carcinoma or originating tissue, and that low expression of NAC1 predicts poor prognosis for patients with PDA.

  19. Phase-Amplitude Cross-Frequency Coupling in the Human Nucleus Accumbens Tracks Action Monitoring during Cognitive Control

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    Stefan eDürschmid

    2013-10-01

    Full Text Available The Nucleus Accumbens (NAcc is an important structure for the transfer of informationbetween cortical and subcortical structures, especially the prefrontal cortex and thehippocampus. However, the mechanism that allows the NAcc to achieve this integration is notwell understood. Phase-amplitude cross-frequency coupling (PAC of oscillations in differentfrequency bands has been proposed as an effective mechanism to form functional networks tooptimize transfer and integration of information. Here we assess PAC between theta and highgamma oscillations as a potential mechanism that facilitates motor adaptation. To address thisissue we recorded intracranial field potentials directly from the bilateral human NAcc in threepatients while they performed a motor learning task that varied in the level of cognitive controlneeded to perform the task. As in rodents, PAC was observable in the human NAcc, transientlyoccurring contralateral to a movement following the motor response. Importantly, PAC correlatedwith the level of cognitive control needed to monitor the action performed.This functional relationindicates that the NAcc is engaged in action monitoring and supports the evaluation of motorprograms during adaptive behavior by means of PAC.

  20. Differential Gene Expression in the Nucleus Accumbens and Frontal Cortex of Lewis and Fischer 344 Rats Relevant to Drug Addiction

    Science.gov (United States)

    Higuera-Matas, A; Montoya, G. L; Coria, S.M; Miguéns, M; García-Lecumberri, C; Ambrosio, E

    2011-01-01

    Drug addiction results from the interplay between social and biological factors. Among these, genetic variables play a major role. The use of genetically related inbred rat strains that differ in their preference for drugs of abuse is one approach of great importance to explore genetic determinants. Lewis and Fischer 344 rats have been extensively studied and it has been shown that the Lewis strain is especially vulnerable to the addictive properties of several drugs when compared with the Fischer 344 strain. Here, we have used microarrays to analyze gene expression profiles in the frontal cortex and nucleus accumbens of Lewis and Fischer 344 rats. Our results show that only a very limited group of genes were differentially expressed in Lewis rats when compared with the Fischer 344 strain. The genes that were induced in the Lewis strain were related to oxygen transport, neurotransmitter processing and fatty acid metabolism. On the contrary genes that were repressed in Lewis rats were involved in physiological functions such as drug and proton transport, oligodendrocyte survival and lipid catabolism. These data might be useful for the identification of genes which could be potential markers of the vulnerability to the addictive properties of drugs of abuse. PMID:21886580

  1. Involvement of tissue plasminogen activator-plasmin system in depolarization-evoked dopamine release in the nucleus accumbens of mice.

    Science.gov (United States)

    Ito, Mina; Nagai, Taku; Kamei, Hiroyuki; Nakamichi, Noritaka; Nabeshima, Toshitaka; Takuma, Kazuhiro; Yamada, Kiyofumi

    2006-11-01

    Tissue plasminogen activator (tPA), a serine protease, catalyzes the conversion of plasminogen to plasmin. In the present study, we investigated the role of the tPA-plasmin system in depolarization-evoked dopamine (DA) and acetylcholine (ACh) release in the nucleus accumbens (NAc) and hippocampus, respectively, of mice, by using in vivo microdialysis. Microinjection of either tPA or plasmin significantly potentiated 40 mM KCl-induced DA release without affecting basal DA levels. In contrast, plasminogen activator inhibitor-1 dose-dependently reduced 60 mM KCl-induced DA release. The 60 mM KCl-evoked DA release in the NAc was markedly diminished in tPA-deficient (tPA-/-) mice compared with wild-type mice, although basal DA levels did not differ between the two groups. Microinjections of either exogenous tPA (100 ng) or plasmin (100 ng) into the NAc of tPA-/-mice restored 60 mM KCl-induced DA release, as observed in wild-type mice. In contrast, there was no difference in either basal or 60 mM KCl-induced ACh release in the hippocampus between wild-type and tPA-/-mice. Our findings suggest that the tPA-plasmin system is involved in the regulation of depolarization-evoked DA release in the NAc.

  2. Effects of tetra hydro cannabinol to the dendritc tree and synapses of the accumbens nucleus of wistar rats

    Directory of Open Access Journals (Sweden)

    Dimitrijević I.

    2013-01-01

    Full Text Available Cannabis is one of the most widely used intoxicants; almost half of all 18 year olds in the USA and in most European countries admit to having tried it at least once, and ~10% of that age group are regular users. Δ9-Tetrahydrocannabinol (THC, the principal psychoactive ingredient in marijuana, produces euphoria and relaxation and impairs motor coordination, time sense, and short term memory. In the hippocampus, CBs inhibit GABA release from a subset of interneurons and inhibit glutamate release from principal neurons. Cannabinoids are reported to produce both rapid and long-term changes in synaptic transmission. Our study was carried out on ten male rats out of which brains of six of them were used as the representative sample for electron microscope analysis, while 4 were used for light microspcopy performed by Golgi method. Three were exposed to THC and 3 were controls. Axodendric synapses in the core and shell of the accumbens nucleus (AN were studied under electron microscope. The results have shown widening of the synaptic cleft in the shell of AN. This result is a leading point to our further investigations which are going to involve a behavioral component, and different aspects of morphological studies. [Projekat Ministarstva nauke Republike Srbije, br. III 41020

  3. Stathmin reduction and cytoskeleton rearrangement in rat nucleus accumbens in response to clozapine and risperidone treatment - Comparative proteomic study.

    Science.gov (United States)

    Kedracka-Krok, S; Swiderska, B; Jankowska, U; Skupien-Rabian, B; Solich, J; Dziedzicka-Wasylewska, M

    2016-03-01

    The complex network of anatomical connections of the nucleus accumbens (NAc) makes it an interface responsible for the selection and integration of cognitive and affective information to modulate appetitive or aversively motivated behaviour. There is evidence for NAc dysfunction in schizophrenia. NAc also seems to be important for antipsychotic drug action, but the biochemical characteristics of drug-induced alterations within NAc remain incompletely characterized. In this study, a comprehensive proteomic analysis was performed to describe the differences in the mechanisms of action of clozapine (CLO) and risperidone (RIS) in the rat NAc. Both antipsychotics influenced the level of microtubule-regulating proteins, i.e., stathmin, and proteins of the collapsin response mediator protein family (CRMPs), and only CLO affected NAD-dependent protein deacetylase sirtuin-2 and septin 6. Both antipsychotics induced changes in levels of other cytoskeleton-related proteins. CLO exclusively up-regulated proteins involved in neuroprotection, such as glutathione synthetase, heat-shock 70-kDa protein 8 and mitochondrial heat-shock protein 75. RIS tuned cell function by changing the pattern of post-translational modifications of some proteins: it down-regulated the phosphorylated forms of stathmin and dopamine and the cyclic AMP-regulated phosphoprotein (DARPP-32) isoform but up-regulated cyclin-dependent kinase 5 (Cdk5). RIS modulated the level and phosphorylation state of synaptic proteins: synapsin-2, synaptotagmin-1 and adaptor-related protein-2 (AP-2) complex.

  4. Morphine treatment enhances glutamatergic input onto neurons of the nucleus accumbens via both disinhibitory and stimulating effect.

    Science.gov (United States)

    Yuan, Kejing; Sheng, Huan; Song, Jiaojiao; Yang, Li; Cui, Dongyang; Ma, Qianqian; Zhang, Wen; Lai, Bin; Chen, Ming; Zheng, Ping

    2016-08-22

    Drug addiction is a chronic brain disorder characterized by the compulsive repeated use of drugs. The reinforcing effect of repeated use of drugs on reward plays an important role in morphine-induced addictive behaviors. The nucleus accumbens (NAc) is an important site where morphine treatment produces its reinforcing effect on reward. However, how morphine treatment produces its reinforcing effect on reward in the NAc remains to be clarified. In the present study, we studied the influence of morphine treatment on the effects of DA and observed whether morphine treatment could directly change glutamatergic synaptic transmission in the NAc. We also explored the functional significance of morphine-induced potentiation of glutamatergic synaptic transmission in the NAc at behavioral level. Our results show that (1) morphine treatment removes the inhibitory effect of DA on glutamatergic input onto NAc neurons; (2) morphine treatment potentiates glutamatergic input onto NAc neurons, especially the one from the basolateral amygdala (BLA) to the NAc; (3) blockade of glutamatergic synaptic transmission in the NAc or ablation of projection neurons from BLA to NAc significantly decreases morphine treatment-induced increase in locomotor activity. These results suggest that morphine treatment enhances glutamatergic input onto neurons of the NAc via both disinhibitory and stimulating effect and therefore increases locomotor activity.

  5. Muscarinic receptors discriminated by pirenzepine are involved in the regulation of neurotransmitter release in rat nucleus accumbens.

    Science.gov (United States)

    de Belleroche, J.; Gardiner, I. M.

    1985-01-01

    The effect of pirenzepine, a selective muscarinic antagonist, was tested on the oxotremorine facilitation of the K+-evoked release of [14C]-dopamine from tissue slices of rat nucleus accumbens. The effect of pirenzepine was compared with that of scopolamine and other antagonists which show no heterogeneity in their action on muscarinic receptors in order to determine whether a selective action at a single receptor subtype, M1 or M2, could be distinguished. Pirenzepine and scopolamine both antagonized the oxotremorine-induced (EC50 = 3 X 10(-7) M) facilitation of [14C]-dopamine release with pA2 values of 7.5 and 8.9 respectively. This result indicated that the high affinity pirenzepine receptor (M1) was involved in this response. Low concentrations of 3-quinuclidinyl benzilate (3 X 10(-10) M), N-methylscopolamine (3 X 10(-9) M) and methyl atropine (10(-8) M) also abolished this facilitatory effect of oxotremorine. PMID:2864975

  6. Positive reinforcement mediated by midbrain dopamine neurons requires D1 and D2 receptor activation in the nucleus accumbens.

    Science.gov (United States)

    Steinberg, Elizabeth E; Boivin, Josiah R; Saunders, Benjamin T; Witten, Ilana B; Deisseroth, Karl; Janak, Patricia H

    2014-01-01

    The neural basis of positive reinforcement is often studied in the laboratory using intracranial self-stimulation (ICSS), a simple behavioral model in which subjects perform an action in order to obtain exogenous stimulation of a specific brain area. Recently we showed that activation of ventral tegmental area (VTA) dopamine neurons supports ICSS behavior, consistent with proposed roles of this neural population in reinforcement learning. However, VTA dopamine neurons make connections with diverse brain regions, and the specific efferent target(s) that mediate the ability of dopamine neuron activation to support ICSS have not been definitively demonstrated. Here, we examine in transgenic rats whether dopamine neuron-specific ICSS relies on the connection between the VTA and the nucleus accumbens (NAc), a brain region also implicated in positive reinforcement. We find that optogenetic activation of dopaminergic terminals innervating the NAc is sufficient to drive ICSS, and that ICSS driven by optical activation of dopamine neuron somata in the VTA is significantly attenuated by intra-NAc injections of D1 or D2 receptor antagonists. These data demonstrate that the NAc is a critical efferent target sustaining dopamine neuron-specific ICSS, identify receptor subtypes through which dopamine acts to promote this behavior, and ultimately help to refine our understanding of the neural circuitry mediating positive reinforcement.

  7. Sex differences in interactions between nucleus accumbens and visual cortex by explicit visual erotic stimuli: an fMRI study.

    Science.gov (United States)

    Lee, S W; Jeong, B S; Choi, J; Kim, J-W

    2015-01-01

    Men tend to have greater positive responses than women to explicit visual erotic stimuli (EVES). However, it remains unclear, which brain network makes men more sensitive to EVES and which factors contribute to the brain network activity. In this study, we aimed to assess the effect of sex difference on brain connectivity patterns by EVES. We also investigated the association of testosterone with brain connection that showed the effects of sex difference. During functional magnetic resonance imaging scans, 14 males and 14 females were asked to see alternating blocks of pictures that were either erotic or non-erotic. Psychophysiological interaction analysis was performed to investigate the functional connectivity of the nucleus accumbens (NA) as it related to EVES. Men showed significantly greater EVES-specific functional connection between the right NA and the right lateral occipital cortex (LOC). In addition, the right NA and the right LOC network activity was positively correlated with the plasma testosterone level in men. Our results suggest that the reason men are sensitive to EVES is the increased interaction in the visual reward networks, which is modulated by their plasma testosterone level.

  8. Nucleus Accumbens and Its Role in Reward and Emotional Circuitry: A Potential Hot Mess in Substance Use and Emotional Disorders

    Directory of Open Access Journals (Sweden)

    Mani Pavuluri

    2017-04-01

    Full Text Available Nucleus accumbens (NAc is a key region in the brain that is integral to both the reward and the emotional systems. The aim of the current paper is to synthesize the basic and the clinical neuroscience discoveries relevant to the NAc for the purpose of two-way translation. Selected literature on the structure and the functionality of the NAc is reviewed across animal and human studies. Dopamine, gamma-aminobutyric acid (GABA and glutamate are the three key neurotransmitters that modulate the reward function and the motor activity. Dissociative roles of the core and the shell of the NAc include getting to the reward and staying on task with discretion, respectively. NAc shows decreased activation to reward in the individuals with major depressive disorder and the bipolar disorder, relative to that healthy controls (HC. The “difficult to please” or insatiability in response to reward in the emotional disorders may possibly be explained by such a neural pattern. Furthermore, it is likely that the increased amygdala activity reported in mood disorders could be accentuating the “wanting” of the reward by the virtue of its connections with the NAc, explaining the potential “hot mess”. In contrast, the NAc shows increased reward response in substance use disorders, relative to HC, in response to reward and emotional tasks. Accurate characterization of the NAc and its functionality in the human imaging studies of mood and substance use has important treatment implications.

  9. The nucleus accumbens is involved in both the pursuit of social reward and the avoidance of social punishment.

    Science.gov (United States)

    Kohls, Gregor; Perino, Michael T; Taylor, James M; Madva, Elizabeth N; Cayless, Sarah J; Troiani, Vanessa; Price, Elinora; Faja, Susan; Herrington, John D; Schultz, Robert T

    2013-09-01

    Human social motivation is characterized by the pursuit of social reward and the avoidance of social punishment. The ventral striatum/nucleus accumbens (VS/Nacc), in particular, has been implicated in the reward component of social motivation, i.e., the 'wanting' of social incentives like approval. However, it is unclear to what extent the VS/Nacc is involved in avoiding social punishment like disapproval, an intrinsically pleasant outcome. Thus, we conducted an event-related functional magnetic resonance imaging (fMRI) study using a social incentive delay task with dynamic video stimuli instead of static pictures as social incentives in order to examine participants' motivation for social reward gain and social punishment avoidance. As predicted, the anticipation of avoidable social punishment (i.e., disapproval) recruited the VS/Nacc in a manner that was similar to VS/Nacc activation observed during the anticipation of social reward gain (i.e., approval). Stronger VS/Nacc activity was accompanied by faster reaction times of the participants to obtain those desired outcomes. This data support the assumption that dynamic social incentives elicit robust VS/Nacc activity, which likely reflects motivation to obtain social reward and to avoid social punishment. Clinical implications regarding the involvement of the VS/Nacc in social motivation dysfunction in autism and social phobia are discussed. Copyright © 2013 Elsevier Ltd. All rights reserved.

  10. Dopamine D2 receptors in the nucleus accumbens are important for social attachment in female prairie voles (Microtus ochrogaster).

    Science.gov (United States)

    Gingrich, B; Liu, Y; Cascio, C; Wang, Z; Insel, T R

    2000-02-01

    The prairie vole (Microtus ochrogaster), a monogamous rodent that forms long-lasting pair bonds, has proven useful for the neurobiological study of social attachment. In the laboratory, pair bonds can be assessed by testing for a partner preference, a choice test in which pair-bonded voles regularly prefer their partner to a conspecific stranger. Studies reported here investigate the role of dopamine D2-like receptors (i.e., D2, D3, and D4 receptors) in the nucleus accumbens (NAcc) for the formation of a partner preference in female voles. Mating facilitated partner preference formation and associated with an approximately 50% increase in extracellular dopamine in the NAcc. Microinjection of the D2 antagonist eticlopride into the NAcc (but not the prelimbic cortex) blocked the formation of a partner preference in mating voles, whereas the D2 agonist quinpirole facilitated formation of a partner preference in the absence of mating. Taken together, these results suggest that D2-like receptors in the NAcc are important for the mediation of social attachments in female voles.

  11. Deep Brain Stimulation of the Nucleus Accumbens Core Affects Trait Impulsivity in a Baseline-Dependent Manner

    Science.gov (United States)

    Schippers, Maria C.; Bruinsma, Bastiaan; Gaastra, Mathijs; Mesman, Tanja I.; Denys, Damiaan; De Vries, Taco J.; Pattij, Tommy

    2017-01-01

    Deep brain stimulation (DBS) of the nucleus accumbens (NA) is explored as a treatment for refractory psychiatric disorders, such as obsessive-compulsive disorder (OCD), depressive disorder (MDD), and substance use disorder (SUD). A common feature of some of these disorders is pathological impulsivity. Here, the effects of NAcore DBS on impulsive choice and impulsive action, two distinct forms of impulsive behavior, were investigated in translational animal tasks, the delayed reward task (DRT) and five-choice serial reaction time task (5-CSRTT), respectively. In both tasks, the effects of NAcore DBS were negatively correlated with baseline impulsive behavior, with more pronounced effects in the 5-CSRTT. To further examine the effects of DBS on trait impulsive action, rats were screened for high (HI) and low (LI) impulsive responding in the 5-CSRTT. NAcore DBS decreased impulsive, premature responding in HI rats under conventional conditions. However, upon challenged conditions to increase impulsive responding, NAcore DBS did not alter impulsivity. These results strongly suggest a baseline-dependent effect of DBS on impulsivity, which is in line with clinical observations. PMID:28386221

  12. Electroacupuncture Suppresses Discrete Cue-Evoked Heroin-Seeking and Fos Protein Expression in the Nucleus Accumbens Core in Rats

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    Sheng Liu

    2012-01-01

    Full Text Available Relapse to drug seeking was studied using a rodent model of reinstatement induced by exposure to drug-related cues. Here, we used intravenous drug self-administration procedures in rats to further investigate the beneficial effects of electroacupuncture (EA on heroin-seeking behavior in a reinstatement model of relapse. We trained Sprague-Dawley rats to nose-poke for i.v. heroin either daily for 4 h or 25 infusions for 14 consecutive days. Then the rats were abstinent from heroin for two weeks. 2 Hz EA stimulation was conducted once daily for 14 days during heroin abstinence. We tested these animals for contextual and discrete cue-induced reinstatement of active responses. We also applied immunohistochemistry to detect Fos-positive nuclei in the nucleus accumbens (NACc core and shell after reinstatement test. We found that active responses elicited by both contextual cues and discrete cues were high in the rats trained with heroin than in saline controls. EA treatment significantly reduced active responses elicited by discrete cues. EA stimulation attenuated Fos expression in the core but not the shell of the NACc. Altogether, these results highlight the therapeutic benefit of EA in preventing relapse to drug addiction.

  13. C-fos protein expression in the anterior amygdaloid area and nc. accumbens in the hypoxic rat brain

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    Babović Siniša S.

    2014-01-01

    Full Text Available Introduction. By examining the production of c-Fos protein, we analyzed the response to the ischemic attack in different brain tissue, two of which are regions of the limbic system: the anterior amygdaloid area and nc. accumbens. Material and Methods. We used the model of rat brain ischemia - four-vessel occlusion, and Pulsinelli’s method. The rats were treated in two ways, according to which they were divided into two groups: a total ischemia (ligation of four blood vessels, i.e. electrocauterization of the vertebral artery with bilateral ligation of the carotid artery - the so-called R-group rats, and transient ischemic attack (ligation of four blood vessels, i.e. electrocauterization of the vertebral artery, with mutual re-ligation of the carotid arteries in the form of transient ischemia - the so-called T-group rats, which can also be called “pre-conditioned group”. Both groups had their own control group. Conclusion. We have concluded that parts of the brain with an important role for the survival have a strong expression of c-fos gene.

  14. Positive reinforcement mediated by midbrain dopamine neurons requires D1 and D2 receptor activation in the nucleus accumbens.

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    Elizabeth E Steinberg

    Full Text Available The neural basis of positive reinforcement is often studied in the laboratory using intracranial self-stimulation (ICSS, a simple behavioral model in which subjects perform an action in order to obtain exogenous stimulation of a specific brain area. Recently we showed that activation of ventral tegmental area (VTA dopamine neurons supports ICSS behavior, consistent with proposed roles of this neural population in reinforcement learning. However, VTA dopamine neurons make connections with diverse brain regions, and the specific efferent target(s that mediate the ability of dopamine neuron activation to support ICSS have not been definitively demonstrated. Here, we examine in transgenic rats whether dopamine neuron-specific ICSS relies on the connection between the VTA and the nucleus accumbens (NAc, a brain region also implicated in positive reinforcement. We find that optogenetic activation of dopaminergic terminals innervating the NAc is sufficient to drive ICSS, and that ICSS driven by optical activation of dopamine neuron somata in the VTA is significantly attenuated by intra-NAc injections of D1 or D2 receptor antagonists. These data demonstrate that the NAc is a critical efferent target sustaining dopamine neuron-specific ICSS, identify receptor subtypes through which dopamine acts to promote this behavior, and ultimately help to refine our understanding of the neural circuitry mediating positive reinforcement.

  15. An examination of nucleus accumbens cell firing during extinction and reinstatement of water reinforcement behavior in rats.

    Science.gov (United States)

    Hollander, Jonathan A; Ijames, Stephanie G; Roop, Richard G; Carelli, Regina M

    2002-03-08

    Electrophysiological recording procedures were used to examine nucleus accumbens (Acb) cell firing in rats (n = 13) during water reinforcement sessions consisting of three phases. During phase one (maintenance), a lever press resulted in water reinforcement (fixed ratio 1; 0.05 ml/press) paired with an auditory stimulus (0.5 s). Of 128 Acb neurons recorded during maintenance, 40 cells (31%) exhibited one of three types of neuronal firing patterns described previously [J. Neurosci. 14 (12) (1994) 7735-7746; J. Neurosci. 20 (11) (2000) 4255-4266]. Briefly, Acb neurons exhibited increases in firing rate within seconds preceding the reinforced response (type PR) or increases (type RFe) or decreases (type RFi) in activity seconds following response completion. In phase two (extinction), subsequent lever pressing had no programmed consequences (i.e., water reinforcement and the auditory stimulus were not presented). After 30 min of no responding, animals were given water reinforcement/auditory stimulus 'primes' to reestablish lever pressing behavior during the third phase (reinstatement). Results indicated that all types of phasic neurons (PR, RFe and RFi) exhibited an attenuated firing rate during extinction, and in some cases recovery of patterned discharges were observed during reinstatement. No significant changes in cell firing were observed for any cell type during presentation of the stimulus prime used to reestablish operant responding following extinction. These findings are discussed in terms of how Acb neurons process information related to 'natural' reinforcers versus drugs of abuse.

  16. Differential gene expression in the nucleus accumbens and frontal cortex of lewis and Fischer 344 rats relevant to drug addiction.

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    Higuera-Matas, A; Montoya, G L; Coria, S M; Miguéns, M; García-Lecumberri, C; Ambrosio, E

    2011-03-01

    Drug addiction results from the interplay between social and biological factors. Among these, genetic variables play a major role. The use of genetically related inbred rat strains that differ in their preference for drugs of abuse is one approach of great importance to explore genetic determinants. Lewis and Fischer 344 rats have been extensively studied and it has been shown that the Lewis strain is especially vulnerable to the addictive properties of several drugs when compared with the Fischer 344 strain. Here, we have used microarrays to analyze gene expression profiles in the frontal cortex and nucleus accumbens of Lewis and Fischer 344 rats. Our results show that only a very limited group of genes were differentially expressed in Lewis rats when compared with the Fischer 344 strain. The genes that were induced in the Lewis strain were related to oxygen transport, neurotransmitter processing and fatty acid metabolism. On the contrary genes that were repressed in Lewis rats were involved in physiological functions such as drug and proton transport, oligodendrocyte survival and lipid catabolism.These data might be useful for the identification of genes which could be potential markers of the vulnerability to the addictive properties of drugs of abuse.

  17. Reduced nucleus accumbens and caudate nucleus activation to a pleasant taste is associated with obesity in older adults.

    Science.gov (United States)

    Green, Erin; Jacobson, Aaron; Haase, Lori; Murphy, Claire

    2011-04-22

    Although obesity is recognized as a global health epidemic, insufficient research has been directed to understanding the rising prevalence of obesity in the fastest growing segment of the population, older adults. Late-life obesity has been linked to declines in physical health and cognitive function, with implications not only for the individual, but also for society. We investigated the hypothesis that altered brain responses to food reward is associated with obesity, using fMRI of response to pleasant and aversive taste stimuli in young and older adults performing a hedonic evaluation task. Correlations between higher levels of abdominal fat/body mass index and reduced fMRI activation to sucrose in dopamine-related brain regions (caudate, nucleus accumbens) were large in older adults. Significant associations between a hypofunctioning reward response and obesity suggest the hypothesis that decreased dopamine functioning may be a plausible mechanism for weight gain in older adults. Copyright © 2011 Elsevier B.V. All rights reserved.

  18. Structural correlates of trait anxiety: reduced thickness in medial orbitofrontal cortex accompanied by volume increase in nucleus accumbens.

    Science.gov (United States)

    Kühn, Simone; Schubert, Florian; Gallinat, Jürgen

    2011-11-01

    Structural deficiencies within the medial prefrontal cortex have been shown in anxiety-related psychiatric disorders such as panic disorder, post traumatic stress disorder and obsessive compulsive disorder. In healthy subjects, trait anxiety as the individual's disposition to experience anxiety-relevant feelings or thoughts has been shown to be a risk factor for psychiatric disorders. We aimed at exploring the structural correlates of trait anxiety in normal participants. We acquired high-resolution MRI scans from 34 subjects and used FreeSurfer to obtain a measure of cortical thickness. We correlated cortical thickness with self-rated trait anxiety in a whole brain analysis. Automatic subcortical segmentations of the FreeSurfer pipeline were used to relate nucleus accumbens (NAcc) and amygdala volume to trait anxiety. Trait anxiety was negatively correlated with cortical thickness in the right medial orbitofrontal cortex (mOFC) and positively correlated with the bilateral volume of NAcc. Cortical thickness measures extracted from mOFC were negatively associated with the volume of left NAcc. Since, like in anxiety-related psychiatric disorders, in the healthy sample studied here, trait anxiety was associated with a reduction of cortical thickness in mOFC we suggest that this thinning is a structural precondition rather than a consequence of psychiatric illnesses. Copyright © 2011 Elsevier B.V. All rights reserved.

  19. Volumetric alterations in the nucleus accumbens and caudate nucleus in bulimia nervosa: a structural magnetic resonance imaging study.

    Science.gov (United States)

    Coutinho, Joana; Ramos, Ana Filipa; Maia, Liliana; Castro, Liliana; Conceição, Eva; Geliebter, Allan; Machado, Paulo P P; Gonçalves, Óscar; Sampaio, Adriana

    2015-03-01

    Bulimia nervosa (BN) is an eating disorder characterized by recurrent episodes of binge eating and inappropriate compensatory behaviors (such as purging, fasting, or excessive exercise) to prevent weight gain. BN has been associated with deficits in inhibitory control processes. The basal ganglia specifically, the nucleus accumbens (NAc) and the caudate nucleus (CN) are part of the frontostriatal circuits involved in inhibitory control. The main goal of this study was to investigate the presence of morphological alterations in the NAc and the CN in a sample of patients diagnosed with BN. Forty-one female participants, 21 diagnosed with BN and 20 healthy matched controls (HC), underwent a structural magnetic resonance imaging (MRI) acquisition and clinical assessment. The NAc and the CN were manually segmented using the software Slicer 3D. The results reveal a significant volumetric decrease in the CN and a preserved NAc volume in BN compared to the control group. These findings suggest a contributory role of the caudate nucleus part of the dorsal striatum in the psychopathology of BN. © 2014 Wiley Periodicals, Inc.

  20. Violence as a source of pleasure or displeasure is associated with specific functional connectivity with the nucleus accumbens

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    Eric C Porges

    2013-08-01

    Full Text Available The appraisal of violent stimuli is dependent on the social context and the perceiver’s individual characteristics. To identify the specific neural circuits involved in the perception of violent videos, forty-nine male participants were scanned with functional MRI while watching video-clips depicting Mixed Martial Arts (MMA and Capoeira as a baseline. Prior to scanning, a self-report measure of pleasure or displeasure when watching MMA was collected. Watching MMA was associated with activation of the anterior insula, brainstem, ventral tegmental area, striatum, medial and lateral prefrontal cortex, orbitofrontal cortex, somatosensory cortex, and supramarginal gyrus. While this pattern of brain activation was not related to participants’ reported experience of pleasure or displeasure, pleasurable ratings of MMA predicted increased functional connectivity seeded in the nucleus accumbens (a structure known to be responsive to anticipating both positive and negative outcomes with the subgenual anterior cingulate cortex and anterior insular cortex (regions involved in positive feelings and visceral somatic representations. Displeasure ratings of MMA were related to increased functional connectivity with regions of the prefrontal cortex and superior parietal lobule, structures implicated in cognitive control and executive attention. These data suggest that functional connectivity is an effective approach to investigate the relationship between subjective feelings of pleasure and pain of neural structures known to respond to both the anticipation of positive and negative outcomes.

  1. Individual differences in nucleus accumbens dopamine receptors predict development of addiction-like behavior: a computational approach.

    Science.gov (United States)

    Piray, Payam; Keramati, Mohammad Mahdi; Dezfouli, Amir; Lucas, Caro; Mokri, Azarakhsh

    2010-09-01

    Clinical and experimental observations show individual differences in the development of addiction. Increasing evidence supports the hypothesis that dopamine receptor availability in the nucleus accumbens (NAc) predisposes drug reinforcement. Here, modeling striatal-midbrain dopaminergic circuit, we propose a reinforcement learning model for addiction based on the actor-critic model of striatum. Modeling dopamine receptors in the NAc as modulators of learning rate for appetitive--but not aversive--stimuli in the critic--but not the actor--we define vulnerability to addiction as a relatively lower learning rate for the appetitive stimuli, compared to aversive stimuli, in the critic. We hypothesize that an imbalance in this learning parameter used by appetitive and aversive learning systems can result in addiction. We elucidate that the interaction between the degree of individual vulnerability and the duration of exposure to drug has two progressive consequences: deterioration of the imbalance and establishment of an abnormal habitual response in the actor. Using computational language, the proposed model describes how development of compulsive behavior can be a function of both degree of drug exposure and individual vulnerability. Moreover, the model describes how involvement of the dorsal striatum in addiction can be augmented progressively. The model also interprets other forms of addiction, such as obesity and pathological gambling, in a common mechanism with drug addiction. Finally, the model provides an answer for the question of why behavioral addictions are triggered in Parkinson's disease patients by D2 dopamine agonist treatments.

  2. Enhanced ability of TRPV1 channels in regulating glutamatergic transmission after repeated morphine exposure in the nucleus accumbens of rat.

    Science.gov (United States)

    Zhang, Haitao; Jia, Dong; Wang, Yuan; Qu, Liang; Wang, Xuelian; Song, Jian; Heng, Lijun; Gao, Guodong

    2017-04-01

    Glutamatergic projections to nucleus accumbens (NAc) drive drug-seeking behaviors during opioids withdrawal. Modulating glutamatergic neurotransmission provides a novel pharmacotherapeutic avenue for treatment of opioids dependence. Great deals of researches have verified that transient receptor potential vanilloid 1 (TRPV1) channels alters synaptic transmitter release and regulate neural plasticity. In the present study, whole-cell patch clamp recordings were adopted to examine the activity of TRPV1 Channels in regulating glutamate-mediated excitatory postsynaptic currents (EPSCs) in NAc of rat during morphine withdrawal for 3days and 3weeks. The data showed that the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) and the amplitudes of evoked excitatory postsynaptic currents (eEPSCs) were increased during morphine withdrawal after applied with capsaicin (TRPV1 agonist). Capsaicin decreased the paired pulse ratio (PPR) and increased sEPSCs frequency but not their amplitudes suggesting a presynaptic locus of action during morphine withdrawal. All these effects were fully blocked by the TRPV1 antagonist Capsazepine. Additionally, In the presence of AM251 (CB1 receptor antagonist), depolarization-induced release of endogenous cannabinoids activated TRPV1 channels to enhance glutamatergic neurotransmission during morphine withdrawal. The functional enhancement of TRPV1 Channels in facilitating glutamatergic transmission was not recorded in dorsal striatum. Our findings demonstrate the ability of TRPV1 in regulating excitatory glutamatergic transmission is enhanced during morphine withdrawal in NAc, which would deepen our understanding of glutamatergic modulation during opioids withdrawal.

  3. ATP signals

    DEFF Research Database (Denmark)

    Novak, Ivana

    2016-01-01

    The Department of Biology at the University of Copenhagen explains the function of ATP signalling in the pancreas......The Department of Biology at the University of Copenhagen explains the function of ATP signalling in the pancreas...

  4. Taurine activates strychnine-sensitive glycine receptors in neurons freshly isolated from nucleus accumbens of young rats.

    Science.gov (United States)

    Jiang, Zhenglin; Krnjević, Kresimir; Wang, Fushun; Ye, Jiang Hong

    2004-01-01

    Although functional glycine receptors (GlyRs) are present in the mature nucleus accumbens (NAcc), an important area of the mesolimbic dopamine system involved in drug addiction, their role has been unclear because the NAcc contains little glycine. However, taurine, an agonist of GlyRs, is abundant throughout the brain, especially during early development. In the present study on freshly dissociated NAcc neurons from young Sprague-Dawley rats (12- to 21-day old), we found that both glycine and taurine can strongly depolarize NAcc neurons and modulate their excitability. In voltage-clamped NAcc neurons, glycine and taurine elicited chloride currents (IGly and ITau) with an EC50 of 0.12 and 1.25 mM, respectively. The reversal potential of IGly or ITau was 0 mV in conventional whole cell mode and -30 mV in gramicidin-perforated mode. At concentrations taurine were very effectively antagonized by strychnine and by picrotoxin (with an IC50 of 60 nM and 36.5 microM for IGly, and 40 nM and 42.2 microM for ITau) but were insensitive to 10 microM bicuculline. The currents elicited by taurine (taurine (10 mM) showed partial cross-desensitization with IGABA, and it was substantially antagonized by 10 microM bicuculline. These results indicate that taurine binds mainly to GlyRs in NAcc, but it could be a partial agonist of GABAA receptors. By activating GlyRs, taurine may play an important physiological role in the control of NAcc function, especially during development.

  5. Acute iboga alkaloid effects on extracellular serotonin (5-HT) levels in nucleus accumbens and striatum in rats.

    Science.gov (United States)

    Wei, D; Maisonneuve, I M; Kuehne, M E; Glick, S D

    1998-08-03

    The iboga alkaloid, ibogaine, its metabolite, noribogaine, and the congener, 18-methoxycoronaridine (18-MC) have all been claimed to have anti-addictive properties in animal models, but the mechanisms underlying these effects are unclear. Ibogaine and noribogaine were shown to have affinity for the serotonin transporter, and inhibition of serotonin reuptake has been proposed to be involved in their anti-addictive actions. It is not known yet if 18-MC also has this property. In vivo microdialysis and HPLC (microbore) were used to determine acute changes in extracellular serotonin levels in nucleus accumbens (NAC) and striatum (STR) after both i.p. (40 mg/kg for all drugs) and i.v. (1-10 mg/kg for ibogaine and noribogaine) drug administration in awake freely moving female Sprague-Dawley rats (250-275 g). After i.p. administration, ibogaine, noribogaine and 18-MC had very different effects on extracellular serotonin levels in both NAC and STR: ibogaine elicited large increases (up to 25-fold in NAC and 10- fold in STR), noribogaine produced moderate increases (up to 8-fold in NAC and 5-fold in STR), and 18-MC had no effect in either brain region. These and other data suggest that (1) the serotonergic system may not be an essential factor in the anti-addictive actions of these drugs; (2) ibogaine (or an unidentified metabolite) may release serotonin as well as inhibit its reuptake; (3) stimulation of the ascending serotonergic system may mediate ibogaine's hallucinogenic effect; and (4) 18-MC probably has no affinity for the serotonin transporter, and is unlikely to be a hallucinogen.

  6. Neuropeptide Y response to alcohol is altered in nucleus accumbens of mice selectively bred for drinking to intoxication

    Science.gov (United States)

    Barkley-Levenson, Amanda M.; Ryabinin, Andrey E.; Crabbe, John C.

    2016-01-01

    The High Drinking in the Dark (HDID) mice have been selectively bred for drinking to intoxicating blood alcohol levels and represent a genetic model of risk for binge-like drinking. Presently, little is known about the specific genetic factors that promote excessive intake in these mice. Previous studies have identified neuropeptide Y (NPY) as a potential target for modulating alcohol intake. NPY expression differs in some rodent lines that have been selected for high and low alcohol drinking phenotypes, as well as inbred mouse strains that differ in alcohol preference. Alcohol drinking and alcohol withdrawal also produce differential effects on NPY expression in the brain. Here, we assessed brain NPY protein levels in HDID mice of two replicates of selection and control heterogeneous stock (HS) mice at baseline (water drinking) and after binge-like alcohol drinking to determine whether selection is associated with differences in NPY expression and its sensitivity to alcohol. NPY levels did not differ between HDID and HS mice in any brain region in the water-drinking animals. HS mice showed a reduction in NPY levels in the nucleus accumbens (NAc) – especially in the shell – in ethanol-drinking animals vs. water-drinking controls. However, HDID mice showed a blunted NPY response to alcohol in the NAc core and shell compared to HS mice. These findings suggest that the NPY response to alcohol has been altered by selection for drinking to intoxication in a region-specific manner. Thus, the NPY system may represent a potential target for altering binge-like alcohol drinking in these mice. PMID:26779672

  7. Sex differences in alcohol consumption and alterations in nucleus accumbens endocannabinoid mRNA in alcohol-dependent rats.

    Science.gov (United States)

    Henricks, Angela M; Berger, Anthony L; Lugo, Janelle M; Baxter-Potter, Lydia N; Bieniasz, Kennedy V; Craft, Rebecca M; McLaughlin, Ryan J

    2016-10-29

    Chronic intermittent alcohol (CIA) exposure produces altered motivational states characterized by anxiety and escalated alcohol consumption during withdrawal. The endocannabinoid (ECB) system contributes to these symptoms, and sex differences in alcohol dependence, as well as bidirectional interactions between ECBs and gonadal hormones have been documented. Thus, we evaluated sex differences in alcohol consumption, anxiety-like behavior, and ECB mRNA expression in the nucleus accumbens (NAc) of alcohol-dependent rats during acute withdrawal. Male rats exposed to six weeks of CIA showed escalated alcohol consumption during acute withdrawal and reductions in NAc N-acyl phosphatidylethanolamine phospholipase D (NAPEPLD), DAG lipase alpha (DAGLα), and monoacylglycerol lipase (MAGL) mRNA. Intact alcohol-dependent female rats also escalated their consumption, but notably, this effect was also present in non-dependent females. No differences in NAc ECB mRNA were observed between CIA- and air-exposed females during acute withdrawal. However, when these data were analyzed according to estrous stage, significant differences in NAPEPLD and MAGL mRNA expression emerged in the NAc of air-exposed control rats, which were absent in alcohol-dependent females. We subsequently measured alcohol consumption and NAc ECB mRNA in ovariectomized (OVX) females with or without estradiol (E2) replacement during withdrawal. Neither E2 nor CIA altered alcohol consumption in OVX females. However, E2 reduced both DAGLα and MAGL mRNA, suggesting that E2 may influence the biosynthesis and degradation of 2-arachidonoylglycerol (2-AG) in the NAc. Collectively, these studies indicate sexual dimorphism in alcohol consumption in non-dependent rats and suggest that E2-mediated alterations in NAc ECB mRNA expression during withdrawal may be a mechanism by which sex differences in alcohol dependence emerge. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

  8. Optogenetic stimulation of accumbens shell or shell projections to lateral hypothalamus produce differential effects on the motivation for cocaine.

    Science.gov (United States)

    Larson, Erin B; Wissman, Anne M; Loriaux, Amy L; Kourrich, Saïd; Self, David W

    2015-02-25

    Previous studies suggest that pharmacological or molecular activation of the nucleus accumbens shell (AcbSh) facilitates extinction of cocaine-seeking behavior. However, overexpression of CREB, which increases excitability of AcbSh neurons, enhances cocaine-seeking behavior while producing depression-like behavior in tests of mood. These discrepancies may reflect activity in differential AcbSh outputs, including those to the lateral hypothalamus (LH), a target region known to influence addictive behavior and mood. Presently, it is unknown whether there is a causal link between altered activity in the AcbSh-LH pathway and changes in the motivation for cocaine. In this study, we used an optogenetics approach to either globally stimulate AcbSh neurons or to selectively stimulate AcbSh terminal projections in the LH, in rats self-administering cocaine. We found that stimulation of the AcbSh-LH pathway enhanced the motivation to self-administer cocaine in progressive ratio testing, and led to long-lasting facilitation of cocaine-seeking behavior during extinction tests conducted after withdrawal from cocaine self-administration. In contrast, global AcbSh stimulation reduced extinction responding. We compared these opposing motivational effects with effects on mood using the forced swim test, where both global AcbSh neuron and selective AcbSh-LH terminal stimulation facilitated depression-like behavioral despair. Together, these findings suggest that the AcbSh neurons convey complex, pathway-specific modulation of addiction and depression-like behavior, and that these motivation and mood phenomenon are dissociable.

  9. Role of dopamine and GABA in the control of motor activity elicited from the rat nucleus accumbens.

    Science.gov (United States)

    Wong, L S; Eshel, G; Dreher, J; Ong, J; Jackson, D M

    1991-04-01

    The application of 1.2 and 12.0 micrograms/side of the GABAA receptor agonist 3-aminopropane sulphonic acid bilaterally into the nucleus accumbens (Acb) of rats nonsignificantly depressed locomotor activity as assessed in automated Animex activity cages, while the highest dose (60 micrograms/side) significantly stimulated activity. The GABAA receptor antagonists picrotoxinin (0.0625 and 0.125 micrograms/saide) and bicuculline (0.895 micrograms/side) produced forward locomotion around the cage accompanied by a number of other behaviours. The GABAB agonist baclofen (0.023 and 0.092 micrograms/side) induced a short-lasting (18 min) locomotor depression. None of the GABAB antagonists tested (2-hydroxysaclofen 2.6 micrograms/side, two novel beta-(benzo[b]furan) analogues of baclofen 9G or 9H each 6.8 micrograms/side, 4-aminobutylphosphonic acid 1.32 micrograms/side and phaclofen 0.535 and 2 micrograms/side) significantly affected locomotor activity. In rats pretreated with reserpine and alpha-methyl-p-tyrosine, picrotoxinin (0.0625 and 0.125 micrograms/side) did not significantly alter locomotor activity. Furthermore, when picrotoxinin (0.0625 micrograms/side) was combined with either the selective dopamine (DA) D1 agonist SKF38393 or the selective D2 agonist quinpirole, no significant alteration in locomotor function occurred. When SKF38393 and quinpirole were coadministered, significant stimulation occurred which was further enhanced by the addition of picrotoxinin. It is concluded that GABAA receptors, together with D1 and D2 receptors, play a major role in modulating the control of motor function by the Acb of rats.

  10. Chronic alcohol consumption leads to neurochemical changes in the nucleus accumbens that are not fully reversed by withdrawal.

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    Pereira, Pedro A; Neves, João; Vilela, Manuel; Sousa, Sérgio; Cruz, Catarina; Madeira, M Dulce

    2014-01-01

    Neuropeptide Y (NPY)- and acetylcholine-containing interneurons of the nucleus accumbens (NAc) seem to play a major role in the rewarding effects of alcohol. This study investigated the relationship between chronic alcohol consumption and subsequent withdrawal and the expression of NPY and acetylcholine in the NAc, and the possible involvement of nerve growth factor (NGF) in mediating the effects of ethanol. Rats ingesting an aqueous ethanol solution over 6months and rats subsequently deprived from ethanol during 2months were used to estimate the total number and the somatic volume of NPY and cholinergic interneurons, and the numerical density of cholinergic varicosities in the NAc. The tissue content of choline acetyltransferase (ChAT) and catecholamines were also determined. The number of NPY interneurons increased during alcohol ingestion and returned to control values after withdrawal. Conversely, the number and the size of cholinergic interneurons, and the amount of ChAT were unchanged in ethanol-treated and withdrawn rats, but the density of cholinergic varicosities was reduced by 50% during alcohol consumption and by 64% after withdrawal. The concentrations of dopamine and norepinephrine were unchanged both during alcohol consumption and after withdrawal. The administration of NGF to withdrawn rats significantly increased the number of NPY-immunoreactive neurons, the size of cholinergic neurons and the density of cholinergic varicosities. Present data show that chronic alcohol consumption leads to long-lasting neuroadaptive changes of the cholinergic innervation of the NAc and suggest that the cholinergic system is a potential target for the development of therapeutic strategies in alcoholism and abstinence.

  11. Optogenetic inhibition of D1R containing nucleus accumbens neurons alters cocaine- mediated regulation of Tiam1

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    Ramesh eChandra

    2013-05-01

    Full Text Available Exposure to psychostimulants results in structural and synaptic plasticity in striatal medium spiny neurons (MSNs. These cellular adaptations arise from alterations in genes that are highly implicated in the rearrangement of the actin cytoskeleton, such as Tiam1. Previous studies have demonstrated a crucial role for dopamine receptor 1 (D1-containing striatal MSNs in mediating psychostimulant induced plasticity changes. These D1-MSNs in the nucleus accumbens (NAc positively regulate drug seeking, reward, and locomotor behavioral effects as well as the morphological adaptations of psychostimulant drugs. Here, we demonstrate that rats that actively self-administer cocaine display reduced levels of Tiam1 in the NAc. To further examine the cell type specific contribution to these changes in Tiam1 we used optogenetics to selectively manipulate NAc D1-MSNs or dopamine receptor 2 (D2 expressing MSNs. We find that repeated ChR2 activation of D1-MSNs but not D2-MSNs caused a down-regulation of Tiam1 levels similar to the effects of cocaine. Further, activation of D2-MSNs, which caused a late blunted cocaine-mediated locomotor behavioral response, did not alter Tiam1 levels. We then examined the contribution of D1-MSNs to the cocaine-mediated decrease of Tiam1. Using the light activated chloride pump, eNpHR3.0, we selectively inhibited D1-MSNs during cocaine exposure, which resulted in a behavioral blockade of cocaine-induced locomotor sensitization. Moreover, inhibiting these NAc D1-MSNs during cocaine exposure reversed the down-regulation of Tiam1 gene expression and protein levels. These data demonstrate that altering activity in specific neural circuits with optogenetics can impact the underlying molecular substrates of psychostimulant mediated behavior and function.

  12. Relief learning requires a coincident activation of dopamine D1 and NMDA receptors within the nucleus accumbens.

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    Bergado Acosta, Jorge R; Kahl, Evelyn; Kogias, Georgios; Uzuneser, Taygun C; Fendt, Markus

    2017-03-01

    Relief learning is the association of a stimulus with the offset of an aversive event. Later, the now conditioned relief stimulus induces appetitive-like behavioral changes. We previously demonstrated that the NMDA receptors within the nucleus accumbens (NAC) are involved in relief learning. The NAC is also important for reward learning and it has been shown that reward learning is mediated by an interaction of accumbal dopamine and NMDA glutamate receptors. Since conditioned relief has reward-like properties, we hypothesized that (a) acquisition of relief learning requires the activation of dopamine D1 receptors in the NAC, and (b) if D1 receptors are involved in this process as expected, a concurrent dopamine D1 and NMDA receptor activation may mediate this learning. The present study tested these hypotheses. Therefore, rats received intra-NAC injections of the dopamine D1 receptor antagonist SCH23390 and the NMDA antagonist AP5, either separately or together, at different time points of a relief conditioning procedure. First, we showed that SCH23390 dose-dependently blocked acquisition and the expression of conditioned relief. Next, we demonstrated that co-injections of SCH23390 and AP5 into the NAC, at doses that were ineffective when applied separately, blocked acquisition but not consolidation or expression of relief learning. Notably, neither of the injections affected the locomotor response of the animals to the aversive stimuli suggesting that their perception is not changed. This data indicates that a co-activation of dopamine D1 and NMDA receptors in the NAC is required for acquisition of relief learning. Copyright © 2016. Published by Elsevier Ltd.

  13. Enriched environment attenuates nicotine self-administration and induces changes in ΔFosB expression in the rat prefrontal cortex and nucleus accumbens.

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    Venebra-Muñoz, Arturo; Corona-Morales, Aleph; Santiago-García, Juan; Melgarejo-Gutiérrez, Montserrat; Caba, Mario; García-García, Fabio

    2014-06-18

    Environment enrichment conditions have important consequences on subsequent vulnerability to drugs of abuse. The present work examined whether exposure to an enriched environment (EE) decreases oral self-consumption of nicotine. Wistar rats were housed either in a standard environment (SE, four rats per standard cage) or in an EE during 60 days after weaning. EE consisted of eight animals housed in larger cages containing a variety of objects such as boxes, toys, and burrowing material that were changed three times a week. After this period, animals were exposed to nicotine for 3 weeks, where animals chose freely between water and a nicotine solution (0.006% in water). Fluid consumption was evaluated on a daily basis. ΔFosB immunohistochemistry in the prefrontal cortex and nucleus accumbens was also performed. Rats of the EE group consumed less nicotine solution (0.25±0.04 mg/kg/day) than SE rats (0.54±0.05 mg/kg/day). EE increased the number of ΔFos-immunoreactive (ΔFos-ir) cells in the nucleus accumbens core and shell and in the prefrontal cortex, compared with animals in the standard condition. However, rats exposed to nicotine in the SE showed higher ΔFos-ir cells in the nucleus accumbens core and shell than nonexposed rats. Nicotine consumption did not modify ΔFos-ir cells in these brain areas in EE animals. These results support the idea of a possible protective effect of the EE on reward sensitivity and the development of an addictive behavior to nicotine.

  14. Selective serotonin receptor stimulation of the medial nucleus accumbens differentially affects appetitive motivation for food on a progressive ratio schedule of reinforcement.

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    Pratt, Wayne E; Schall, Megan A; Choi, Eugene

    2012-03-09

    Previously, we reported that stimulation of selective serotonin (5-HT) receptor subtypes in the nucleus accumbens shell differentially affected consumption of freely available food. Specifically, activation of 5-HT(6) receptors caused a dose-dependent increase in food intake, while the stimulation of 5-HT(1/7) receptor subtypes decreased feeding [34]. The current experiments tested whether similar pharmacological activation of nucleus accumbens serotonin receptors would also affect appetitive motivation, as measured by the amount of effort non-deprived rats exerted to earn sugar reinforcement. Rats were trained to lever press for sugar pellets on a progressive ratio 2 schedule of reinforcement. Across multiple treatment days, three separate groups (N=8-10) received bilateral infusions of the 5-HT(6) agonist EMD 386088 (at 0.0, 1.0 and 4.0 μg/0.5 μl/side), the 5-HT(1/7) agonist 5-CT (at 0, 0.5, 1.0, or 4.0 μg/0.5 μl/side), or the 5-HT(2C) agonist RO 60-0175 fumarate (at 0, 2.0, or 5.0 μg/0.5 μl/side) into the anterior medial nucleus accumbens prior to a 1-h progressive ratio session. Stimulation of 5-HT(6) receptors caused a dose-dependent increase in motivation as assessed by break point, reinforcers earned, and total active lever presses. Stimulation of 5-HT(1/7) receptors increased lever pressing at the 0.5 μg dose of 5-CT, but inhibited lever presses and break point at 4.0 μg/side. Injection of the 5-HT(2C) agonist had no effect on motivation within the task. Collectively, these experiments suggest that, in addition to their role in modulating food consumption, nucleus accumbens 5-HT(6) and 5-HT(1/7) receptors also differentially regulate the appetitive components of food-directed motivation.

  15. Decreased Caffeine-Induced Locomotor Activity via Microinjection of CART Peptide into the Nucleus Accumbens Is Linked to Inhibition of the pCaMKIIa-D3R Interaction.

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    Qiang Fu

    Full Text Available The purpose of this study was to characterize the inhibitory modulation of cocaine- and amphetamine-regulated transcript (CART peptides, particularly with respect to the function of the D3 dopamine receptor (D3R, which is activated by its interaction with phosphorylated CaMKIIα (pCaMKIIα in the nucleus accumbens (NAc. After repeated oral administration of caffeine (30 mg/kg for five days, microinjection of CART peptide (0.08 μM/0.5 μl/hemisphere into the NAc affected locomotor behavior. The pCaMKIIα-D3R interaction, D3R phosphorylation and cAMP/PKA/phosphorylated CREB (pCREB signaling pathway activity were measured in NAc tissues, and Ca2+ influx and pCaMKIIα levels were measured in cultured NAc neurons. We found that CART attenuated the caffeine-mediated enhancement of depolarization-induced Ca2+ influx and CaMKIIα phosphorylation in cultured NAc neurons. Repeated microinjection of CART peptides into the NAc decreased the caffeine-induced enhancement of Ca2+ channels activity, pCaMKIIα levels, the pCaMKIIα-D3R interaction, D3R phosphorylation, cAMP levels, PKA activity and pCREB levels in the NAc. Furthermore, behavioral sensitization was observed in rats that received five-day administration of caffeine following microinjection of saline but not in rats that were treated with caffeine following microinjection of CART peptide. These results suggest that caffeine-induced CREB phosphorylation in the NAc was ameliorated by CART peptide due to its inhibition of D3R phosphorylation. These effects of CART peptides may play a compensatory role by inhibiting locomotor behavior in rats.

  16. Signaling aggression.

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    van Staaden, Moira J; Searcy, William A; Hanlon, Roger T

    2011-01-01

    From psychological and sociological standpoints, aggression is regarded as intentional behavior aimed at inflicting pain and manifested by hostility and attacking behaviors. In contrast, biologists define aggression as behavior associated with attack or escalation toward attack, omitting any stipulation about intentions and goals. Certain animal signals are strongly associated with escalation toward attack and have the same function as physical attack in intimidating opponents and winning contests, and ethologists therefore consider them an integral part of aggressive behavior. Aggressive signals have been molded by evolution to make them ever more effective in mediating interactions between the contestants. Early theoretical analyses of aggressive signaling suggested that signals could never be honest about fighting ability or aggressive intentions because weak individuals would exaggerate such signals whenever they were effective in influencing the behavior of opponents. More recent game theory models, however, demonstrate that given the right costs and constraints, aggressive signals are both reliable about strength and intentions and effective in influencing contest outcomes. Here, we review the role of signaling in lieu of physical violence, considering threat displays from an ethological perspective as an adaptive outcome of evolutionary selection pressures. Fighting prowess is conveyed by performance signals whose production is constrained by physical ability and thus limited to just some individuals, whereas aggressive intent is encoded in strategic signals that all signalers are able to produce. We illustrate recent advances in the study of aggressive signaling with case studies of charismatic taxa that employ a range of sensory modalities, viz. visual and chemical signaling in cephalopod behavior, and indicators of aggressive intent in the territorial calls of songbirds.

  17. Stress-Induced Locomotor Sensitization to Amphetamine in Adult, but not in Adolescent Rats, Is Associated with Increased Expression of ΔFosB in the Nucleus Accumbens

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    Carneiro de Oliveira, Paulo E.; Leão, Rodrigo M.; Bianchi, Paula C.; Marin, Marcelo T.; Planeta, Cleopatra da Silva; Cruz, Fábio C.

    2016-01-01

    While clinical and pre-clinical evidence suggests that adolescence is a risk period for the development of addiction, the underlying neural mechanisms are largely unknown. Stress during adolescence has a huge influence on drug addiction. However, little is known about the mechanisms related to the interaction among stress, adolescence and addiction. Studies point to ΔFosB as a possible target for this phenomenon. In the present study, adolescent and adult rats (postnatal day 28 and 60, respectively) were restrained for 2 h once a day for 7 days. Three days after their last exposure to stress, the animals were challenged with saline or amphetamine (1.0 mg/kg i.p.) and amphetamine-induced locomotion was recorded. Immediately after the behavioral tests, rats were decapitated and the nucleus accumbens was dissected to measure ΔFosB protein levels. We found that repeated restraint stress increased amphetamine-induced locomotion in both the adult and adolescent rats. Furthermore, in adult rats, stress-induced locomotor sensitization was associated with increased expression of ΔFosB in the nucleus accumbens. Our data suggest that ΔFosB may be involved in some of the neuronal plasticity changes associated with stress induced-cross sensitization with amphetamine in adult rats. PMID:27672362

  18. The effect of electroacupuncture on extinction responding of heroin-seeking behavior and FosB expression in the nucleus accumbens core.

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    Hu, Airong; Lai, Miaojun; Wei, Jianzi; Wang, Lina; Mao, Huijuan; Zhou, Wenhua; Liu, Sheng

    2013-02-08

    Augmentation of extinction with learning enhancing therapy may offer an effective strategy to combat heroin relapse. Our lab previously found that electroacupuncture (EA) not only significantly reduced cue-induced reinstatement of heroin seeking but also exhibited a promoting effect on the ability of learning and memory. In the present study, we further investigated the effects of EA on the extinction of heroin-seeking behavior in rats with a history of intravenous heroin self-administration. We trained Sprague-Dawley rats to nose-poke for i.v. heroin either daily for 4h or 25 infusions for 14 consecutive days; then the rats underwent 7 daily 3h extinction sessions in the operant chamber. To assess EA's effects on the extinction response of heroin-associated cues, 2Hz EA was administered 1h before each of the 7 extinction sessions. We also applied immunohistochemistry to detect FosB-positive nuclei in the nucleus accumbens core. We found that EA treatment facilitated the extinction response of heroin seeking but did not alter the locomotor activity in an open field testing environment. EA stimulation attenuated the FosB expression in the core of the nucleus accumbens, a brain region involved in the learning and execution of motor responses. Altogether, these results suggest that EA may provide a novel nonpharmacological approach to enhance extinction learning when combined with extinction therapy for the treatment of heroin addiction.

  19. The gamma-aminobutyric acid type B (GABAB receptor agonist baclofen inhibits morphine sensitization by decreasing the dopamine level in rat nucleus accumbens

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    Fu Zhenyu

    2012-07-01

    Full Text Available Abstract Background Repeated morphine exposure can induce behavioral sensitization. There are evidences have shown that central gamma-aminobutyric acid (GABA system is involved in morphine dependence. However, the effect of a GABAB receptor agonist baclofen on morphine-induced behavioral sensitization in rats is unclear. Methods We used morphine-induced behavioral sensitization model in rat to investigate the effects of baclofen on behavioral sensitization. Moreover, dopamine release in the shell of the nucleus accumbens was evaluated using microdialysis assay in vivo. Results The present study demonstrated that morphine challenge (3 mg/kg, s.c. obviously enhanced the locomotor activity following 4-day consecutive morphine administration and 3-day withdrawal period, which indicated the expression of morphine sensitization. In addition, chronic treatment with baclofen (2.5, 5 mg/kg significantly inhibited the development of morphine sensitization. It was also found that morphine challenge 3 days after repeated morphine administration produced a significant increase of extracellular dopamine release in nucleus accumbens. Furthermore, chronic treatment with baclofen decreased the dopamine release induced by morphine challenge. Conclusions Our results indicated that gamma-aminobutyric acid system plays an important role in the morphine sensitization in rat and suggested that behavioral sensitization is a promising model to study the mechanism underlying drug abuse.

  20. N-Methyl-d-aspartate Modulation of Nucleus Accumbens Dopamine Release by Metabotropic Glutamate Receptors: Fast Cyclic Voltammetry Studies in Rat Brain Slices in Vitro.

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    Yavas, Ersin; Young, Andrew M J

    2017-02-15

    The N-methyl-d-aspartate (NMDA) receptor antagonist, phencyclidine, induces behavioral changes in rodents mimicking symptoms of schizophrenia, possibly mediated through dysregulation of glutamatergic control of mesolimbic dopamine release. We tested the hypothesis that NMDA receptor activation modulates accumbens dopamine release, and that phencyclidine pretreatment altered this modulation. NMDA caused a receptor-specific, dose-dependent decrease in electrically stimulated dopamine release in nucleus accumbens brain slices. This decrease was unaffected by picrotoxin, making it unlikely to be mediated through GABAergic neurones, but was decreased by the metabotropic glutamate receptor antagonist, (RS)-α-methyl-4-sulfonophenylglycine, indicating that NMDA activates mechanisms controlled by these receptors to decrease stimulated dopamine release. The effect of NMDA was unchanged by in vivo pretreatment with phencyclidine (twice daily for 5 days), with a washout period of at least 7 days before experimentation, which supports the hypothesis that there is no enduring direct effect of PCP at NMDA receptors after this pretreatment procedure. We propose that NMDA depression of accumbal dopamine release is mediated by metabotropic glutamate receptors located pre- or perisynaptically, and suggest that NMDA evoked increased extrasynaptic spillover of glutamate is sufficient to activate these receptors that, in turn, inhibit dopamine release. Furthermore, we suggest that enduring functional changes brought about by subchronic phencyclidine pretreatment, modeling deficits in schizophrenia, are downstream effects consequent on chronic blockade of NMDA receptors, rather than direct effects on NMDA receptors themselves.

  1. Individual prolactin reactivity modulates response of nucleus accumbens to erotic stimuli during acute cannabis intoxication: an fMRI pilot study.

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    Androvicova, R; Horacek, J; Tintera, J; Hlinka, J; Rydlo, J; Jezova, D; Balikova, M; Hlozek, T; Miksatkova, P; Kuchar, M; Roman, M; Tomicek, P; Tyls, F; Viktorinova, M; Palenicek, T

    2017-07-01

    Self-report studies indicate that cannabis could increase sexual desire in some users. We hypothesized that intoxication increases activation of brain areas responsive to visual erotica, which could be useful in the treatment of hypoactive sexual desire disorder, a condition marked by a lack of sexual desire. The aim of this study is to assess the aphrodisiacal properties of cannabis. We conducted an open-randomized study with 21 heterosexual casual cannabis users. A 3T MRI was used to measure brain activation in response to erotic pictures. Blood samples were collected to determine the serum levels of cannabinoids, cortisol and prolactin. Participants were grouped according to whether they had ever experienced any aphrodisiacal effects during intoxication (Group A) or not (Group non-A). Intoxication was found to significantly increase activation in the right nucleus accumbens in the Group A while significantly decreasing activation in the Group non-A. There was also a significant interaction between the group and intoxication, with elevated prolactin in the Group non-A during intoxication. No intoxication-related differences in subjective picture evaluations were found. Cannabis intoxication increases activation of the right nucleus accumbens to erotic stimuli. This effect is limited to users whose prolactin is not elevated in response to intoxication. This effect may be useful in the treatment of low sexual desire.

  2. Stress-induced locomotor sensitization to amphetamine in adult, but not in adolescent rats, is associated with increased expression of ΔFosB in the nucleus accumbens.

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    Paulo Eduardo Carneiro de Oliveira

    2016-09-01

    Full Text Available While clinical and pre-clinical evidence suggests that adolescence is a risk period for the development of addiction, the underlying neural mechanisms are largely unknown. Stress during adolescence has a huge influence on drug addiction. However, little is known about the mechanisms related to the interaction among stress, adolescence and addiction. Studies point to ΔFosB as a possible target for this phenomenon. In the present study, adolescent and adult rats (postnatal day 28 and 60, respectively were restrained for 2 hours once a day for 7 days. Three days after their last exposure to stress, the animals were challenged with saline or amphetamine (1.0 mg/kg i.p. and amphetamine-induced locomotion was recorded. Immediately after the behavioral tests, rats were decapitated and the nucleus accumbens was dissected to measure ΔFosB protein levels. We found that repeated restraint stress increased amphetamine-induced locomotion in both adult and adolescent rats. Furthermore, in adult rats, stress-induced locomotor sensitization was associated with increased expression of ΔFosB in the nucleus accumbens. Our data suggest that ΔFosB may be involved in some of the neuronal plasticity changes associated with stress induced-cross sensitization with amphetamine in adult rats.

  3. Nicotinic α7 receptor activation selectively potentiates the function of NMDA receptors in glutamatergic terminals of the nucleus accumbens

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    Stefania eZappettini

    2014-10-01

    Full Text Available We here provide functional and immunocytochemical evidence supporting the co-localization and functional interaction between nicotinic acetylcholine receptors (nAChRs and N-methyl-D-aspartic acid receptors (NMDARs in glutamatergic terminals of the nucleus accumbens (NAc. Immunocytochemical studies showed that a significant percentage of NAc terminals were glutamatergic and possessed GluN1 and α7-containing nAChR. A short-term pre-exposure of synaptosomes to nicotine (30 µM or choline (1 mM caused a significant potentiation of the 100 µM NMDA-evoked [3H]D-aspartate ([3H]D-Asp outflow, which was prevented by α-bungarotoxin (100 nM. The pre-exposure to nicotine (100 µM or choline (1 mM also enhanced the NMDA-induced cytosolic free calcium levels, as measured by FURA-2 fluorescence imaging in individual NAc terminals, an effect also prevented by α-bungarotoxin. Pre-exposure to the α4-nAChR agonists 5IA85380 (10 nM or RJR2429 (1 µM did not modify NMDA-evoked ([3H]D-Asp outflow and calcium transients. The NMDA-evoked ([3H]D-Asp overflow was partially antagonized by the NMDAR antagonists MK801, D-AP5, 5,7-DCKA and R(-CPP and unaffected by the GluN2B-NMDAR antagonists Ro256981 and ifenprodil. Notably, pre-treatment with choline increased GluN2A biotin-tagged proteins. In conclusion, our results show that the GluN2A-NMDA receptor function can be positively regulated in NAc terminals in response to a brief incubation with α7 but not α4 nAChRs agonists. This might be a general feature in different brain areas since a similar nAChR-mediated bolstering of NMDA-induced ([3H]D-Aspoverflow was also observed in hippocampal synaptosomes.

  4. Local Control of Extracellular Dopamine Levels in the Medial Nucleus Accumbens by a Glutamatergic Projection from the Infralimbic Cortex.

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    Quiroz, César; Orrú, Marco; Rea, William; Ciudad-Roberts, Andrés; Yepes, Gabriel; Britt, Jonathan P; Ferré, Sergi

    2016-01-20

    It is generally assumed that infralimbic cortex (ILC) and prelimbic cortex, two adjacent areas of the medial prefrontal cortex (mPFC) in rodents, provide selective excitatory glutamatergic inputs to the nucleus accumbens (NAc) shell and core, respectively. It is also generally believed that mPFC influences the extracellular levels of dopamine in the NAc primarily by an excitatory collateral to the ventral tegmental area (VTA). In the present study, we first established the existence of a selective functional connection between ILC and the posteromedial portions of the VTA (pmVTA) and the mNAc shell (pmNAc shell), by measuring striatal neuronal activation (immunohistochemical analysis of ERK1/2 phosphorylation) and glutamate release (in vivo microdialysis) upon ILC electrical stimulation. A novel optogenetic-microdialysis approach allowed the measurement of extracellular concentrations of glutamate and dopamine in the pmNAc shell upon local light-induced stimulation of glutamatergic terminals from ILC. Cortical electrical and local optogenetic stimulation produced significant increases in the extracellular concentrations of glutamate and dopamine in the pmNAc shell. Local blockade of glutamate release by perfusion of an adenosine A2A receptor antagonist in the pmNAc shell blocked the dopamine release induced by local optogenetic stimulation but only partially antagonized dopamine release induced by cortical electrical stimulation. The results demonstrate that ILC excitatory afferents directly modulate the extracellular concentration of dopamine in the pmNAc shell, but also support the involvement of an indirect mechanism of dopamine control, through a concomitant ILC-mediated activation of the pmVTA. Significance statement: We established the existence of a functional connection between the infralimbic cortex (ILC) and the posteromedial portions of the ventral tegmental area (pmVTA) and the medial nucleus acumbens shell (pmNAc shell). A novel optogenetic

  5. Histamine H3 receptor activation inhibits dopamine synthesis but not release or uptake in rat nucleus accumbens.

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    Aquino-Miranda, Guillermo; Escamilla-Sánchez, Juan; González-Pantoja, Raúl; Bueno-Nava, Antonio; Arias-Montaño, José-Antonio

    2016-07-01

    We studied the effect of activating histamine H3 receptors (H3Rs) on rat nucleus accumbens (rNAcc) dopaminergic transmission by analyzing [(3)H]-dopamine uptake by synaptosomes, and dopamine synthesis and depolarization-evoked [(3)H]-dopamine release in slices. The uptake of [(3)H]-dopamine by rNAcc synaptosomes was not affected by the H3R agonist RAMH (10(-10)-10(-6) M). In rNAcc slices perfusion with RAMH (1 μM) had no significant effect on [(3)H]-dopamine release evoked by depolarization with 30 mM K(+) (91.4 ± 4.5% of controls). The blockade of dopamine D2 autoreceptors with sulpiride (1 μM) enhanced K(+)-evoked [(3)H]-dopamine release (168.8 ± 15.5% of controls), but under this condition RAMH (1 μM) also failed to affect [(3)H]-dopamine release. Dopamine synthesis was evaluated in rNAcc slices incubated with the l-dihydroxyphenylalanine (DOPA) decarboxylase inhibitor NSD-1015 (1 mM). Forskolin-induced DOPA accumulation (220.1 ± 10.4% of controls) was significantly reduced by RAMH (41.1 ± 6.5% and 43.5 ± 9.1% inhibition at 100 nM and 1 μM, respectively), and this effect was prevented by the H3R antagonist ciproxifan (10 μM). DOPA accumulation induced by preventing cAMP degradation with IBMX (iso-butyl-methylxantine, 1 mM) or by activating receptors for the vasoactive intestinal peptide (VIP)/pituitary adenylate cyclase-activating peptide (PACAP) with PACAP-27 (1 μM) was reduced (IBMX) or prevented (PACAP-27) by RAMH (100 nM). In contrast, DOPA accumulation induced by 8-Bromo-cAMP (1 mM) was not affected by RAMH (100 nM). These results indicate that in rNAcc H3Rs do not modulate dopamine uptake or release, but regulate dopamine synthesis by inhibiting cAMP formation and thus PKA activation. This article is part of the Special Issue entitled 'Histamine Receptors'.

  6. Effects on serotonin of (-)nicotine and dimethylphenylpiperazinium in the dorsal raphe and nucleus accumbens of freely behaving rats.

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    Ma, Z; Strecker, R E; McKenna, J T; Thakkar, M M; McCarley, R W; Tao, R

    2005-01-01

    The aim of this study was to investigate the neurochemical mechanism underlying the effect of nicotine and dimethylphenylpiperazinium (DMPP) on 5-hydroxytryptamine (5-HT) release in the dorsal raphe nucleus and nucleus accumbens of freely behaving rats. For comparison, lobeline, cytisine and RJR-2403 were also investigated. It was found that all drugs, when infused locally, evoked an increase of 5-HT in the dorsal raphe nucleus. However, the magnitudes of the 5-HT increase were comparatively different between the drugs in the ranking of their potency: DMPP>RJR 2403>nicotine>lobeline>cytisine. Both methyllycaconitine, a nicotinic acetylcholine receptor (nAChR) antagonist and methyllycaconitine, a selective alpha7-containing nAChR antagonist blocked the effects of nicotine and DMPP, suggesting that alpha7 subunit mediated the increases in 5-HT. However, DMPP was reported to increase 5-HT using non-nAChR mechanism [Lendvai B, Sershen H, Lajtha A, Santha E, Baranyi M, Vizi ES (1996) Differential mechanisms involved in the effect of nicotinic agonists DMPP and lobeline to release [3H]5-HT from rat hippocampal slices. Neuropharmacology 35:1769-1777]. To test if 5-HT carriers were involved, a selective 5-HT reuptake inhibitor citalopram (1 microM) was infused into the dorsal raphe nucleus before administration of nicotine or DMPP. As a result, citalopram significantly blocked the effect of DMPP, whereas it had no influence on nicotine. Finally, the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) was used to test whether the increases in 5-HT were depolarization-dependent. Administration of 8-OH-DPAT (0.1 mg/kg, s.c.) produced significant decreases in 5-HT in the animals treated with nicotine. In contrast, the effect of DMPP was not altered by 8-OH-DPAT, suggesting that the increases in 5-HT were independent of cell membrane depolarization. In conclusion, there are different mechanisms involved in nicotine- and DMPP-evoked increases in 5-HT. This

  7. Effects of lesions of the nucleus accumbens core on choice between small certain rewards and large uncertain rewards in rats

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    Howes Nathan J

    2005-05-01

    Full Text Available Abstract Background Animals must frequently make choices between alternative courses of action, seeking to maximize the benefit obtained. They must therefore evaluate the magnitude and the likelihood of the available outcomes. Little is known of the neural basis of this process, or what might predispose individuals to be overly conservative or to take risks excessively (avoiding or preferring uncertainty, respectively. The nucleus accumbens core (AcbC is known to contribute to rats' ability to choose large, delayed rewards over small, immediate rewards; AcbC lesions cause impulsive choice and an impairment in learning with delayed reinforcement. However, it is not known how the AcbC contributes to choice involving probabilistic reinforcement, such as between a large, uncertain reward and a small, certain reward. We examined the effects of excitotoxic lesions of the AcbC on probabilistic choice in rats. Results Rats chose between a single food pellet delivered with certainty (p = 1 and four food pellets delivered with varying degrees of uncertainty (p = 1, 0.5, 0.25, 0.125, and 0.0625 in a discrete-trial task, with the large-reinforcer probability decreasing or increasing across the session. Subjects were trained on this task and then received excitotoxic or sham lesions of the AcbC before being retested. After a transient period during which AcbC-lesioned rats exhibited relative indifference between the two alternatives compared to controls, AcbC-lesioned rats came to exhibit risk-averse choice, choosing the large reinforcer less often than controls when it was uncertain, to the extent that they obtained less food as a result. Rats behaved as if indifferent between a single certain pellet and four pellets at p = 0.32 (sham-operated or at p = 0.70 (AcbC-lesioned by the end of testing. When the probabilities did not vary across the session, AcbC-lesioned rats and controls strongly preferred the large reinforcer when it was certain, and strongly

  8. A role for nucleus accumbens glutamate in the expression but not the induction of behavioural sensitization to ethanol.

    Science.gov (United States)

    Nona, Christina N; Nobrega, José N

    2017-09-14

    Mechanisms underlying differential sensitivity to behavioural sensitization to ethanol (EtOH) remain poorly understood, although accumulating evidence suggests a role for glutamatergic processes in the ventral striatum. Efforts to address this issue can benefit from the well-documented fact that in any given cohort, some of the mice (High sensitized; HS) show robust sensitization, while others (Low sensitized; LS) show little, if any, sensitization. Here, we examined whether this variability might be differentially associated with nucleus accumbens (NAc) glutamate processes. Male DBA mice received 5 EtOH (2.2g/kg) or saline injections twice a week and were challenged with EtOH (1.8g/kg) 2 weeks after injection 5. When an EtOH challenge was administered 2 weeks following the induction of sensitization, HS, but not LS, mice showed a robust increase in glutamate levels (67%, P<0.01) as measured by in vivo microdialysis. In a separate cohort, the mGlu2/3 agonist LY354740 (10mg/kg), given prior to the EtOH challenge, abolished the expression of sensitization. To ascertain whether enhanced release could also be observed during the induction of sensitization, glutamate levels were measured after the 1st and 5th EtOH injection and were found to be unchanged in HS mice, although briefly elevated in LS mice at injection 5. To further assess possible glutamate involvement during the induction of sensitization, sensitizing EtOH injections were co-administered with NMDAR antagonists. At the doses used, MK-801 (0.25mg/kg) and CGS 19755 (10mg/kg) blocked the expression of sensitization, but did not significantly interfere with the development of EtOH sensitization. Within the limitations of the present design, the results suggest an important role for EtOH-induced glutamate release in the NAc when sensitization is well established, but not necessarily during the development of sensitization. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. Nucleus Accumbens Shell and mPFC but not Insula Orexin-1 Receptors Promote Excessive Alcohol Drinking

    Directory of Open Access Journals (Sweden)

    Kelly Lei

    2016-08-01

    Full Text Available Addiction to alcohol remains a major social and economic problem, in part because of the high motivation for alcohol that humans exhibit and the hazardous binge intake this promotes. Orexin-1-type receptors (OX1Rs promote reward intake under conditions of strong drives for reward, including excessive alcohol intake. While systemic modulation of OX1Rs can alter alcohol drinking, the brain regions that mediate this OX1R enhancement of excessive drinking remain unknown. Given the importance of the nucleus accumbens (NAc and anterior insular cortex (aINS in driving many addictive behaviors, including OX1Rs within these regions, we examined the importance of OX1Rs in these regions on excessive alcohol drinking in C57BL/6 mice during limited-access alcohol drinking in the dark cycle. Inhibition of OX1Rs with the widely used SB-334867 within the medial NAc Shell (mNAsh significantly reduced drinking of alcohol, with no effect on saccharin intake, and no effect on alcohol consumption when infused above the mNAsh. In contrast, intra-mNAsh infusion of the orexin-2 receptor TCS-OX2-29 had no impact on alcohol drinking. In addition, OX1R inhibition within the aINS had no effect on excessive drinking, which was surprising given the importance of aINS-NAc circuits in promoting alcohol consumption and the role for aINS OX1Rs in driving nicotine intake. However, OX1R inhibition within the mPFC did reduce alcohol drinking, indicating cortical OXR involvement in promoting intake. Also, in support of the critical role for mNAsh OX1Rs, SB within the mNAsh also significantly reduced operant alcohol self-administration in rats. Finally, orexin ex vivo enhanced firing in mNAsh neurons from alcohol-drinking mice, with no effect on evoked EPSCs or input resistance; a similar orexin increase in firing without a change in input resistance was observed in alcohol-naïve mice. Taken together, our results strongly suggest that OX1Rs within the mNAsh, but not the aINS, play a

  10. Importancia dopaminérgica en farmacodinamia de cocaína evaluada por alteraciones de GABA y glutamato en el núcleo accumbens de ratas

    Directory of Open Access Journals (Sweden)

    Edgar A. Gélvez

    1996-06-01

    Full Text Available Este trabajo se propuso demostrar la importancia del sistema dopaminérgico en la farmacodinamia de cocaína en el SNC de ratas. Este postulado se verificó evaluando las alteraciones de GABA y glutamato en el núcleo accumbens. Este enfoque se sustenta en la gran cantidad de evidencias que muestran, consistentemente alteraciones en la actividad dopaminérgica por cocaína. Además, el GABA y el glutamato tienen gran importancia en los efectos agudos y crónicos por cocaína. Es bien conocida la interrelación de GABA y glutamato con la actividad dopaminérgica en el núcleo accumbens. Se diseñó un estudio por 16 días de administración de cocaína a ratas a la dosis inicial de 30 mglkgldía (IP con incremento de 5 mglkg cada 4 días, a las cuales se les había lesionado la actividad dopaminérgica en el núcleo accumbens con la neurotoxina 6- hidroxidopamina en ácido ascórbico. Además, se conformó un grupo basal que recibió estereotáxicamante, en el núcleo accumbens, ácido ascórbico en solución salina 0,9% y se trató con un volumen correspondiente de solución salina (IP y, un grupo control, al cual estereotáxicamente, en el núcleo mencionado, se le administró 6-OHDA (en ácido ascórbico, recibiendo posteriormente como tratamiento solución salina (IP. La determinación de los niveles de GABA y glutamato se realizó por métodos enzimáticos. Se observó que la administración crónica de cocaína produce una disminución significativa en el nivel de GABA en el núcleo accumbens del grupo problema, con relación a los grupos basal y control. En tanto, el nivel de glutamato en el grupo problema mostró un incremento significativo con relación al grupo basal, pero, no con relación al grupo control. En conclusión, los resultados de este trabajo sostienen la hipótesis del papel importante que tiene la dopamina en la farmacoterapia de cocaína a través de las alteraciones en los niveles de GABA y glutamato o alteraciones en

  11. Bayesian signaling

    OpenAIRE

    Hedlund, Jonas

    2014-01-01

    This paper introduces private sender information into a sender-receiver game of Bayesian persuasion with monotonic sender preferences. I derive properties of increasing differences related to the precision of signals and use these to fully characterize the set of equilibria robust to the intuitive criterion. In particular, all such equilibria are either separating, i.e., the sender's choice of signal reveals his private information to the receiver, or fully disclosing, i.e., the outcome of th...

  12. INCREASE IN DOPAMINE RELEASE FROM THE NUCLEUS-ACCUMBENS IN RESPONSE TO FEEDING - A MODEL TO STUDY INTERACTIONS BETWEEN DRUGS AND NATURALLY ACTIVATED DOPAMINERGIC-NEURONS IN THE RAT-BRAIN

    NARCIS (Netherlands)

    WESTERINK, BHC; TEISMAN, A; DEVRIES, JB

    1994-01-01

    The aim of the present study was to investigate the interactions between the in vivo release of dopamine and certain drugs, during conditions of increased dopaminergic activity. Dopaminergic neurons in the nucleus accumbens were activated by feeding hungry rats. 48-96 h after implantation of a micro

  13. Non-opiate [beta]-endorphin fragments and dopamine--III [gamma]-type endorphins and various neuroleptics counteract the hypoactivity elicited by injection of apomorphine into the nucleus accumbens

    NARCIS (Netherlands)

    Ree, J.M. van; Caffe, A.R.; Wolterink, G.

    1982-01-01

    The hypoactivity in rats induced by small doses of apomorphine, injected bilaterally into the nucleus accumbens area of the brain, could be antagonized by pretreatment with the neuroleptic-like neuropeptide des-enkephalin-γ-endorphin (DEγE, β-endorphin 6–17) as well as with the neuroleptic drugs hal

  14. Non-opiate β-endorphin fragments and dopamine—VI Behavioural analysis of the interaction between γ-type endorphins and dopaminergic systems in the nucleus accumbens of rats

    NARCIS (Netherlands)

    Ree, J.M. van; Király, I.

    1984-01-01

    Injection of small doses of apomorphine, bromocriptine and the new ergoline compound, GYKI-32887 into the nucleus accumbens decreased locomotor activity when rats were tested in a small open field. This effect was observed following injection of 1 pg of these substances; GYKI-32887 being more potent

  15. Insulin enhances striatal dopamine release by activating cholinergic interneurons and thereby signals reward

    Science.gov (United States)

    Stouffer, Melissa A.; Woods, Catherine A.; Patel, Jyoti C.; Lee, Christian R.; Witkovsky, Paul; Bao, Li; Machold, Robert P.; Jones, Kymry T.; de Vaca, Soledad Cabeza; Reith, Maarten E. A.; Carr, Kenneth D.; Rice, Margaret E.

    2015-01-01

    Insulin activates insulin receptors (InsRs) in the hypothalamus to signal satiety after a meal. However, the rising incidence of obesity, which results in chronically elevated insulin levels, implies that insulin may also act in brain centres that regulate motivation and reward. We report here that insulin can amplify action potential-dependent dopamine (DA) release in the nucleus accumbens (NAc) and caudate–putamen through an indirect mechanism that involves striatal cholinergic interneurons that express InsRs. Furthermore, two different chronic diet manipulations in rats, food restriction (FR) and an obesogenic (OB) diet, oppositely alter the sensitivity of striatal DA release to insulin, with enhanced responsiveness in FR, but loss of responsiveness in OB. Behavioural studies show that intact insulin levels in the NAc shell are necessary for acquisition of preference for the flavour of a paired glucose solution. Together, these data imply that striatal insulin signalling enhances DA release to influence food choices. PMID:26503322

  16. Activation of PKCzeta and PKMzeta in the nucleus accumbens core is necessary for the retrieval, consolidation and reconsolidation of drug memory.

    Directory of Open Access Journals (Sweden)

    Jose A Crespo

    Full Text Available One of the greatest challenges in the treatment of substance dependence is to reverse the control that drug-associated stimuli have gained over the addict's behavior, as these drug-associated memories increase the risk of relapse even after long periods of abstinence. We report here that inhibition of the atypical protein kinase C isoform PKCzeta and its constitutively active isoform PKMzeta with the pseudosubstrate inhibitor ZIP administered locally into the nucleus accumbens core reversibly inhibited the retrieval of drug-associated memory and drug (remifentanil seeking, whereas a scrambled ZIP peptide or staurosporine, an effective inhibitor of c/nPKC-, CaMKII-, and PKA kinases that does not affect PKCzeta/PKMzeta activity, was without effect on these memory processes. Acquisition or extinction of drug-associated memory remained unaffected by PKCzeta- and PKMzeta inhibition.

  17. Early social isolation disrupts latent inhibition and increases dopamine D2 receptor expression in the medial prefrontal cortex and nucleus accumbens of adult rats.

    Science.gov (United States)

    Han, Xiao; Li, Nanxin; Xue, Xiaofang; Shao, Feng; Wang, Weiwen

    2012-04-04

    Adolescence is a critical period for neurodevelopment. In the present study, we investigated the effects of peri-adolescent social isolation on latent inhibition (LI) and dopamine D2 receptor expression in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) of young adult rats. Male Sprague-Dawley rats were randomly divided into adolescent isolation (ISO; isolated housing, 21-34 days of age) and social housing (SOC) groups. LI was tested at postnatal day 56. After behavioral testing, the number of dopamine D2 receptor-expressing cells was determined using immunohistochemistry. Adolescent social isolation impaired LI and increased the number of cells expressing the D2 receptor in the mPFC and NAc. The results suggest that adolescent social isolation produces profound effects on cognitive and dopaminergic function in adult rats, and could be used as an animal model of various neurodevelopmental disorders.

  18. Aversive behavior induced by optogenetic inactivation of ventral tegmental area dopamine neurons is mediated by dopamine D2 receptors in the nucleus accumbens.

    Science.gov (United States)

    Danjo, Teruko; Yoshimi, Kenji; Funabiki, Kazuo; Yawata, Satoshi; Nakanishi, Shigetada

    2014-04-29

    Dopamine (DA) transmission from the ventral tegmental area (VTA) is critical for controlling both rewarding and aversive behaviors. The transient silencing of DA neurons is one of the responses to aversive stimuli, but its consequences and neural mechanisms regarding aversive responses and learning have largely remained elusive. Here, we report that optogenetic inactivation of VTA DA neurons promptly down-regulated DA levels and induced up-regulation of the neural activity in the nucleus accumbens (NAc) as evaluated by Fos expression. This optogenetic suppression of DA neuron firing immediately evoked aversive responses to the previously preferred dark room and led to aversive learning toward the optogenetically conditioned place. Importantly, this place aversion was abolished by knockdown of dopamine D2 receptors but not by that of D1 receptors in the NAc. Silencing of DA neurons in the VTA was thus indispensable for inducing aversive responses and learning through dopamine D2 receptors in the NAc.

  19. GS 455534 selectively suppresses binge eating of palatable food and attenuates dopamine release in the accumbens of sugar-bingeing rats.

    Science.gov (United States)

    Bocarsly, Miriam E; Hoebel, Bartley G; Paredes, Daniel; von Loga, Isabell; Murray, Susan M; Wang, Miaoyuan; Arolfo, Maria P; Yao, Lina; Diamond, Ivan; Avena, Nicole M

    2014-04-01

    Binge eating palatable foods has been shown to have behavioral and neurochemical similarities to drug addiction. GS 455534 is a highly selective reversible aldehyde dehydrogenase 2 inhibitor that has been shown to reduce alcohol and cocaine intake in rats. Given the overlaps between binge eating and drug abuse, we examined the effects of GS 455534 on binge eating and subsequent dopamine release. Sprague-Dawley rats were maintained on a sugar (experiment 1) or fat (experiment 2) binge eating diet. After 25 days, GS 455534 was administered at 7.5 and 15 mg/kg by an intraperitoneal injection, and food intake was monitored. In experiment 3, rats with cannulae aimed at the nucleus accumbens shell were maintained on the binge sugar diet for 25 days. Microdialysis was performed, during which GS 455534 15 mg/kg was administered, and sugar was available. Dialysate samples were analyzed to determine extracellular levels of dopamine. In experiment 1, GS 455534 selectively decreased sugar intake food was made available in the Binge Sugar group but not the Ad libitum Sugar group, with no effect on chow intake. In experiment 2, GS 455534 decreased fat intake in the Binge Fat group, but not the Ad libitum Fat group, however, it also reduced chow intake. In experiment 3, GS 455534 attenuated accumbens dopamine release by almost 50% in binge eating rats compared with the vehicle injection. The findings suggest that selective reversible aldehyde dehydrogenase 2 inhibitors may have the therapeutic potential to reduce binge eating of palatable foods in clinical populations.

  20. The nucleus accumbens as a nexus between values and goals in goal-directed behaviour: a review and a new hypothesis

    Directory of Open Access Journals (Sweden)

    Francesco eMannella

    2013-10-01

    Full Text Available Goal-directed behaviour is a fundamental means by which animals can flexibly solve the challenges posed by variable external and internal conditions. Recently, the processes and brain mechanisms underlying such behaviour have been extensively studied from behavioural, neuroscientific and computational perspectives. This research has highlighted the processes underlying goal-directed behaviour and associated brain systems including prefrontal cortex, basal ganglia and, in particular therein, the nucleus accumbens. This paper focusses on one particular process at the core of goal-directed behaviour: how motivational value is assigned to goals on the basis of internal states and environmental stimuli, and how this supports goal selection processes. Various biological and computational accounts have been given of this problem and of related multiple neural and behaviour phenomena, but we still lack an integrated hypothesis on the generation and use of value for goal selection. This paper proposes an hypothesis that aims to solve this problem and is based on this key elements: (a amygdala and hippocampus establish the motivational value of stimuli and goals; (b prefrontal cortex encodes various types of action outcomes; (c nucleus accumbens integrates different sources of value, representing them in terms of a common currency with the aid of dopamine, and thereby plays a major role in selecting action outcomes within prefrontal cortex. The ‘goals’ pursued by the organism are the outcomes selected by these processes. The hypothesis is developed in the context of a critical review of relevant biological and computational literature which offer it support. The paper shows how the hypothesis has the potential to integrate existing interpretations of motivational value and goal selection.

  1. Role of dopamine D2-like receptors within the ventral tegmental area and nucleus accumbens in antinociception induced by lateral hypothalamus stimulation.

    Science.gov (United States)

    Moradi, Marzieh; Yazdanian, Mohamadreza; Haghparast, Abbas

    2015-10-01

    Several lines of evidence have shown that stimulation of the lateral hypothalamus (LH) can induce antinociception. It has been indicated that hypothalamic orexinergic neurons send projections throughout the dopamine mesolimbic pathway. Functional interaction between the LH and the main area of the mesolimbic pathway such as the ventral tegmental area (VTA) and the nucleus accumbens (NAc) implicates in pain modulation. Thus, in this study, we investigated the role of D2-like dopamine receptors within the VTA and NAc in the LH stimulation-induced antinociception. Male Wistar rats weighing 230-280 g were unilaterally implanted with two separate cannulae into the LH and VTA or NAc. Animals received intra-VTA (0.25, 1 and 4 μg/0.3 μl DMSO) and intra-accumbal (0.125, 0.25, 1 and 4 μg/0.5 μl DMSO) infusions of sulpiride as a selective D2-like receptor antagonist, prior to intra-LH carbachol (125 nM/rat) administration. In the tail-flick test, the antinociceptive effects were measured using a tail-flick algesiometer and represented as maximal possible effect (%MPE) within 5, 15, 30, 45 and 60 min after injections. Our results showed that intra-VTA and intra-accumbal sulpiride dose-dependently attenuated the LH stimulation-induced antinociception. However, the blockade of D2-like receptors within the NAc was more significant than that of the VTA. These findings show that D2-like dopamine receptors in these regions play an important role in the LH-mediated modulation of nociceptive information in the acute model of pain in the rats. It seems that this pain modulating system is more relevant to D2-like receptors in the nucleus accumbens. Copyright © 2015 Elsevier B.V. All rights reserved.

  2. Stimulant mechanisms of cathinones - effects of mephedrone and other cathinones on basal and electrically evoked dopamine efflux in rat accumbens brain slices.

    Science.gov (United States)

    Opacka-Juffry, Jolanta; Pinnell, Thomas; Patel, Nisha; Bevan, Melissa; Meintel, Meghan; Davidson, Colin

    2014-10-01

    Mephedrone, an erstwhile "legal high", and some non-abused cathinones (ethcathinone, diethylpropion and bupropion) were tested for stimulant effects in vitro, through assessing their abilities to increase basal and electrically evoked dopamine efflux in rat accumbens brain slices, and compared with cocaine and amphetamine. We also tested mephedrone against cocaine in a dopamine transporter binding study. Dopamine efflux was electrically evoked and recorded using voltammetry in the rat accumbens core. We constructed concentration response curves for these cathinones for effects on basal dopamine levels; peak efflux after local electrical stimulation and the time-constant of the dopamine decay phase, an index of dopamine reuptake. We also examined competition between mephedrone or cocaine and [(125)I]RTI121 at the dopamine transporter. Mephedrone was less potent than cocaine at displacing [(125)I]RTI121. Mephedrone and amphetamine increased basal levels of dopamine in the absence of electrical stimulation. Cocaine, bupropion, diethylpropion and ethcathinone all increased the peak dopamine efflux after electrical stimulation and slowed dopamine reuptake. Cocaine was more potent than bupropion and ethcathinone, while diethylpropion was least potent. Notably, cocaine had the fastest onset of action. These data suggest that, with respect to dopamine efflux, mephedrone is more similar to amphetamine than cocaine. These findings also show that cocaine was more potent than bupropion and ethcathinone while diethylpropion was least potent. Mephedrone's binding to the dopamine transporter is consistent with stimulant effects but its potency was lower than that of cocaine. These findings confirm and further characterize stimulant properties of mephedrone and other cathinones in adolescent rat brain.

  3. Dendritic morphology changes in neurons from the ventral hippocampus, amygdala and nucleus accumbens in rats with neonatal lesions into the prefrontal cortex.

    Science.gov (United States)

    Lazcano, Zayda; Solis, Oscar; Díaz, Alfonso; Brambila, Eduardo; Aguilar-Alonso, Patricia; Guevara, Jorge; Flores, Gonzalo

    2015-06-01

    Neonatal prefrontal cortex (nPFC) lesions in rats could be a potential animal model to study the early neurodevelopmental abnormalities associated with the behavioral and morphological brain changes observed in schizophrenia. Morphological alterations in pyramidal neurons from the ventral hippocampus (VH) have been observed in post-mortem schizophrenic brains, mainly because of decreased dendritic arbor and spine density. We assessed the effects of nPFC-lesions on the dendritic morphology of neurons from the VH, basolateral-amygdala (BLA) and the nucleus accumbens (NAcc) in rats. nPFC lesions were made on postnatal day 7 (PD7), after dendritic morphology was studied by the Golgi-Cox stain procedure followed by Sholl analysis at PD35 (prepubertal) and PD60 (adult) ages. We also evaluated the effects of PFC-lesions on locomotor activity caused by a novel environment. Adult animals with nPFC lesions showed a decreased spine density in pyramidal neurons from the VH and in medium spiny cells from the NAcc. An increased locomotion was observed in a novel environment for adult animals with a PFC-lesion. Our results indicate that PFC-lesions alter the neuronal dendrite morphology of the NAcc and the VH, suggesting a disconnection between these limbic structures. The locomotion paradigms suggest that dopaminergic transmission is altered in the PFC lesion model. This could help to understand the consequences of an earlier PFC dysfunction in schizophrenia. To evaluate possible dendritic changes in neonatal prefrontal cortex lesions in schizophrenia-related regions including nucleus accumbens, ventral hippocampus and basolateral amygdala, we used the Golgi-Cox stain samples at PD35 and PD70. Our results suggest that neonatal prefrontal cortex damage alters dendritic parameters in limbic regions, and this has potential implications for schizophrenia.

  4. Effects of adolescent methamphetamine and nicotine exposure on behavioral performance and MAP-2 immunoreactivity in the nucleus accumbens of adolescent mice.

    Science.gov (United States)

    Buck, Jordan M; Morris, Alysse S; Weber, Sydney J; Raber, Jacob; Siegel, Jessica A

    2017-04-14

    The neurotoxic effects of methamphetamine (MA) exposure in the developing and adult brain can lead to behavioral alterations and cognitive deficits in adults. Previous increases in the rates of adolescent MA use necessitate that we understand the behavioral and cognitive effects of MA exposure during adolescence on the adolescent brain. Adolescents using MA exhibit high rates of nicotine (NIC) use, but the effects of concurrent MA and NIC in the adolescent brain have not been examined, and it is unknown if NIC mediates any of the effects of MA in the adolescent. In this study, the long-term effects of a neurotoxic dose of MA with or without NIC exposure during early adolescence (postnatal day 30-31) were examined later in adolescence (postnatal day 41-50) in male C57BL/6J mice. Effects on behavioral performance in the open field, Porsolt forced swim test, and conditioned place preference test, and cognitive performance in the novel object recognition test and Morris water maze were assessed. Additionally, the effects of MA and/or NIC on levels of microtubule associated-2 (MAP-2) protein in the nucleus accumbens and plasma corticosterone were examined. MA and NIC exposure during early adolescence separately decreased anxiety-like behavior in the open field test, which was not seen following co-administration of MA/NIC. There was no significant effect of early adolescent MA and/or NIC exposure on the intensity of MAP-2 immunoreactivity in the nucleus accumbens or on plasma corticosterone levels. These results show that early adolescent MA and NIC exposure separately decrease anxiety-like behavior in the open field, and that concurrent MA and NIC exposure does not induce the same behavioral change as either drug alone.

  5. Prosocial Signalling

    DEFF Research Database (Denmark)

    Kahsay, Goytom Abraha

    suggested that consumers pay price premium because this sends the signal that the consumer has prosocial preferences and a few empirical studies have documented that reputation plays a key role when consumers choose products containing prosocial components. However, little is known about consumers...... consumer goods and presents empirical evidences from a natural consumption data. This thesis also investigates consumers’ behaviour under a newly introduced pricing system called Pay-What-You-Want (PWYW) and investigates empirically whether reputation signalling can be used as a policy instrument in other...... on the role of social network in facilitating factor input transactions and the role of reputation in reducing enforcement. Finally, the third part consists of one paper which is concerned with investigating the effect of climate change and adaptation policy on agricultural production in Eastern Africa...

  6. Signal Processing

    Science.gov (United States)

    1989-03-01

    34ESPIRIT Estimation of signal parameters via rotational imvariance techin+I,-- 1\\I111;1 Smith. A. Faradani "Local and ( Moba ! tomography" I’ Nitlerer and...Feb 1 - Jul 30 Friedman, Avner IMA Gader, Paul University of Wisconsin Jun 27 - Jul 24 Games , Richard MITRE Corp Jun 27 - Aug 5 Garvan, Francis U. of...Gader, Paul University of Wisconsin Jun 27 - Jul 24 Games , Richard MITRE Corp Jun 27 - Aug 5 Garvan, Francis U. of Wisconsin Jun 26 - Jul 31 Habsieger

  7. 毁损伏隔核、腹侧苍白球对大鼠觅药行为的影响%The effect of the nucleus accumbens and ventral pallidum lesions on seeking behavior in rats

    Institute of Scientific and Technical Information of China (English)

    贺世明; 高国栋; 胡三觉; 王学廉

    2001-01-01

    Objective To study the reinforcing effect of the nucleus accumbens and ventral pallidum in rats.Method Electrolytic lesions of the nucleus accumbens and ventral pallidum was done separately in 20 rats amd hbejavopr was ,easired by conditioned place preference paradigm in rats.Result Electrolytic lesions of the nucleus accumbens showed an extinction of the place- preference for morphine- paired environment in rats and ventral pallidum lesions significantly decreased the place- preference.Conclusion The nucleus accumbens and ventral pallidum are important sites mediating the reinforcing effects of morphine and the nucleus accumbens- ventral pallidum circuit is a common pathway for opiate reinforcement.%目的探讨伏隔核和腹侧苍白球在药物强化中的作用。方法分别毁损成瘾大鼠伏隔核、腹侧苍白球,利用条件性地点偏好实验测定术前、术后成瘾大鼠对注射吗啡的偏好分,评价伏隔核和腹侧苍白球在药物强化效应的作用。结果毁损大鼠双侧伏隔核能够完全消除大鼠对注射吗啡侧的偏好,毁损腹侧苍白球明显减少成瘾大鼠的地点偏好行为。结论伏隔核和腹侧苍白球是调节强化作用的重要位置,伏隔核-腹侧苍白球通路是药物强化的共同环路。

  8. The non-peptidic delta opioid receptor agonist TAN-67 enhances dopamine efflux in the nucleus accumbens of freely moving rats via a mechanism that involves both glutamate and free radicals.

    NARCIS (Netherlands)

    Fusa, K.; Takahashi, I.; Watanabe, S.; Aono, Y.; Ikeda, H.; Saigusa, T.; Nagase, H.; Suzuki, T.; Koshikawa, N.; Cools, A.R.

    2005-01-01

    The activation of the delta-opioid receptors in the nucleus accumbens is known to induce a large and rapid increase of accumbal dopamine efflux. (+/-)-TAN-67 (2-methyl-4a(alpha)-(3-hydroxyphenyl)-1,2,3,4,4a,5,12,12a(alpha)-octahydro -quinolino[2,3,3,-g]isoquinoline) is a centrally acting non-peptidi

  9. gamma-Hydroxybutyrate (GHB) induces GABA(B) receptor independent intracellular Ca2+ transients in astrocytes, but has no effect on GHB or GABA(B) receptors of medium spiny neurons in the nucleus accumbens.

    Science.gov (United States)

    Molnár, T; Antal, K; Nyitrai, G; Emri, Z

    2009-08-18

    We report on cellular actions of the illicit recreational drug gamma-hydroxybutyrate (GHB) in the brain reward area nucleus accumbens. First, we compared the effects of GHB and the GABA(B) receptor agonist baclofen. Neither of them affected the membrane currents of medium spiny neurons in rat nucleus accumbens slices. GABAergic and glutamatergic synaptic potentials of medium spiny neurons, however, were reduced by baclofen but not GHB. These results indicate the lack of GHB as well as postsynaptic GABA(B) receptors, and the presence of GHB insensitive presynaptic GABA(B) receptors in medium spiny neurons. In astrocytes GHB induced intracellular Ca(2+) transients, preserved in slices from GABA(B) receptor type 1 subunit knockout mice. The effects of tetrodotoxin, zero added Ca(2+) with/without intracellular Ca(2+) store depletor cyclopiazonic acid or vacuolar H-ATPase inhibitor bafilomycin A1 indicate that GHB-evoked Ca(2+) transients depend on external Ca(2+) and intracellular Ca(2+) stores, but not on vesicular transmitter release. GHB-induced astrocytic Ca(2+) transients were not affected by the GHB receptor-specific antagonist NCS-382, suggesting the presence of a novel NCS-382-insensitive target for GHB in astrocytes. The activation of astrocytes by GHB implies their involvement in physiological actions of GHB. Our findings disclose a novel profile of GHB action in the nucleus accumbens. Here, unlike in other brain areas, GHB does not act on GABA(B) receptors, but activates an NCS-382 insensitive GHB-specific target in a subpopulation of astrocytes. The lack of either post- or presynaptic effects on medium spiny neurons in the nucleus accumbens distinguishes GHB from many drugs and natural rewards with addictive properties and might explain why GHB has only a weak reinforcing capacity.

  10. Prosocial Signalling

    DEFF Research Database (Denmark)

    Kahsay, Goytom Abraha

    In contrast to the standard economic theory predictions, it seems clear that people do spend their time and resource to benefit others. Many lab and field experiment studies show that people display prosocial preferences such as altruism, reciprocity and conditional cooperation, fairness, etc...... economic and environmental domains. This thesis consists of five papers which can be divided into three parts. The first part consists of three papers which all investigate consumers’ behavior when prosocial signalling is important. The second part of the thesis consists of one paper which focuses...... empirical evidence on the role of indigenous social networks, namely iddir associations, in facilitating factor-input transactions among smallholder farmers. Iddir networks provide information advantages, trust, and reputation based contract enforcement. It finds that iddir membership improves household...

  11. Florigen signaling.

    Science.gov (United States)

    Tsuji, Hiroyuki; Taoka, Ken-Ichiro

    2014-01-01

    Florigen is a systemic signal that promotes flowering. Its molecular nature is a conserved FLOWERING LOCUS T (FT) protein that belongs to the PEBP family. FT is expressed in the leaf phloem and transported to the shoot apical meristem where it initiates floral transition. In the cells of the meristem, FT binds 14-3-3 proteins and bZIP transcription factor FD to form the florigen activation complex, FAC, which activates floral meristem identity genes such as AP1. The FAC model provides molecular basis for multiple functions of FT beyond flowering through changes of its partners and transcriptional targets. The surface of FT protein includes several regions essential for transport and functions, suggesting the binding of additional components that support its function. FT expression is under photoperiodic control, involving a conserved GIGANTEA-CONSTANS-FT regulatory module with species-specific modifications that contribute variations of flowering time in natural populations.

  12. Effects of intra-amygdala R(+) 7-OH-DPAT on intra-accumbens d-amphetamine-associated learning. I. Pavlovian conditioning.

    Science.gov (United States)

    Hitchcott, P K; Phillips, G D

    1998-12-01

    We have previously obtained evidence that the mesoamygdaloid dopamine projection modulates the acquisition of a conditioned response (CR) elicited by presentation of a conditioned stimulus (CS) predicting the availability of a natural (sucrose) reward. This property was found to be dependent upon D3, but not D1 or D2, dopamine receptor activation. The aim of the present study was to determine whether the mesoamygdaloid dopamine projection is similarly involved in the acquisition of a drug-associated CR. Thus, two groups of rats with guide cannulae aimed at the nucleus accumbens and amygdala were trained using a Pavlovian conditioning procedure in which an initially neutral CS was paired with a computer-controlled, bilateral intraaccumbens infusion of d-amphetamine (the unconditioned stimulus: US). Conditioning sessions were conducted in standard operant chambers, with each session consisting of a single CS-US trial. For one group of rats, CS presentation was positively correlated with the drug US (Paired group), while for the second group CS and US presentations were negatively correlated (Unpaired group). During training, locomotor activity was recorded and was utilised as the measure both of the unconditioned (UR) and conditioned response (CR). A within-subjects design was utilised to investigate the effect of post-session bilateral intraamygdala administration of R(+) 7-OH-DPAT on the development of the drug-associated CR. Hence, both Paired and Unpaired groups were exposed to two different CSs which were presented on alternate sessions. Post-session bilateral intra-amygdala administration of R(+) 7-OH-DPAT (10 nmol) followed sessions in which one CS was presented, while intra-amygdala vehicle followed sessions in which the alternate CS was presented. The development of a CR occurred only in the presence of a CS that had been positively correlated with presentation of the drug US. Post-session, intra-amygdala administration of R(+) 7-OH-DPAT enhanced the

  13. Nucleus accumbens injections of the mGluR2/3 agonist LY379268 increase cue-induced sucrose seeking following adult, but not adolescent sucrose self-administration.

    Science.gov (United States)

    Myal, S; O'Donnell, P; Counotte, D S

    2015-10-01

    Adolescence is often portrayed as a period of enhanced sensitivity to reward, with long-lasting neurobiological changes upon reward exposure. However, we previously found that time-dependent increases in cue-induced sucrose seeking were more pronounced in rats trained to self-administer sucrose as adults than as adolescents. In addition, adult, but not adolescent sucrose self-administration led to a decreased α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/N-Methyl-D-aspartate (AMPA/NMDA) ratio in the nucleus accumbens core, suggesting that long-lasting changes in glutamatergic transmission may affect adult processing of natural rewards. Here we tested whether altering glutamatergic transmission in the nucleus accumbens core via local injection of an mGluR2/3 agonist and antagonist affects cue-induced sucrose seeking following abstinence and whether this is different in the two age groups. Rats began oral sucrose self-administration training (10 days) on postnatal day (P) 35 (adolescents) or P70 (adults). Following 21 days of abstinence, rats received microinjections of the mGluR2/3 agonist LY379268 (0.3 or 1.0 μg/side) or vehicle into the nucleus accumbens core, and 15 min later cue-induced sucrose seeking was assessed. An additional group of rats trained as adults received nucleus accumbens core microinjections of the mGluR2/3 antagonist (RS)-α-Methyl-4-phosphonophenylglycine (MPPG) (0.12 or 0.5 μg/side). Confirming our previous results, adult rats earned more sucrose reinforcers, while sucrose intake per body weight was similar across ages. On abstinence day 22, local injection of the mGluR2/3 agonist LY379268 increased cue-induced sucrose seeking only in adult rats, and had no effect in adolescents. Local injections of the mGluR2/3 antagonist MPPG had no effect on sucrose seeking in adult rats. These data suggest an important developmental difference in the neural substrates of natural reward, specifically a difference in glutamatergic transmission in

  14. Neurochemical evidence that cocaine- and amphetamine-regulated transcript (CART) 55-102 peptide modulates the dopaminergic reward system by decreasing the dopamine release in the mouse nucleus accumbens.

    Science.gov (United States)

    Rakovska, Angelina; Baranyi, Maria; Windisch, Katalin; Petkova-Kirova, Polina; Gagov, Hristo; Kalfin, Reni

    2017-08-09

    CART (Cocaine- and Amphetamine-Regulated Transcript) peptide is a neurotransmitter naturally occurring in the CNS and found mostly in nucleus accumbens, ventrotegmental area, ventral pallidum, amygdalae and striatum, brain regions associated with drug addiction. In the nucleus accumbens, known for its significant role in motivation, pleasure, reward and reinforcement learning, CART peptide inhibits cocaine and amphetamine-induced dopamine-mediated increases in locomotor activity and behavior, suggesting a CART peptide interaction with the dopaminergic system. Thus in the present study, we examined the effect of CART (55-102) peptide on the basal, electrical field stimulation-evoked (EFS-evoked) (30V, 2Hz, 120 shocks) and returning basal dopamine (DA) release and on the release of the DA metabolites 3,4-dihydroxyphenyl acetaldehyde (DOPAL), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 3,4-dihydroxyphenylethanol (DOPET), 3-methoxytyramine (3-MT) as well as on norepinephrine (NE) and dopamine-o-quinone (Daq) in isolated mouse nucleus accumbens, in a preparation, in which any CART peptide effects on the dendrites or soma of ventral tegmental projection neurons have been excluded. We further extended our study to assess the effect of CART (55-102) peptide on basal cocaine-induced release of dopamine and its metabolites DOPAL, DOPAC, HVA, DOPET and 3-MT as well as on NE and Daq. To analyze the amount of [(3)H]dopamine, dopamine metabolites, Daq and NE in the nucleus accumbens superfusate, a high-pressure liquid chromatography (HPLC), coupled with electrochemical, UV and radiochemical detections was used. CART (55-102) peptide, 0.1μM, added alone, exerted: (i) a significant decrease in the basal and EFS-evoked levels of extracellular dopamine (ii) a significant increase in the EFS-evoked and returning basal levels of the dopamine metabolites DOPAC and HVA, major products of dopamine degradation and (iii) a significant decrease in the returning basal

  15. Interactions of the dorsal hippocampus, medial prefrontal cortex and nucleus accumbens in formation of fear memory: difference in inhibitory avoidance learning and contextual fear conditioning.

    Science.gov (United States)

    Yang, Fang-Chi; Liang, K C

    2014-07-01

    Learning active or reactive responses to fear involves different brain circuitry. This study examined how the nuclus accumbens (NAc), dorsal hippocampus (DH) and medial prefrontal cortex (mPFC) may interact in memory processing for these two kinds of responses. Male Wistar rats with cannulae implanted in these areas were trained on a contextual fear conditioning or inhibitory avoidance task that respectively engaged a reactive or active response to fear in the test. Immediately after training, a memory modulating factor released by stress, norepinephrine (NE), was infused into one region and 4% lidocaine into another to examine if an upstream activation effect could be blocked by the downstream suppression. Retention tested 1 day later showed that in both tasks posttraining infusion of NE at different doses into either the DH or mPFC enhanced retention but the enhancement was blocked by concurrent infusion of lidocaine into the other region, suggesting reliance of the effect on functional integrity of both regions. Further, posttraining intra-NAc lidocaine infusion attenuated memory enhancement of NE infused to the DH or mPFC in the inhibitory avoidance task but did not do so in contextual fear conditioning. These results suggest that NE regulation of memory formation for the reactive and active responses to fear may rely on distinct interactions among the DH, mPFC and NAc. Copyright © 2014 Elsevier Inc. All rights reserved.

  16. Decreased functional connectivity between ventral tegmental area and nucleus accumbens in Internet gaming disorder: evidence from resting state functional magnetic resonance imaging.

    Science.gov (United States)

    Zhang, Jin-Tao; Ma, Shan-Shan; Yip, Sarah W; Wang, Ling-Jiao; Chen, Chao; Yan, Chao-Gan; Liu, Lu; Liu, Ben; Deng, Lin-Yuan; Liu, Qin-Xue; Fang, Xiao-Yi

    2015-11-18

    Internet gaming disorder (IGD) has become an increasing mental health problem worldwide. Decreased resting-state functional connectivity (rsFC) between the ventral tegmental area (VTA) and the nucleus accumbens (NAcc) has been found in substance use and is thought to play an important role in the development of substance addiction. However, rsFC between the VTA and NAcc in a non-substance addiction, such as IGD, has not been assessed previously. The current study aimed to investigate: (1) if individuals with IGD exhibit alterations in VTA-NAcc functional connectivity; and (2) whether VTA-NAcc functional connectivity is associated with subjective Internet craving. Thirty-five male participants with IGD and 24 healthy control (HC) individuals participated in resting-state functional magnetic resonance imaging. Regions of interest (left NAcc, right NAcc and VTA) were selected based on the literature and were defined by placing spheres centered on Talairach Daemon coordinates. In comparison with HCs, individuals with IGD had significantly decreased rsFC between the VTA and right NAcc. Resting-state functional connectivity strength between the VTA and right NAcc was negatively correlated with self-reported subjective craving for the Internet. These results suggest possible neural functional similarities between individuals with IGD and individuals with substance addictions.

  17. Characterization of Mitogen-Activated Protein Kinase Expression in Nucleus Accumbens and Hippocampus of Rats Subjected to Food Selection in the Cafeteria Diet Protocol.

    Science.gov (United States)

    Sarro-Ramírez, Andrea; Sánchez, Daniel; Tejeda-Padrón, Alma; Buenfil-Canto, Linda Vianey; Valladares-García, Jorge; Pacheco-Pantoja, Elda; Arias-Carrión, Oscar; Murillo-Rodríguez, Eric

    2016-01-01

    Obesity is a world-wide health problem that requires different experimental perspectives to understand the onset of this disease, including the neurobiological basis of food selection. From a molecular perspective, obesity has been related with activity of several endogenous molecules, including the mitogenactivated protein kinases (MAP-K). The aim of this study was to characterize MAP-K expression in hedonic and learning and memory brain-associated areas such as nucleus accumbens (AcbC) and hippocampus (HIPP) after food selection. We show that animals fed with cafeteria diet during 14 days displayed an increase in p38 MAP-K activity in AcbC if chose cheese. Conversely, a diminution was observed in animals that preferred chocolate in AcbC. Also, a decrease of p38 MAP-K phosphorylation was found in HIPP in rats that selected either cheese or chocolate. Our data demonstrate a putative role of MAP-K expression in food selection. These findings advance our understanding of neuromolecular basis engaged in obesity.

  18. Prolonged Consumption of Sucrose in a Binge-Like Manner, Alters the Morphology of Medium Spiny Neurons in the Nucleus Accumbens Shell.

    Directory of Open Access Journals (Sweden)

    Paul M Klenowski

    2016-03-01

    Full Text Available The modern diet has become highly sweetened, resulting in unprecedented levels of sugar consumption, particularly among adolescents. While chronic long-term sugar intake is known to contribute to the development of metabolic disorders including obesity and type II diabetes, little is known regarding the direct consequences of long-term, binge-like sugar consumption on the brain. Because sugar can cause the release of dopamine in the nucleus accumbens (NAc similarly to drugs of abuse, we investigated changes in the morphology of neurons in this brain region following short- (4 weeks and long-term (12 weeks binge-like sucrose consumption using an intermittent two-bottle choice paradigm. We used Golgi-Cox staining to impregnate medium spiny neurons (MSNs from the NAc core and shell of short- and long-term sucrose consuming rats and compared these to age matched water controls. We show that prolonged binge-like sucrose consumption significantly decreased the total dendritic length of NAc shell MSNs compared to age-matched control rats. We also found that the restructuring of these neurons resulted primarily from reduced distal dendritic complexity. Conversely, we observed increased spine densities at the distal branch orders of NAc shell MSNs from long-term sucrose consuming rats. Combined, these results highlight the neuronal effects of prolonged binge-like intake of sucrose on NAc shell MSN morphology.

  19. Dopamine and serotonin uptake inhibitors on the release of dopamine and serotonin in the nucleus accumbens of young and aged rats.

    Science.gov (United States)

    Yoshimoto, K; Kato, B; Ueda, S; Noritake, K; Sakai, K; Shibata, M; Hori, M; Kawano, H; Takeuchi, Y; Wakabayashi, Y; Yasuhara, M

    2001-10-01

    Nucleus accumbens (ACC) of young (4 months old) and aged (24 months old) Wistar rats were perfused with dopamine (DA) uptake blocker, cocaine, or the serotonin (5-HT) selective reuptake inhibitor, fluoxetine, through the microdialysis probe membrane, used to assess the dopamine transporter (DAT) or serotonin transporter (SERT) modulation. The basal extracellular DA release in the ACC was significantly lower in aged rats than young rats. Analysis of DA and 5-HT concentrations in the ACC with increased positive GFAP revealed that DA and DOPAC levels of aged rats were decreased to 55 and 60% of those in young rats, respectively. After co-perfusion with cocaine, both DA and 5-HT releases in the ACC were increased in the young and aged groups. However, the magnitude of the increased DA release was lower in aged rats than young rats. Co-perfusion with fluoxetine showed lower magnitude of the increased DA release in aged rats. It appears that the DAT and SERT system responds initially to ACC cell loss with age, and that especially ACC DAT in the aged rat is more degenerative compared with the young rats. These findings suggest that the serotonergic system with SERT in the remaining ACC neurons show an early adaptive response and resistance to the normal aging and maintain the multiple regulatory system in the ACC despite neural loss since the dopaminergic neurons in the aged animals are vulnerable to aging.

  20. Modulation of synaptic potentials and cell excitability by dendritic KIR and KAS channels in nucleus accumbens medium spiny neurons: A computational study

    Indian Academy of Sciences (India)

    Jessy John; Rohit Manchanda

    2011-06-01

    The nucleus accumbens (NAc), a critical structure of the brain reward circuit, is implicated in normal goal-directed behaviour and learning as well as pathological conditions like schizophrenia and addiction. Its major cellular substrates, the medium spiny (MS) neurons, possess a wide variety of dendritic active conductances that may modulate the excitatory post synaptic potentials (EPSPs) and cell excitability. We examine this issue using a biophysically detailed 189-compartment stylized model of the NAc MS neuron, incorporating all the known active conductances. We find that, of all the active channels, inward rectifying K+ (KIR) channels play the primary role in modulating the resting membrane potential (RMP) and EPSPs in the down-state of the neuron. Reduction in the conductance of KIR channels evokes facilitatory effects on EPSPs accompanied by rises in local input resistance and membrane time constant. At depolarized membrane potentials closer to up-state levels, the slowly inactivating A-type potassium channel (KAs) conductance also plays a strong role in determining synaptic potential parameters and cell excitability. We discuss the implications of our results for the regulation of accumbal MS neuron biophysics and synaptic integration by intrinsic factors and extrinsic agents such as dopamine.

  1. Distinct Effects of Nalmefene on Dopamine Uptake Rates and Kappa Opioid Receptor Activity in the Nucleus Accumbens Following Chronic Intermittent Ethanol Exposure

    Directory of Open Access Journals (Sweden)

    Jamie H. Rose

    2016-07-01

    Full Text Available The development of pharmacotherapeutics that reduce relapse to alcohol drinking in patients with alcohol dependence is of considerable research interest. Preclinical data support a role for nucleus accumbens (NAc κ opioid receptors (KOR in chronic intermittent ethanol (CIE exposure-induced increases in ethanol intake. Nalmefene, a high-affinity KOR partial agonist, reduces drinking in at-risk patients and relapse drinking in rodents, potentially due to its effects on NAc KORs. However, the effects of nalmefene on accumbal dopamine transmission and KOR function are poorly understood. We investigated the effects of nalmefene on dopamine transmission and KORs using fast scan cyclic voltammetry in NAc brain slices from male C57BL/6J mice following five weeks of CIE or air exposure. Nalmefene concentration-dependently reduced dopamine release similarly in air and CIE groups, suggesting that dynorphin tone may not be present in brain slices. Further, nalmefene attenuated dopamine uptake rates to a greater extent in brain slices from CIE-exposed mice, suggesting that dopamine transporter-KOR interactions may be fundamentally altered following CIE. Additionally, nalmefene reversed the dopamine-decreasing effects of a maximal concentration of a KOR agonist selectively in brain slices of CIE-exposed mice. It is possible that nalmefene may attenuate withdrawal-induced increases in ethanol consumption by modulation of dopamine transmission through KORs.

  2. MAM (E17) rodent developmental model of neuropsychiatric disease: disruptions in learning and dysregulation of nucleus accumbens dopamine release, but spared executive function.

    Science.gov (United States)

    Howe, William M; Tierney, Patrick L; Young, Damon A; Oomen, Charlotte; Kozak, Rouba

    2015-11-01

    Gestational day 17 methylazoxymethanol (MAM) treatment has been shown to reproduce, in rodents, some of the alterations in cortical and mesolimbic circuitries thought to contribute to schizophrenia. We characterized the behavior of MAM animals in tasks dependent on these circuitries to see what behavioral aspects of schizophrenia the model captures. We then characterized the integrity of mesolimbic dopamine neurotransmission in a subset of animals used in the behavioral experiments. MAM animals' capacity for working memory, attention, and resilience to distraction was tested with two different paradigms. Cue-reward learning and motivation were assayed with Pavlovian conditioned approach. Measurements of electrically stimulated phasic and tonic DA release in the nucleus accumbens with fast-scan cyclic voltammetry were obtained from the same animals used in the Pavlovian task. MAM animals' basic attentional capacities were intact. MAM animals took longer to acquire the working memory task, but once learned, performed at the same level as shams. MAM animals were also slower to develop a Pavlovian conditioned response, but otherwise no different from controls. These same animals showed alterations in terminal DA release that were unmasked by an amphetamine challenge. The predominant behavioral-cognitive feature of the MAM model is a learning impairment that is evident in acquisition of executive function tasks as well as basic Pavlovian associations. MAM animals also have dysregulated terminal DA release, and this may contribute to observed behavioral differences. The MAM model captures some functional impairments of schizophrenia, particularly those related to acquisition of goal-directed behavior.

  3. Opposing effects of 5,7-DHT lesions to the core and shell of the nucleus accumbens on the processing of irrelevant stimuli.

    Science.gov (United States)

    Nelson, Andrew J D; Thur, Karen E; Marsden, Charles A; Cassaday, Helen J

    2012-05-01

    There is good evidence that forebrain serotonergic systems modulate cognitive flexibility. Latent inhibition (LI) is a cross-species phenomenon which manifests as poor conditioning to a stimulus that has previously been experienced without consequence and is widely considered an index of the ability to ignore irrelevant stimuli. While much research has focused on dopaminergic mechanisms underlying LI, there is also considerable evidence of serotonergic modulation. However, the neuroanatomical locus of these effects remains poorly understood. Previous work has identified the nucleus accumbens (NAc) as a key component of the neural circuit underpinning LI and furthermore, this work has shown that the core and shell subregions of the NAc contribute differentially to the expression of LI. To examine the role of the serotonergic input to NAc in LI, we tested animals with 5,7-dihydroxytryptamine (5,7-DHT) lesions to the core and shell subregions on LI assessed under experimental conditions that produce LI in shams and subsequently with weak stimulus pre-exposure designed to prevent the emergence of LI in shams. We found that serotonergic deafferentation of the core disrupted LI whereas 5,7-DHT lesions to the shell produced the opposite effect and potentiated LI.

  4. NMDA antagonist MK 801 in nucleus accumbens core but not shell disrupts the restraint stress-induced reinstatement of extinguished cocaine-conditioned place preference in rats.

    Science.gov (United States)

    De Giovanni, Laura N; Guzman, Andrea S; Virgolini, Miriam B; Cancela, Liliana M

    2016-12-15

    Relapse is a common feature of cocaine addiction. In rodents, it can be elicited by cues, stress or the drug. Restraint stress-induced reinstatement of cocaine-conditioned place preference (CPP) is a useful model to study the mechanisms involved in stress-induced relapse of drug-seeking behavior. There is evidence that the glutamate NMDA receptors are critically involved in drug- and cue-induced reinstatement of seeking behavior and drug-CPP responses. The aim of this study was to investigate the contribution of NMDA receptors within core vs. shell nucleus accumbens (NAc) subregions to restraint stress-induced reinstatement of extinguished cocaine-CPP. After extinction of cocaine-conditioned preference, animals were administered MK 801 systemically or directly into intra-core or intra-shell, and restrained for 30min or left undisturbed in their home-cages. First, we demonstrated that restraint stress-induced reinstatement of extinguished cocaine-CPP depends on the duration of restraint as well as on the context in which it is applied. Second, this effect was blocked by systemic MK 801 administration either before or after restraint. Third, intra-core but not intra-shell administration abrogated the restraint stress-induced reinstatement. These findings show that NMDA receptors within NAc core, but not shell, play a critical role in restraint stress-induced reinstatement of cocaine-CPP.

  5. The role of nucleus accumbens core/shell in sleep-wake regulation and their involvement in modafinil-induced arousal.

    Directory of Open Access Journals (Sweden)

    Mei-Hong Qiu

    Full Text Available BACKGROUND: We have previously shown that modafinil promotes wakefulness via dopamine receptor D(1 and D(2 receptors; however, the locus where dopamine acts has not been identified. We proposed that the nucleus accumbens (NAc that receives the ventral tegmental area dopamine inputs play an important role not only in reward and addiction but also in sleep-wake cycle and in mediating modafinil-induced arousal. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, we further explored the role of NAc in sleep-wake cycle and sleep homeostasis by ablating the NAc core and shell, respectively, and examined arousal response following modafinil administration. We found that discrete NAc core and shell lesions produced 26.5% and 17.4% increase in total wakefulness per day, respectively, with sleep fragmentation and a reduced sleep rebound after a 6-hr sleep deprivation compared to control. Finally, NAc core but not shell lesions eliminated arousal effects of modafinil. CONCLUSIONS/SIGNIFICANCE: These results indicate that the NAc regulates sleep-wake behavior and mediates arousal effects of the midbrain dopamine system and stimulant modafinil.

  6. Chronic loss of noradrenergic tone produces β-arrestin2-mediated cocaine hypersensitivity and alters cellular D2 responses in the nucleus accumbens.

    Science.gov (United States)

    Gaval-Cruz, Meriem; Goertz, Richard B; Puttick, Daniel J; Bowles, Dawn E; Meyer, Rebecca C; Hall, Randy A; Ko, Daijin; Paladini, Carlos A; Weinshenker, David

    2016-01-01

    Cocaine blocks plasma membrane monoamine transporters and increases extracellular levels of dopamine (DA), norepinephrine (NE) and serotonin (5-HT). The addictive properties of cocaine are mediated primarily by DA, while NE and 5-HT play modulatory roles. Chronic inhibition of dopamine β-hydroxylase (DBH), which converts DA to NE, increases the aversive effects of cocaine and reduces cocaine use in humans, and produces behavioral hypersensitivity to cocaine and D2 agonism in rodents, but the underlying mechanism is unknown. We found a decrease in β-arrestin2 (βArr2) in the nucleus accumbens (NAc) following chronic genetic or pharmacological DBH inhibition, and overexpression of βArr2 in the NAc normalized cocaine-induced locomotion in DBH knockout (Dbh -/-) mice. The D2/3 agonist quinpirole decreased excitability in NAc medium spiny neurons (MSNs) from control, but not Dbh -/- animals, where instead there was a trend for an excitatory effect. The Gαi inhibitor NF023 abolished the quinpirole-induced decrease in excitability in control MSNs, but had no effect in Dbh -/- MSNs, whereas the Gαs inhibitor NF449 restored the ability of quinpirole to decrease excitability in Dbh -/- MSNs, but had no effect in control MSNs. These results suggest that chronic loss of noradrenergic tone alters behavioral responses to cocaine via decreases in βArr2 and cellular responses to D2/D3 activation, potentially via changes in D2-like receptor G-protein coupling in NAc MSNs.

  7. The roles of the nucleus accumbens core, dorsomedial striatum, and dorsolateral striatum in learning: performance and extinction of Pavlovian fear-conditioned responses and instrumental avoidance responses.

    Science.gov (United States)

    Wendler, Etieli; Gaspar, Jessica C C; Ferreira, Tatiana L; Barbiero, Janaína K; Andreatini, Roberto; Vital, Maria A B F; Blaha, Charles D; Winn, Philip; Da Cunha, Claudio

    2014-03-01

    This study examined the effects of bilateral excitotoxic lesions of the nucleus accumbens core (NAc-co), dorsomedial striatum (DMS) or dorsolateral striatum (DLS) of rats on the learning and extinction of Pavlovian and instrumental components of conditioned avoidance responses (CARs). None of the lesions caused sensorimotor deficits that could affect locomotion. Lesions of the NAc-co, but not DMS or DLS, decreased unconditioned and conditioned freezing. The NAc-co and DLS lesioned rats learned the 2-way active avoidance task more slowly. These results suggest: (i) CARs depend on both Pavlovian and instrumental learning; (ii) learning the Pavlovian component of CARs depends on the NAc-co; learning the instrumental component of CARs depends on the DLS, NAc and DMS; (iii) although the NAc-co is also needed for learning the instrumental component, it is not clear whether it plays a role in learning the instrumental component per se or if it simply allows learning of the Pavlovian component which is a pre-condition for learning the instrumental component; (iv) we did not find evidence that the DMS and DLS play the same roles in habit and goal-directed aspects of the instrumental component of CARs as observed in appetitive motivated instrumental responding.

  8. Opposing roles of the nucleus accumbens and anterior lateral hypothalamic area in the control of sexual behaviour in the male rat.

    Science.gov (United States)

    Kippin, Tod E; Sotiropoulos, Veneta; Badih, Julia; Pfaus, James G

    2004-02-01

    Opposing roles have been implicated for the nucleus accumbens (NAc) and anterior portion of the lateral hypothalamic area (aLHA) in the regulation of sexual behaviour in male rats based on in vivo neurochemical correlates. The present study provides functional evidence supporting this hypothesis by examining the effects of lesions to these structures on copulation, noncontact erection and receptive female preference. Sexually naïve male Long-Evans rats received either bilateral 1.0- micro L injections of NMDA (10 micro g/ micro L/side) or vehicle (shams) into either the aLHA or the NAc. During repeated tests of copulation most of the sham-lesioned males, but few of the aLHA-lesioned and NAc-lesioned males, copulated to ejaculation. Most of the NAc-lesioned males also failed to intromit, whereas the majority of the aLHA-lesioned males intromitted repeatedly. During exposure to an inaccessible receptive female behind a wire-mesh screen, aLHA-lesioned males displayed facilitation of noncontact erections, whereas NAc-lesioned males displayed impaired noncontact erections. Conversely, during simultaneous exposure to inaccessible receptive and nonreceptive females in different compartments, all males spent more time in the proximity of the receptive female. These findings indicate that the aLHA plays an inhibitory role in the regulation of sexual arousal and an excitatory role in the regulation of ejaculation. Conversely, the NAc plays an excitatory role in the regulation in sexual arousal.

  9. Changes of CREB in rat hippocampus, prefrontal cortex and nucleus accumbens during three phases of morphine induced conditioned place preference in rats

    Institute of Scientific and Technical Information of China (English)

    ZHOU Lian-fang; ZHU Yong-ping

    2006-01-01

    Objective: To investigate the changes in CREB (cAMP response element binding protein) in hippocampus, PFC(prefrontal cortex) and NAc (nucleus accumbens) during three phases of morphine induced CPP (conditioned place preference) in rats, and to elucidate the role of CREB during the progress of conditioned place preference. Methods: Morphine induced CPP acquisition, extinction and drug primed reinstatement model was established, and CREB expression in each brain area was measured by Western Blot methods. Results: Eight alternating injections of morphine (10 mg/kg) induced CPP, and 8 d saline extinction training that extinguished CPP. CPP was reinstated following a priming injection of morphine (2.5 mg/kg). During the phases of CPP acquisition and reinstatement, the level of CREB expression was significantly changed in different brain areas.Conclusion: It was proved that CPP model can be used as an effective tool to investigate the mechanisms underlying drug-induced reinstatement of drug seeking after extinction, and that morphine induced CPP and drug primed reinstatement may involve activation of the transcription factor CREB in several brain areas, suggesting that the CREB and its target gene regulation pathway may mediate the basic mechanism underlying opioid dependence and its drug seeking behavior.

  10. Functional interaction of medial mediodorsal thalamic nucleus but not nucleus accumbens with amygdala and orbital prefrontal cortex is essential for adaptive response selection after reinforcer devaluation.

    Science.gov (United States)

    Izquierdo, Alicia; Murray, Elisabeth A

    2010-01-13

    In nonhuman primates, reward-based decision making may be assessed through choices of objects overlying two different foods, one of which has been devalued by selective satiation. The most adaptive object choices yield the food of higher value. A large body of data identifies the amygdala and orbital prefrontal cortex (PFo) as neural mediators of adaptive responses to reinforcer devaluation. More recent work in nonhuman primates reveals the critical role of the medial, magnocellular portion of the mediodorsal nucleus of the thalamus (MDm) as well. Because both the nucleus accumbens (NA) and the MDm are anatomically related to the amygdala and PFo, and because both regions are implicated in reward processing, we tested whether either region necessarily interacts with the amygdala and PFo to mediate reinforcer devaluation effects. We used a crossed-disconnection design in which monkeys received amygdala and PFo lesions in one hemisphere combined with either NA or MDm lesions in the contralateral hemisphere. Monkeys that sustained NA disconnection, like controls, showed robust shifts in object choices in response to reinforcer devaluation. In contrast, monkeys that sustained MDm disconnection failed to adjust their object choices. Thus, MDm, but not NA, works together with the amygdala and PFo to support reward-based decision making.

  11. Orexin receptors within the nucleus accumbens shell mediate the stress but not drug priming-induced reinstatement of morphine conditioned place preference

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    Keke eQi

    2013-10-01

    Full Text Available Orexins are recently found to participate in mediating stress-induced drug relapse. However, the neuroanatomical basis that orexin transmission modulates stress-induced drug seeking remains unknown. The nucleus accumbens shell (NAcSh, best known for its role in appetitive and negative motivation via dopamine receptors, is likely to be the potential important brain area where the orexin system mediates stress-induced drug relapse since the function of dopamine system in the NAcSh can be regulated by orexin transmission. In the present study, a morphine conditioned place preference (CPP model was used to determine whether the two types of orexin receptors would be involved into footshock-induced and/or drug priming-induced CPP reinstatement differentially. The results showed that blockade of orexin-1 or orexin-2 receptor in the NAcSh significantly attenuated stress-induced morphine CPP reinstatement, but neither of the orexin antagonists had any effect on morphine priming-induced reinstatement. These findings indicate that the NAcSh is a brain area through which orexins participate in stress but not drug priming-induced relapse of opioid seeking.

  12. Gene expression changes in the medial prefrontal cortex and nucleus accumbens following abstinence from cocaine self-administration

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    Morgan Drake

    2010-02-01

    Full Text Available Abstract Background Many studies of cocaine-responsive gene expression have focused on changes occurring during cocaine exposure, but few studies have examined the persistence of these changes with cocaine abstinence. Persistent changes in gene expression, as well as alterations induced during abstinence may underlie long-lasting drug craving and relapse liability. Results Whole-genome expression analysis was conducted on a rat cocaine binge-abstinence model that has previously been demonstrated to engender increased drug seeking and taking with abstinence. Gene expression changes in two mesolimbic terminal fields (mPFC and NAc were identified in a comparison of cocaine-naïve rats with rats after 10 days of cocaine self-administration followed by 1, 10, or 100 days of enforced abstinence (n = 6-11 per group. A total of 1,461 genes in the mPFC and 414 genes in the NAc were altered between at least two time points (ANOVA, p Conclusions Together, these changes help to illuminate processes and networks involved in abstinence-induced behaviors, including synaptic plasticity, MAPK signaling, and TNF signaling.

  13. General, kappa, delta and mu opioid receptor antagonists mediate feeding elicited by the GABA-B agonist baclofen in the ventral tegmental area and nucleus accumbens shell in rats: reciprocal and regional interactions.

    Science.gov (United States)

    Miner, Patricia; Shimonova, Lyudmila; Khaimov, Arthur; Borukhova, Yaffa; Ilyayeva, Ester; Ranaldi, Robert; Bodnar, Richard J

    2012-03-14

    Food intake is significantly increased following administration of agonists of GABA and opioid receptors into the nucleus accumbens shell (NACs) and ventral tegmental area (VTA). GABA-A or GABA-B receptor antagonist pretreatment within the VTA or NACs differentially affects mu-opioid agonist-induced feeding elicited from the same site. Correspondingly, general or selective opioid receptor antagonist pretreatment within the VTA or NACs differentially affects GABA agonist-induced feeding elicited from the same site. Regional interactions have been evaluated in feeding studies by administering antagonists in one site prior to agonist administration in a second site. Thus, opioid antagonist-opioid agonist and GABA antagonist-GABA agonist feeding interactions have been identified between the VTA and NACs. However, pretreatment with GABA-A or GABA-B receptor antagonists in the VTA failed to affect mu opioid agonist-induced feeding elicited from the NACs, and correspondingly, these antagonists administered in the NACs failed to affect mu opioid-induced feeding elicited from the VTA. To evaluate whether regional and reciprocal VTA and NACs feeding interactions occur for opioid receptor modulation of GABA agonist-mediated feeding, the present study examined whether feeding elicited by the GABA-B agonist, baclofen microinjected into the NACs was dose-dependently blocked by pretreatment with general (naltrexone: NTX), mu (beta-funaltrexamine: BFNA), kappa (nor-binaltorphamine: NBNI) or delta (naltrindole: NTI) opioid antagonists in the VTA, and correspondingly, whether VTA baclofen-induced feeding was dose-dependently blocked by NACs pretreatment with NTX, BFNA, NBNI or NTI in rats. Bilateral pairs of cannulae aimed at the VTA and NACs were stereotaxically implanted in rats, and their food intakes were assessed following vehicle and baclofen (200 ng) in each site. Baclofen produced similar magnitudes of increased food intake following VTA and NACs treatment. Baclofen

  14. Nucleus Accumbens-Associated Protein 1 Expression Has Potential as a Marker for Distinguishing Oral Epithelial Dysplasia and Squamous Cell Carcinoma.

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    Joji Sekine

    Full Text Available Oral epithelial dysplasia (OED and carcinoma in situ (CIS are defined by dysplastic cells in the epithelium. Over a third of oral squamous cell carcinoma (OSCC patients present with associated OED. However, accurate histopathological diagnosis of such lesions is difficult. Nucleus accumbens-associated protein 1 (NAC1 is a member of the Pox virus and Zinc finger/Bric-a-brac Tramtrack Broad complex family of proteins, and is overexpressed in OSCC. This study aimed to determine whether NAC1 has the potential to be used as a marker to distinguish OED and OSCC.The study included 114 patients (64 men, 50 women. There were 67, 10, and 37 patients with OED, CIS, and OSCC, respectively. NAC1 labeling indices (LIs and immunoreactivity intensities (IRI were evaluated. The patients' pathological classification was significantly associated with age, sex, NAC1 LIs, and NAC1 IRI (p = 0.025, p = 0.022, p 50% positivity the sensitivity, specificity, positive predictive value (PPV, and negative predictive value (NPV were 0.766, 0.910, 0.857, and 0.847, respectively. For NAC1 IRI with ≤ 124 positive pixels, the sensitivity, specificity, PPV, and NPV were 0.787, 0.866, 0.804, and 0.853, respectively. Though there are several potential limitations to this study and the results were obtained from a retrospective analysis of a single site cohort, the data suggest that the NAC1 LIs/IRI is a strong predictor of CIS/OSCC.NAC1 has potential as a marker for distinguishing OED from CIS/OSCC.

  15. Dual projections of single orexin- or CART-immunoreactive, lateral hypothalamic neurons to the paraventricular thalamic nucleus and nucleus accumbens shell in the rat: Light microscopic study.

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    Lee, Eun Y; Lee, Hyun S

    2016-03-01

    The paraventricular thalamic nucleus (PVT) is a major relay station to the limbic forebrain areas such as the nucleus accumbens shell (AcbSh). Both PVT and AcbSh are known to receive feeding/arousal-related peptidergic fibers including orexin (ORX) and cocaine- and amphetamine-regulated transcript (CART) peptide. In the first series of experiments, we examined the peptidergic fiber distribution in the AcbSh; the density of ORX (or CART) fibers in the AcbSh was substantially lower than that in the PVT. At the light microscopic level, ORX (or CART) terminals formed close appositions to choline acetyltransferase (ChAT)-, glutamate decarboxylase (GAD)-, or enkephalin (Enk)-immunoreactive neuronal elements in the AcbSh. In the second series of experiments, we addressed the question of whether single ORX (or CART) cells in the hypothalamus provided divergent axon collaterals to the PVT and AcbSh. ORX neurons with dual projections were found in the medial, central, and lateral subdivisions of the lateral hypothalamus (LH), which amounted to an average of 1.6% of total ORX cells. CART neurons with divergent axon collaterals were observed in the LH, zona incerta, dorsal hypothalamic area, and retrochiasmatic nucleus, which represented a mean of 2.5% of total CART cells. None of arcuate CART cells sent dual projections. These data suggested that a portion of ORX (or CART) neurons in the hypothalamus, via divergent axon collaterals, might concurrently modulate the activity of PVT and AcbSh cells to affect feeding and drug-seeking behaviors.

  16. Injection of Cocaine-Amphetamine Regulated Transcript (CART) peptide into the nucleus accumbens does not inhibit caffeine-induced locomotor activity: Implications for CART peptide mechanism.

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    Job, Martin O

    2016-09-01

    Much evidence suggests that intra-nucleus accumbens (NAc) CART peptide (CART 55-102) injection inhibits locomotor activity (LMA) when there is an increase in the release and activity of dopamine (DA) in the NAc. However, this hypothesis has not been fully tested. One way to examine this is to determine if there is a lack of effect of intra-NAc CART peptide on LMA that does not involve increases in DA release in the NAc. Several studies have suggested that caffeine-induced LMA does not involve extracellular DA release in the NAc core. Therefore, in this study, we have examined the effect of injections of CART peptide (2.5μg) into the NAc core on the locomotor effects of caffeine in male Sprague-Dawley rats. Several LMA relevant doses of caffeine were used (0, 10, 20mg/kg i.p.), and an inverted U response curve was found as expected. We determined, in the same animals, that intra-NAc CART peptide had no effect on caffeine-induced LMA whereas it blunted cocaine-mediated LMA, as shown by other reports. We also extended a previous observation in mice by showing that at a LMA activating dose of caffeine there is no alteration of CART peptide levels in the NAc of rats. Our study supports the hypothesis that the inhibitory effects of CART peptide in the NAc may be exerted only under conditions of increased extracellular DA release and activity in this region. Our results also suggest that intra-NAc CART 55-102 does not generally inhibit increases in LMA due to all drugs, but has a more specific inhibitory effect on dopaminergic neurotransmission.

  17. The Effects of Maternal Separation on Adult Methamphetamine Self-Administration, Extinction, Reinstatement, and MeCP2 Immunoreactivity in the Nucleus Accumbens

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    Candace R. Lewis

    2013-06-01

    Full Text Available The maternal separation (MS paradigm is an animal model of early life stress. Animals subjected to MS during the first two weeks of life display altered behavioral and neuroendocrinological stress responses as adults. MS also produces altered responsiveness to and self-administration (SA of various drugs of abuse including cocaine, ethanol, opioids, and amphetamine. Methamphetamine (METH causes great harm to both the individual user and to society; yet, no studies have examined the effects of MS on METH SA. This study was performed to examine the effects of MS on the acquisition of METH SA, extinction, and reinstatement of METH-seeking behavior in adulthood. Given the known influence of early life stress and drug exposure on epigenetic processes, group differences in levels of the epigenetic marker methyl CpG binding protein 2 (MeCP2 in the nucleus accumbens (NAc core were also investigated. Long-Evans pups and dams were separated on postnatal days (PND 2-14 for either 180 (MS180 or 15 min (MS15. Male offspring were allowed to acquire METH SA (0.05 mg/kg/infusion in 15 2-hr daily sessions starting at PND67, followed by extinction training and cue-induced reinstatement of METH-seeking behavior. Rats were then assessed for MeCP2 levels in the NAc core by immunohistochemistry. The MS180 group self-administered significantly more METH and acquired SA earlier than the MS15 group. No group differences in extinction or cue-induced reinstatement were observed. MS15 rats had significantly elevated MeCP2-immunoreactive cells in the NAc core as compared to MS180 rats. Together, these data suggest that MS has lasting influences on METH SA as well as epigenetic processes in the brain reward circuitry.

  18. Functional interaction between the orexin-1 and CB1 receptors within the nucleus accumbens in the conditioned place preference induced by the lateral hypothalamus stimulation.

    Science.gov (United States)

    Fatahi, Zahra; Assar, Nasim; Mahmoudi, Dorna; Pahlevani, Pouyan; Moradi, Marzieh; Haghparast, Abbas

    2015-02-28

    Several studies have shown that chemical stimulation of the lateral hypothalamus (LH) by carbachol induces the conditioned place preference (CPP) in rats. LH is the main source of the orexinergic neurons and sends projections to some areas of the brain such as the nucleus accumbens (NAc). We tried to determine the role of intra-accumbal orexin-1 (OX1) receptors in development (acquisition) and expression of reward-related behaviors induced by LH stimulation and involvement of CB1 cannabinoid receptors in this area. Adult male Wistar rats were unilaterally implanted by two separate cannulae into the LH and NAc. The CPP paradigm was done; conditioning scores and locomotor activities were recorded. The results showed that intra-accumbal administration of SB334867 as a selective OX1 receptor antagonist (1, 3, 10 and 30nM/0.5μl DMSO) 5min before intra-LH carbachol (250nM/0.5μl saline) during 3-day conditioning phase, could dose-dependently inhibit the development of LH-induced CPP. In expression experiments, intra-NAc administration of SB334867 on the test day could decrease the expression of LH stimulation-induced CPP. Furthermore, concurrent intra-accumbal administration of effective/ineffective doses of SB334867 and AM251 (45 and 15μM) as a CB1 receptor antagonist, before carbachol during the conditioning phase, could attenuate the development of LH stimulation-induced CPP. It seems that the orexinergic projection from the LH to the NAc is involved in the LH stimulation-induced CPP and OX1 receptor in the NAc has a substantial role in this phenomenon. Our findings also suggest the existence a functional interaction between OX1 and CB1 receptors within the NAc in place preference.

  19. Enhanced upregulation of CRH mRNA expression in the nucleus accumbens of male rats after a second injection of methamphetamine given thirty days later.

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    Jean Lud Cadet

    Full Text Available Methamphetamine (METH is a widely abused amphetamine analog. Few studies have investigated the molecular effects of METH exposure in adult animals. Herein, we determined the consequences of an injection of METH (10 mg/kg on transcriptional effects of a second METH (2.5 mg/kg injection given one month later. We thus measured gene expression by microarray analyses in the nucleus accumbens (NAc of 4 groups of rats euthanized 2 hours after the second injection: saline-pretreated followed by saline-challenged (SS or METH-challenged (SM; and METH-pretreated followed by saline-challenged (MS or METH-challenged (MM. Microarray analyses revealed that METH (2.5 mg/kg produced acute changes (1.8-fold; P<0.01 in the expression of 412 (352 upregulated, 60 down-regulated transcripts including cocaine and amphetamine regulated transcript, corticotropin-releasing hormone (Crh, oxytocin (Oxt, and vasopressin (Avp that were upregulated. Injection of METH (10 mg/kg altered the expression of 503 (338 upregulated, 165 down-regulated transcripts measured one month later (MS group. These genes also included Cart and Crh. The MM group showed altered expression of 766 (565 upregulated, 201 down-regulated transcripts including Avp, Cart, and Crh. The METH-induced increased Crh expression was enhanced in the MM group in comparison to SM and MS groups. Quantitative PCR confirmed the METH-induced changes in mRNA levels. Therefore, a single injection of METH produced long-lasting changes in gene expression in the rodent NAc. The long-term increases in Crh, Cart, and Avp mRNA expression suggest that METH exposure produced prolonged activation of the endogenous stress system. The METH-induced changes in oxytocin expression also suggest the possibility that this neuropeptide might play a significant role in the neuroplastic and affiliative effects of this drug.

  20. Anti-nociceptive role of neuropeptide Y in the nucleus accumbens in rats with inflammation, an effect modulated by mu- and kappa-opioid receptors

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    Recent study in our laboratory showed that neuropeptide Y (NPY) plays an antinociceptive role in the nucleus accumbens (NAc) in intact rats. The present study was performed to further investigate the effect of NPY in nociceptive modulation in the NAc of rats with inflammation, and the possible interaction between NPY and the opioid systems. Experimental inflammation was induced by subcutaneous injection of carrageenan into the left hindpaw of rats. Intra-NAc administration of NPY induced a dose-dependent increase of hindpaw withdrawal latencies (HWLs) to thermal and mechanical stimulations in rats with inflammation. The anti-nociceptive effect of NPY was significantly blocked by subsequent intra-NAc injection of the Y1 receptor antagonist NPY28-36, suggesting an involvement of Y1 receptor in the NPY-induced anti-nociception. Furthermore, intra-NAc administration of the opioid antagonist naloxone significantly antagonized the increased HWLs induced by preceding intra-NAc injection of NPY, suggesting an involvement of the endogenous opioid system in the NPY-induced anti-nociception in the NAc during inflammation. Moreover, the NPY-induced anti-nociception was attenuated by following intra-NAc injection of the μ-opioid antagonist β-funaltrexamine (β-FNA), and κ-opioid antagonist nor-binaltorphimine (norBNI), but not by δ-opioid antagonist naltrindole, indicating that μ- and κ-opioid receptors, not δ-opioid receptor, are involved in the NPY-induced anti-nociception in the NAc in rats with inflammation.

  1. Long-lasting alterations in membrane properties, K+ currents and glutamatergic synaptic currents of nucleus accumbens medium spiny neurons in a rat model of alcohol dependence

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    Igor eSpigelman

    2012-06-01

    Full Text Available Chronic alcohol exposure causes marked changes in reinforcement mechanisms and motivational state that are thought to contribute to the development of cravings and relapse during protracted withdrawal. The nucleus accumbens (NAcc is a key structure of the mesolimbic dopaminergic reward system. Although the NAcc plays an important role in mediating alcohol-seeking behaviors, little is known about the molecular mechanisms underlying alcohol-induced neuroadaptive changes in NAcc function. The aim of this study was to investigate the effects of chronic intermittent ethanol (CIE treatment, a rat model of alcohol withdrawal and dependence, on intrinsic electrical membrane properties and glutamatergic synaptic transmission of medium spiny neurons (MSNs in the NAcc core during protracted withdrawal. We show that CIE treatment followed by prolonged withdrawal increased the inward rectification of MSNs observed at hyperpolarized potentials. In addition, MSNs from CIE-treated animals displayed a lower input resistance, faster action potentials (APs and larger fast afterhyperpolarizations (fAHPs than MSNs from vehicle-treated animals, all suggestive of increases in K+-channel conductances. Significant increases in the Cs+-sensitive inwardly-rectifying K+-current accounted for the increased input resistance, while increases in the A-type K+-current accounted for the faster APs and increased fAHPs in MSNs from CIE rats. We also show that the amplitude and the conductance of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR-mediated mEPSCs were enhanced in CIE-treated animals due to an increase in a small fraction of functional postsynaptic GluA2-lacking AMPARs. These long-lasting modifications of excitability and excitatory synaptic receptor function of MSNs in the NAcc core could play a critical role in the neuroadaptive changes underlying alcohol withdrawal and dependence.

  2. N-methyl-D-aspartate receptor-mediated glutamate transmission in nucleus accumbens plays a more important role than that in dorsal striatum in cognitive flexibility

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    Xuekun eDing

    2014-09-01

    Full Text Available Cognitive flexibility is a critical ability for adapting to an ever-changing environment in humans and animals. Deficits in cognitive flexibility are observed in most schizophrenia patients. Previous studies reported that the medial prefrontal cortex-to-ventral striatum and orbital frontal cortex-to-dorsal striatum circuits play important roles in extra- and intra-dimensional strategy switching, respectively. However, the precise function of striatal subregions in flexible behaviors is still unclear. N-methyl-D-aspartate receptors (NMDARs are major glutamate receptors in the striatum that receive glutamatergic projections from the frontal cortex. The membrane insertion of Ca2+-permeable α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors (AMPARs depends on NMDAR activation and is required in learning and memory processes. In the present study, we measured set-shifting and reversal learning performance in operant chambers in rats and assessed the effects of blocking NMDARs and Ca2+-permeable AMPARs in striatal subregions on behavioral flexibility. The blockade of NMDARs in the nucleus accumbens (NAc core by AP5 impaired set-shifting ability by causing a failure to modify prior learning. The suppression of NMDAR-mediated transmission in the NAc shell induced a deficit in set-shifting by disrupting the learning and maintenance of novel strategies. During reversal learning, infusions of AP5 into the NAc shell and core impaired the ability to learn and maintain new strategies. However, behavioral flexibility was not significantly affected by blocking NMDARs in the dorsal striatum. We also found that the blockade of Ca2+-permeable AMPARs by NASPM in any subregion of the striatum did not affect strategy switching. These findings suggest that NMDAR-mediated glutamate transmission in the NAc contributes more to cognitive execution compared with the dorsal striatum.

  3. Reduced dopamine and glutamate neurotransmission in the nucleus accumbens of quinpirole-sensitized rats hints at inhibitory D2 autoreceptor function.

    Science.gov (United States)

    Escobar, Angélica P; Cornejo, Francisca A; Olivares-Costa, Montserrat; González, Marcela; Fuentealba, José A; Gysling, Katia; España, Rodrigo A; Andrés, María E

    2015-09-01

    Dopamine from the ventral tegmental area and glutamate from several brain nuclei converge in the nucleus accumbens (NAc) to drive motivated behaviors. Repeated activation of D2 receptors with quinpirole (QNP) induces locomotor sensitization and compulsive behaviors, but the mechanisms are unknown. In this study, in vivo microdialysis and fast scan cyclic voltammetry in adult anesthetized rats were used to investigate the effect of repeated QNP on dopamine and glutamate neurotransmission within the NAc. Following eight injections of QNP, a significant decrease in phasic and tonic dopamine release was observed in rats that displayed locomotor sensitization. Either a systemic injection or the infusion of QNP into the NAc decreased dopamine release, and the extent of this effect was similar in QNP-sensitized and control rats, indicating that inhibitory D2 autoreceptor function is maintained despite repeated activation of D2 receptors and decreased dopamine extracellular levels. Basal extracellular levels of glutamate in the NAc were also significantly lower in QNP-treated rats than in controls. Moreover, the increase in NAc glutamate release induced by direct stimulation of medial prefrontal cortex was significantly lower in QNP-sensitized rats. Together, these results indicate that repeated activation of D2 receptors disconnects NAc from medial prefrontal cortex and ventral tegmental area. Repeated administration of the dopamine D2 receptor agonist quinpirole (QNP) induces locomotor sensitization. We found that the NAc of QNP-sensitized rats has reduced glutamate levels coming from prefrontal cortex together with a decreased phasic and tonic dopamine neurotransmission but a conserved presynaptic D2 receptor function. We suggest that locomotor sensitization is because of increased affinity state of D2 post-synaptic receptors. © 2015 International Society for Neurochemistry.

  4. Dynamic interaction between medial prefrontal cortex and nucleus accumbens as a function of both motivational state and reinforcer magnitude: A c-Fos immunocytochemistry study

    Science.gov (United States)

    Moscarello, Justin M.; Ben-Shahar, Osnat; Ettenberg, Aaron

    2007-01-01

    This study examined the effects of simultaneous variations in motivational state (food deprivation) and reinforcer magnitude (food presentation) on c-Fos immunoreactivity in the pre-and infralimbic medial prefrontal cortex (mPFC), nucleus accumbens (NAcc) core and shell, and dorsal striatum. In the first experiment, c-Fos was reliably increased in pre- and infralimbic mPFC of animals 12- and 36-h compared to 0-h deprived. In the second experiment, a small meal (2.5g) selectively increased c-Fos immunoreactivity in both mPFC subdivisions of 36-h deprived animals, as well as in both NAcc subdivisions of 12-h deprived animals. Correlational analyses revealed a changing relationship between mPFC subregions and the NAcc compartments to which they project. In subjects 12-h deprived and allowed a small meal, c-Fos counts in prelimbic mPFC and NAcc core were positively correlated, as were those in infralimbic mPFC and NAcc shell (r = . 83 and .76, respectively). The opposite was true of animals 36-h deprived, with prelimbic mPFC/NAcc core and infralimbic mPFC/NAcc shell negatively correlated (r = -.85 and -.82, respectively). The third experiment examined the effects of unrestricted feeding (presentation of 20g food) after 0, 12, or 36-h deprivation. No differences between mean c-Fos counts were found, though prelimbic mPFC/NAcc core, and mPFC/NAcc shell were positively correlated in animals 36-h deprived (r = .76 and .89, respectively). These data suggest that the activity within the mPFC and NAcc, as well as the interaction between the two, change as a complex combinatorial function of motivational state and reinforcer magnitude. Section: Cognitive and Behavioral Neuroscience PMID:17706947

  5. Chronic cocaine-induced H3 acetylation and transcriptional activation of CaMKIIalpha in the nucleus accumbens is critical for motivation for drug reinforcement.

    Science.gov (United States)

    Wang, Lei; Lv, Zhigang; Hu, Zhaoyang; Sheng, Jian; Hui, Bin; Sun, Jie; Ma, Lan

    2010-03-01

    The regulation of gene expression in the brain reward regions is known to contribute to the pathogenesis and persistence of drug addiction. Increasing evidence suggests that the regulation of gene transcription is mediated by epigenetic mechanisms that alter the chromatin structure at specific gene promoters. To better understand the involvement of epigenetic regulation in drug reinforcement properties, rats were subjected to cocaine self-administration paradigm. Daily histone deacetylase (HDAC) inhibitor infusions in the shell of the nucleus accumbens (NAc) caused an upward shift in the dose-response curve under fixed-ratio schedule and increased the break point under progressive-ratio schedule, indicating enhanced motivation for self-administered drug. The effect of the HDAC inhibitor is attributed to the increased elevation of histone acetylation induced by chronic, but not acute, cocaine experience. In contrast, neutralizing the chronic cocaine-induced increase in histone modification by the bilateral overexpression of HDAC4 in the NAc shell reduced drug motivation. The association between the motivation for cocaine and the transcriptional activation of addiction-related genes by H3 acetylation in the NAc shell was analyzed. Among the genes activated by chronic cocaine experiences, the expression of CaMKIIalpha, but not CaMKIIbeta, correlated positively with motivation for the drug. Lentivirus-mediated shRNA knockdown experiments showed that CaMKIIalpha, but not CaMKIIbeta, in the NAc shell is essential for the maintenance of motivation to self-administered cocaine. These findings suggest that chronic drug-use-induced transcriptional activation of genes, such as CaMKIIalpha, modulated by H3 acetylation in the NAc is a critical regulatory mechanism underlying motivation for drug reinforcement.

  6. Nucleus accumbens neurotransmission and effort-related choice behavior in food motivation: effects of drugs acting on dopamine, adenosine, and muscarinic acetylcholine receptors.

    Science.gov (United States)

    Nunes, Eric J; Randall, Patrick A; Podurgiel, Samantha; Correa, Mercè; Salamone, John D

    2013-11-01

    Mesolimbic dopamine (DA) is a critical component of the brain circuitry regulating behavioral activation and effort-related processes. Although nucleus accumbens (NAc) DA depletions or antagonism leave aspects of appetite and primary food motivation intact, rats with impaired DA transmission reallocate their instrumental behavior away from food-reinforced tasks with high response requirements, and instead select less effortful food-seeking behaviors. Previous work showed that adenosine A2A antagonists can reverse the effects of DA D2 antagonists on effort-related choice, and that stimulation of adenosine A2A receptors produces behavioral effects that are similar to those induced by DA antagonism. The present review summarizes the literature on the role of NAc DA and adenosine in effort-related processes, and also presents original data on the effects of local stimulation of muscarinic acetylcholine receptors in NAc core. Local injections of the muscarinic agonist pilocarpine directly into NAc core produces shifts in effort-related choice behavior similar to those induced by DA antagonism or A2A receptor stimulation, decreasing lever pressing but increasing chow intake in rats responding on a concurrent fixed ratio/chow feeding choice task. In contrast, injections into a neostriatal control site dorsal to the NAc were ineffective. The actions of pilocarpine on this task were attenuated by co-administration of the muscarinic antagonist scopolamine. Thus, drugs that act on DA, adenosine A2A, and muscarinic receptors regulate effort-related choice behavior, which may have implications for the treatment of psychiatric symptoms such as psychomotor slowing, fatigue or anergia that can be observed in depression and other disorders. Copyright © 2013 Elsevier Ltd. All rights reserved.

  7. Nicotine restores morphine-induced memory deficit through the D1 and D2 dopamine receptor mechanisms in the nucleus accumbens.

    Science.gov (United States)

    Azizbeigi, Ronak; Ahmadi, Shamseddin; Babapour, Vahab; Rezayof, Ameneh; Zarrindast, Mohammad Reza

    2011-08-01

    Involvement of the dopamine D1 and D2 receptors in the nucleus accumbens (NAc) with interaction between morphine and nicotine on inhibitory avoidance (IA) memory was investigated. A step-through type of inhibitory avoidance tasks was used to assess memory in male Wistar rats. The results showed that subcutaneous (s.c.) administration of morphine (7.5 mg/kg) after training decreased retrieval of IA memory in the animals when tested 24 h later. Pre-test administration of the same dose of morphine significantly reversed the deficiency in retrieval. The results also showed that pre-test administration of nicotine (0.2 and 0.4 mg/kg, s.c.) by itself mimicked the effect of pre-test morphine, and lower doses of nicotine (0.1 and 0.2 mg/kg) also improved the effect of a low dose of morphine (2.5 mg/kg) on retrieval of IA memory. Pre-test intra-NAc administration of the dopamine D1 receptor antagonist, SCH 23390 (0.001 and 0.01 µg/rat), and the dopamine D2 receptor antagonist, sulpiride (0.5 and 1 µg/rat) caused no significant effects on IA memory by themselves, but both prevented reinstatement of the retrieval of IA memory by the effective dose of nicotine (0.4 mg/kg). It can be concluded that the dopaminergic mechanism(s) in the NAc is a crosslink for the effect of morphine and nicotine on reinstatement of retrieval of IA memory impaired by post-training administration of morphine.

  8. Structural and Functional Plasticity within the Nucleus Accumbens and Prefrontal Cortex Associated with Time-Dependent Increases in Food Cue Seeking Behavior.

    Science.gov (United States)

    Dingess, Paige M; Darling, Rebecca A; Derman, Rifka C; Wulff, Shaun S; Hunter, Melissa L; Ferrario, Carrie R; Brown, Travis E

    2017-03-15

    Urges to consume food can be driven by stimuli in the environment that are associated with previous food experience. Identifying adaptations within brain reward circuits that facilitate cue-induced food seeking is critical for understanding and preventing the overconsumption of food and subsequent weight gain. Utilizing electrophysiological, biochemical, and DiI labeling we examined functional and structural changes in the nucleus accumbens (NAc) and prefrontal cortex (PFC) associated with time-dependent increases in food craving ('incubation of craving'). Rats self-administered 60% high-fat or chow 45 mg pellets and were then tested for incubation of craving either 1 or 30 days after training (1d, 30d). High-fat was chosen for comparison to determine if palatability differentially affected incubation and/or plasticity. Rats showed robust incubation of craving for both food rewards, although responding for cues previously associated with high-fat was greater than chow at both 1d and 30d. In addition, previous experience with high-fat consumption reduced dendritic spine density in the PFC at both time points. In contrast, incubation was associated with an increase in NAc spine density and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated transmission at 30d in both groups. Finally, incubation of craving for chow and high-fat was accompanied by an increase in calcium-permeable and calcium-impermeable AMPARs, respectively. Our results suggest that incubation of food craving alters brain reward circuitry and macronutrient composition specifically induces cortical changes in a way that may facilitate maladaptive food seeking behaviors.Neuropsychopharmacology accepted article preview online, 15 March 2017. doi:10.1038/npp.2017.57.

  9. Alterations in blood glucose and plasma glucagon concentrations during deep brain stimulation in the shell region of the nucleus accumbens in rats

    Directory of Open Access Journals (Sweden)

    Charlene eDiepenbroek

    2013-12-01

    Full Text Available Deep brain stimulation (DBS of the nucleus accumbens (NAc is an effective therapy for obsessive compulsive disorder (OCD and is currently under investigation as a treatment for eating disorders. DBS of this area is associated with altered food intake and pharmacological treatment of OCD is associated with the risk of developing type 2 diabetes. Therefore we examined if DBS of the NAc-shell (sNAc influences glucose metabolism. Male Wistar rats were subjected to DBS, or sham stimulation, for a period of one hour. To assess the effects of stimulation on blood glucose and glucoregulatory hormones, blood samples were drawn before, during and after stimulation. Subsequently, all animals were used for quantitative assessment of Fos immunoreactivity in the lateral hypothalamic area (LHA using computerized image analysis. DBS of the sNAc rapidly increased plasma concentrations of glucagon and glucose while sham stimulation and DBS outside the sNAc were ineffective. In addition, the increase in glucose was dependent on DBS intensity. In contrast, the DBS-induced increase in plasma corticosterone concentrations was independent of intensity and region, indicating that the observed DBS-induced metabolic changes were not due to corticosterone release. Stimulation of the sNAc with 200 μA increased Fos immunoreactivity in the LHA compared to sham or 100 μA stimulated animals. These data show that DBS of the sNAc alters glucose metabolism in a region- and intensity dependent manner in association with neuronal activation in the LHA. Moreover, these data illustrate the need to monitor changes in glucose metabolism during DBS-treatment of OCD patients.

  10. Overexpression of 5-HT(1B) mRNA in nucleus accumbens shell projection neurons differentially affects microarchitecture of initiation and maintenance of ethanol consumption.

    Science.gov (United States)

    Furay, Amy R; Neumaier, John F; Mullenix, Andrew T; Kaiyala, Karl K; Sandygren, Nolan K; Hoplight, Blair J

    2011-02-01

    Serotonin 1B (5-HT(1B)) heteroreceptors on nucleus accumbens shell (NAcSh) projection neurons have been shown to enhance the voluntary consumption of alcohol by rats, presumably by modulating the activity of the mesolimbic reward pathway. The present study examined whether increasing 5-HT(1B) receptors expressed on NAcSh projection neurons by means of virus-mediated gene transfer enhances ethanol consumption during the initiation or maintenance phase of drinking and alters the temporal pattern of drinking behavior. Animals received stereotaxic injections of viral vectors expressing either 5-HT(1B) receptor and green fluorescent protein (GFP) or GFP alone. Home cages equipped with a three-bottle (water and 6 and 12% ethanol) lickometer system recorded animals' drinking behaviors continuously, capturing either initiation or maintenance of drinking behavior patterns. Overexpression of 5-HT(1B) receptors during initiation increased consumption of 12% ethanol during both forced-access and free-choice consumption. There was a shift in drinking pattern for 6% ethanol with an increase in number of drinking bouts per day, although the total number of drinking bouts for 12% ethanol was not different. Finally, increased 5-HT(1B) expression induced more bouts with very high-frequency licking from the ethanol bottle sippers. During the maintenance phase of drinking, there were no differences between groups in total volume of ethanol consumed; however, there was a shift toward drinking bouts of longer duration, especially for 12% ethanol. This suggests that during maintenance drinking, increased 5-HT(1B) receptors facilitate longer drinking bouts of more modest volumes. Taken together, these results indicate that 5-HT(1B) receptors expressed on NAcSh projection neurons facilitate ethanol drinking, with different effects during initiation and maintenance of ethanol-drinking behavior. Copyright © 2011 Elsevier Inc. All rights reserved.

  11. Trafficking of calcium-permeable and calcium-impermeable AMPA receptors in nucleus accumbens medium spiny neurons co-cultured with prefrontal cortex neurons.

    Science.gov (United States)

    Werner, Craig T; Murray, Conor H; Reimers, Jeremy M; Chauhan, Niravkumar M; Woo, Kenneth K Y; Molla, Hanna M; Loweth, Jessica A; Wolf, Marina E

    2017-04-01

    AMPA receptor (AMPAR) transmission onto medium spiny neurons (MSNs) of the adult rat nucleus accumbens (NAc) is normally dominated by GluA2-containing, Ca(2+)-impermeable AMPAR (CI-AMPARs). However, GluA2-lacking, Ca(2+)-permeable AMPA receptors (CP-AMPARs) accumulate after prolonged withdrawal from extended-access cocaine self-administration and thereafter their activation is required for the intensified (incubated) cue-induced cocaine craving that characterizes prolonged withdrawal from such regimens. These findings suggest the existence of mechanisms in NAc MSNs that differentially regulate CI-AMPARs and CP-AMPARs. Here, we compared trafficking of GluA1A2 CI-AMPARs and homomeric GluA1 CP-AMPARs using immunocytochemical assays in cultured NAc MSNs plated with prefrontal cortical neurons to restore excitatory inputs. We began by evaluating constitutive internalization of surface receptors and found that this occurs more rapidly for CP-AMPARs. Next, we studied receptor insertion into the membrane; combined with past results, the present findings suggest that activation of protein kinase A accelerates insertion of both CP-AMPARs and CI-AMPARs. We also studied constitutive cycling (net loss of receptors from the membrane under conditions where internalization and recycling are both occurring). Interestingly, although CP-AMPARs exhibit faster constitutive internalization, they cycle at similar rates as CI-AMPARs, suggesting faster reinsertion of CP-AMPARs. In studies of synaptic scaling, long-term (24 h) activity blockade increased surface expression and cycling rates of CI-AMPARs but not CP-AMPARs, whereas long-term increases in activity produced more pronounced scaling down of CI-AMPARs than CP-AMPARs but did not alter receptor cycling. These findings can be used to evaluate and generate hypotheses regarding AMPAR plasticity in the rat NAc following cocaine exposure. Copyright © 2016 Elsevier Ltd. All rights reserved.

  12. Central amygdala opioid transmission is necessary for increased high-fat intake following 24-h food deprivation, but not following intra-accumbens opioid administration.

    Science.gov (United States)

    Parker, Kyle E; Johns, Howard W; Floros, Ted G; Will, Matthew J

    2014-03-01

    Previous research has demonstrated a dissociation of certain neural mediators that contribute to the increased consumption of a high-fat diet that follows intra-accumbens (Acb) administration of μ-opioid receptor agonists vs. 24-h food deprivation. These two models, both which induce rapid consumption of the diet, have been shown to involve a distributed corticolimbic circuitry, including the amygdala. Specifically, the central amygdala (CeA) has been shown to be involved in high-fat feeding within both opioid and food-deprivation driven models. The present experiments were conducted to examine the more specific role of CeA opioid transmission in mediating high-fat feeding driven by either intra-Acb administration of the μ-opioid agonist d-Ala2-NMe-Phe4-Glyol5-enkephalin (DAMGO) or 24-h home cage food deprivation. Injection of DAMGO into the Acb (0.25 μg/0.5 μl/side) increased consumption of the high-fat diet, but this feeding was unaffected by administration of opioid antagonist, naltrexone (5 μg/0.25 μl/side) administered into the CeA. In contrast, intra-CeA naltrexone administration attenuated high-fat intake driven by 24-h food deprivation, demonstrating a specific role for CeA opioid transmission in high-fat consumption. Intra-CeA naltrexone administration alone had no effect on baseline feeding levels within either feeding model. These findings suggest that CeA opioid transmission mediates consumption of a palatable high-fat diet driven by short-term negative-energy balance (24-h food deprivation), but not intra-Acb opioid receptor activation.

  13. Projections of nucleus accumbens adenosine A2A receptor neurons in the mouse brain and their implications in mediating sleep-wake regulation

    Directory of Open Access Journals (Sweden)

    Jianping eZhang

    2013-12-01

    Full Text Available Adenosine A2A receptors (A2ARs in the nucleus accumbens (Acb have been demonstrated to play an important role in the arousal effect of adenosine receptor antagonist caffeine, and may be involved in physiological sleep. To better understand the functions of these receptors in sleep, projections of A2AR neurons were mapped utilizing adeno-associated virus (AAV encoding humanized Renilla green fluorescent protein (hrGFP as a tracer for long axonal pathways. The Cre-dependent AAV was injected into the core (AcbC and shell (AcbSh of the Acb in A2AR-Cre mice. Immunohistochemistry was then used to visualize hrGFP, highlighting the perikarya of the A2AR neurons in the injection sites, and their axons in projection regions. The data revealed that A2AR neurons exhibit medium-sized and either round or elliptic perikarya with their processes within the Acb. Moreover, the projections from the Acb distributed to nuclei in the forebrain, diencephalon, and brainstem. In the forebrain, A2AR neurons from all Acb sub-regions jointly projected to the ventral pallidum, the nucleus of the diagonal band, and the substantia innominata. Heavy projections from the AcbC and the ventral AcbSh, and weaker projections from the medial AcbSh, were observed in the lateral hypothalamus and lateral preoptic area. In the brainstem, the Acb projections were found in the ventral tegmental area, while AcbC and ventral AcbSh also projected to the median raphe nucleus, the dorsal raphe nucleus, and the ventrolateral periaqueductal gray. The results supply a solid base for understanding the roles of the A2AR and A2AR neurons in the Acb, especially in the regulation of sleep.

  14. Mechanisms of activation of nucleus accumbens neurons by cocaine via sigma-1 receptor-inositol 1,4,5-trisphosphate-transient receptor potential canonical channel pathways.

    Science.gov (United States)

    Barr, Jeffrey L; Deliu, Elena; Brailoiu, G Cristina; Zhao, Pingwei; Yan, Guang; Abood, Mary E; Unterwald, Ellen M; Brailoiu, Eugen

    2015-08-01

    Cocaine promotes addictive behavior primarily by blocking the dopamine transporter, thus increasing dopamine transmission in the nucleus accumbens (nAcc); however, additional mechanisms are continually emerging. Sigma-1 receptors (σ1Rs) are known targets for cocaine, yet the mechanisms underlying σ1R-mediated effects of cocaine are incompletely understood. The present study examined direct effects of cocaine on dissociated nAcc neurons expressing phosphatidylinositol-linked D1 receptors. Endoplasmic reticulum-located σ1Rs and inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs) were targeted using intracellular microinjection. IP3 microinjection robustly elevated intracellular Ca(2+) concentration, [Ca(2+)]i. While cocaine alone was devoid of an effect, the IP3-induced response was σ1R-dependently enhanced by cocaine co-injection. Likewise, cocaine augmented the [Ca(2+)]i increase elicited by extracellularly applying an IP3-generating molecule (ATP), via σ1Rs. The cocaine-induced enhancement of the IP3/ATP-mediated Ca(2+) elevation occurred at pharmacologically relevant concentrations and was mediated by transient receptor potential canonical channels (TRPC). IP3 microinjection elicited a slight, transient depolarization, further converted to a greatly enhanced, prolonged response, by cocaine co-injection. The cocaine-triggered augmentation was σ1R-dependent, TRPC-mediated and contingent on [Ca(2+)]i elevation. ATP-induced depolarization was similarly enhanced by cocaine. Thus, we identify a novel mechanism by which cocaine promotes activation of D1-expressing nAcc neurons: enhancement of IP3R-mediated responses via σ1R activation at the endoplasmic reticulum, resulting in augmented Ca(2+) release and amplified depolarization due to subsequent stimulation of TRPC. In vivo, intra-accumbal blockade of σ1R or TRPC significantly diminished cocaine-induced hyperlocomotion and locomotor sensitization, endorsing a physio-pathological significance of the pathway

  15. Increased palatable food intake and response to food cues in intrauterine growth-restricted rats are related to tyrosine hydroxylase content in the orbitofrontal cortex and nucleus accumbens.

    Science.gov (United States)

    Alves, Márcio Bonesso; Dalle Molle, Roberta; Desai, Mina; Ross, Michael G; Silveira, Patrícia Pelufo

    2015-01-01

    Intrauterine growth restriction (IUGR) is associated with altered food preferences, which may contribute to increased risk of obesity. We evaluated the effects of IUGR on attention to a palatable food cue, as well as tyrosine hydroxylase (TH) content in the orbitofrontal cortex (OFC) and nucleus accumbens (NAcc) in response to sweet food intake. From day 10 of gestation and through lactation, Sprague-Dawley rats received either an ad libitum (Adlib) or a 50% food-restricted (FR) diet. At birth, pups were cross-fostered, generating four groups (gestation/lactation): Adlib/Adlib (control), FR/Adlib (intrauterine growth-restricted), Adlib/FR, and FR/FR. Adult attention to palatable food cues was measured using the Attentional Set-Shifting Task (ASST), which uses a sweet pellet as reward. TH content in the OFC and NAcc was measured at baseline and in response to palatable food intake. At 90 days of age, FR/Adlib males ate more sweet food than controls, without differences in females. However, when compared to Controls, FR/Adlib females needed fewer trials to reach criterion in the ASST (p=0.04) and exhibited increased TH content in the OFC in response to sweet food (p=0.03). In the NAcc, there was a differential response of TH content after sweet food intake in both FR/Adlib males and females (pfood preferences involves the central response to palatable food cues and intake, affecting dopamine release in select structures of the brain reward system. Copyright © 2015 Elsevier B.V. All rights reserved.

  16. A critical role of nucleus accumbens dopamine D1-family receptors in renewal of alcohol seeking after punishment-imposed abstinence.

    Science.gov (United States)

    Marchant, Nathan J; Kaganovsky, Konstantin

    2015-06-01

    In humans, places or contexts previously associated with alcohol use often provoke relapse during abstinence. This phenomenon is modeled in laboratory animals using the ABA renewal procedure, in which extinction training in context (B) suppresses alcohol seeking, and renewal of this seeking occurs when the animal returns to the original training context (A). However, extinction training does not adequately capture the motivation for abstinence in human alcoholics who typically self-initiate abstinence in response to the negative consequences of excessive use. We recently developed a procedure to study renewal in laboratory rats after abstinence imposed by negative consequences (footshock punishment). The mechanisms of renewal of punished alcohol seeking are largely unknown. Here, we used the D1-family receptor antagonist SCH 23390 to examine the role of nucleus accumbens (NAc) shell and core dopamine in renewal of alcohol seeking after punishment-imposed abstinence. We trained alcohol-preferring "P rats" to self-administer 20% alcohol in Context A and subsequently suppressed alcohol taking via response-contingent footshock punishment in Context B. We tested the effects of systemic, NAc shell, or NAc core injections of SCH 23390 on renewal of alcohol seeking after punishment-imposed abstinence. We found that both systemic and NAc shell and core injections of SCH 23390 decreased renewal of punished alcohol seeking. Our results demonstrate a critical role of NAc dopamine in renewal of alcohol seeking after punishment-imposed abstinence. We discuss these results in reference to the brain mechanisms of renewal of alcohol seeking after extinction versus punishment.

  17. Nucleus accumbens deep-brain stimulation efficacy in ACTH-pretreated rats: alterations in mitochondrial function relate to antidepressant-like effects

    Science.gov (United States)

    Kim, Y; McGee, S; Czeczor, J K; Walker, A J; Kale, R P; Kouzani, A Z; Walder, K; Berk, M; Tye, S J

    2016-01-01

    Mitochondrial dysfunction has a critical role in the pathophysiology of mood disorders and treatment response. To investigate this, we established an animal model exhibiting a state of antidepressant treatment resistance in male Wistar rats using 21 days of adrenocorticotropic hormone (ACTH) administration (100 μg per day). First, the effect of ACTH treatment on the efficacy of imipramine (10 mg kg−1) was investigated alongside its effect on the prefrontal cortex (PFC) mitochondrial function. Second, we examined the mood-regulatory actions of chronic (7 day) high-frequency nucleus accumbens (NAc) deep-brain stimulation (DBS; 130 Hz, 100 μA, 90 μS) and concomitant PFC mitochondrial function. Antidepressant-like responses were assessed in the open field test (OFT) and forced swim test (FST) for both conditions. ACTH pretreatment prevented imipramine-mediated improvement in mobility during the FST (P0.05). Analyses of PFC mitochondrial function revealed that ACTH-treated animals had decreased capacity for adenosine triphosphate production compared with controls. In contrast, ACTH animals following NAc DBS demonstrated greater mitochondrial function relative to controls. Interestingly, a proportion (30%) of the ACTH-treated animals exhibited heightened locomotor activity in the OFT and exaggerated escape behaviors during the FST, together with general hyperactivity in their home-cage settings. More importantly, the induction of this mania-like phenotype was accompanied by overcompensative increased mitochondrial respiration. Manifestation of a DBS-induced mania-like phenotype in imipramine-resistant animals highlights the potential use of this model in elucidating mechanisms of mood dysregulation. PMID:27327257

  18. Deep brain stimulation reveals a dissociation of consummatory and motivated behaviour in the medial and lateral nucleus accumbens shell of the rat.

    Directory of Open Access Journals (Sweden)

    Geoffrey van der Plasse

    Full Text Available Following the successful application of deep brain stimulation (DBS in the treatment of Parkinson's disease and promising results in clinical trials for obsessive compulsive disorder and major depression, DBS is currently being tested in small patient-populations with eating disorders and addiction. However, in spite of its potential use in a broad spectrum of disorders, the mechanisms of action of DBS remain largely unclear and optimal neural targets for stimulation in several disorders have yet to be established. Thus, there is a great need to examine site-specific effects of DBS on a behavioural level and to understand how DBS may modulate pathological behaviour. In view of the possible application of DBS in the treatment of disorders characterized by impaired processing of reward and motivation, like addiction and eating disorders, we examined the effect of DBS of the nucleus accumbens (NAcc on food-directed behavior. Rats were implanted with bilateral stimulation electrodes in one of three anatomically and functionally distinct sub-areas of the NAcc: the core, lateral shell (lShell and medial shell (mShell. Subsequently, we studied the effects of DBS on food consumption, and the motivational and appetitive properties of food. The data revealed a functional dissociation between the lShell and mShell. DBS of the lShell reduced motivation to respond for sucrose under a progressive ratio schedule of reinforcement, mShell DBS, however, profoundly and selectively increased the intake of chow. DBS of the NAcc core did not alter any form of food-directed behavior studied. DBS of neither structure affected sucrose preference. These data indicate that the intake of chow and the motivation to work for palatable food can independently be modulated by DBS of subregions of the NAcc shell. As such, these findings provide important leads for the possible future application of DBS as a treatment for eating disorders such as anorexia nervosa.

  19. Differential influence of the ventral subiculum on dopaminergic responses observed in core and dorsomedial shell subregions of the nucleus accumbens in latent inhibition.

    Science.gov (United States)

    Peterschmitt, Y; Meyer, F; Louilot, A

    2008-06-26

    It has previously been reported that dopamine (DA) responses observed in the core and dorsomedial shell parts of the nucleus accumbens (Nacc) in latent inhibition (LI) are dependent on the left entorhinal cortex (ENT). The present study was designed to investigate the influence of the left ventral subiculum (SUB) closely linked to the ENT on the DA responses obtained in the Nacc during LI, using an aversive conditioned olfactory paradigm and in vivo voltammetry in freely moving rats. In the first (pre-exposure) session, functional blockade of the left SUB was achieved by local microinjection of tetrodotoxin (TTX). In the second session, rats were aversively conditioned to banana odor, the conditional stimulus (CS). In the retention (test) session the results were as follows: (1) pre-exposed (PE) conditioned animals microinjected with TTX, displayed aversion toward the CS; (2) in the core part of the Nacc, for PE-TTX-conditioned rats as for non-pre-exposed (NPE) conditioned animals, DA levels remained close to the baseline whereas DA variations in both groups were significantly different from the DA increases observed in PE-conditioned rats microinjected with the solvent (phosphate-buffered saline (PBS)); (3) in the shell part of the Nacc, for PE-TTX-conditioned rats, DA variations were close to or above the baseline. They were situated between the rapid DA increases observed in NPE-conditioned animals and the transient DA decreases obtained in PE-PBS-conditioned animals. These findings suggest that, in parallel to the left ENT, the left SUB controls DA LI-related responses in the Nacc. The present data may also offer new insight into the pathophysiology of schizophrenia.

  20. The uncompetitive N-methyl-D-aspartate antagonist memantine reduces binge-like eating, food-seeking behavior, and compulsive eating: role of the nucleus accumbens shell.

    Science.gov (United States)

    Smith, Karen L; Rao, Rahul R; Velázquez-Sánchez, Clara; Valenza, Marta; Giuliano, Chiara; Everitt, Barry J; Sabino, Valentina; Cottone, Pietro

    2015-03-13

    Binge-eating disorder is characterized by excessive, uncontrollable consumption of palatable food within brief periods of time. The role of the glutamatergic N-methyl-D-aspartate (NMDA) receptor system in hedonic feeding is poorly understood. The aim of this study was to characterize the effects of the uncompetitive NMDA receptor antagonist memantine on palatable food-induced behavioral adaptations using a rat model, which mimics the characteristic symptomatology observed in binge-eating disorder. For this purpose, we allowed male Wistar rats to respond to obtain a highly palatable, sugary diet (Palatable group) or a regular chow diet (Chow control group), for 1 h a day, under a fixed-ratio 1 (FR1) schedule of reinforcement. Upon stabilization of food responding, we tested the effects of memantine on the Chow and Palatable food groups' intake. Then, we tested the effects of memantine on food-seeking behavior, under a second-order schedule of reinforcement. Furthermore, we investigated the effects of memantine on the intake of food when it was offered in an aversive, bright compartment of a light/dark conflict test. Finally, we evaluated the effects of memantine on FR1 responding for food, when microinfused into the nucleus accumbens (NAcc) shell or core. Memantine dose-dependently decreased binge-like eating and fully blocked food-seeking behavior and compulsive eating, selectively in the Palatable food group. The drug treatment did not affect performance of the control Chow food group. Finally, intra-NAcc shell, but not core, microinfusion of memantine decreased binge-like eating. Together, these findings substantiate a role of memantine as a potential pharmacological treatment for binge-eating disorder.

  1. Oxytocin receptors are expressed on dopamine and glutamate neurons in the mouse ventral tegmental area that project to nucleus accumbens and other mesolimbic targets.

    Science.gov (United States)

    Peris, Joanna; MacFadyen, Kaley; Smith, Justin A; de Kloet, Annette D; Wang, Lei; Krause, Eric G

    2017-04-01

    The mesolimbic dopamine (DA) circuitry determines which behaviors are positively reinforcing and therefore should be encoded in the memory to become a part of the behavioral repertoire. Natural reinforcers, like food and sex, activate this pathway, thereby increasing the likelihood of further consummatory, social, and sexual behaviors. Oxytocin (OT) has been implicated in mediating natural reward and OT-synthesizing neurons project to the ventral tegmental area (VTA) and nucleus accumbens (NAc); however, direct neuroanatomical evidence of OT regulation of DA neurons within the VTA is sparse. To phenotype OT-receptor (OTR) expressing neurons originating within the VTA, we delivered Cre-inducible adeno-associated virus that drives the expression of fluorescent marker into the VTA of male mice that had Cre-recombinase driven by OTR gene expression. OTR-expressing VTA neurons project to NAc, prefrontal cortex, the extended amygdala, and other forebrain regions but less than 10% of these OTR-expressing neurons were identified as DA neurons (defined by tyrosine hydroxylase colocalization). Instead, almost 50% of OTR-expressing cells in the VTA were glutamate (GLU) neurons, as indicated by expression of mRNA for the vesicular GLU transporter (vGluT). About one-third of OTR-expressing VTA neurons did not colocalize with either DA or GLU phenotypic markers. Thus, OTR expression by VTA neurons implicates that OT regulation of reward circuitry is more complex than a direct action on DA neurotransmission. J. Comp. Neurol. 525:1094-1108, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  2. Effects of ketamine administration on mTOR and reticulum stress signaling pathways in the brain after the infusion of rapamycin into prefrontal cortex.

    Science.gov (United States)

    Abelaira, Helena M; Réus, Gislaine Z; Ignácio, Zuleide M; Dos Santos, Maria Augusta B; de Moura, Airam B; Matos, Danyela; Demo, Júlia P; da Silva, Júlia B I; Michels, Monique; Abatti, Mariane; Sonai, Beatriz; Dal Pizzol, Felipe; Carvalho, André F; Quevedo, João

    2017-04-01

    Recent studies show that activation of the mTOR signaling pathway is required for the rapid antidepressant actions of glutamate N-methyl-D-aspartate (NMDA) receptor antagonists. A relationship between mTOR kinase and the endoplasmic reticulum (ER) stress pathway, also known as the unfolded protein response (UPR) has been shown. We evaluate the effects of ketamine administration on the mTOR signaling pathway and proteins of UPR in the prefrontal cortex (PFC), hippocampus, amygdala and nucleus accumbens, after the inhibiton of mTOR signaling in the PFC. Male adult Wistar rats received pharmacological mTOR inhibitor, rapamycin (0.2 nmol), or vehicle into the PFC and then a single dose of ketamine (15 mg/kg, i.p.). The immunocontent of mTOR, eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), eukaryotic elongation factor 2 kinase (eEF2K) homologous protein (CHOP), PKR-like ER kinase (PERK) and inositol-requiring enzyme 1 (IRE1) - alpha were determined in the brain. The mTOR levels were reduced in the rapamycin group treated with saline and ketamine in the PFC; p4EBP1 levels were reduced in the rapamycin group treated with ketamine in the PFC and nucleus accumbens; the levels of peEF2K were increased in the PFC in the vehicle group treated with ketamine and reduced in the rapamycin group treated with ketamine. The PERK and IRE1-alpha levels were decreased in the PFC in the rapamycin group treated with ketamine. Our results suggest that mTOR signaling inhibition by rapamycin could be involved, at least in part, with the mechanism of action of ketamine; and the ketamine antidepressant on ER stress pathway could be also mediated by mTOR signaling pathway in certain brain structures. Copyright © 2016 Elsevier Ltd. All rights reserved.

  3. Signal Processing of Random Physiological Signals

    CERN Document Server

    Lessard, Charles

    2006-01-01

    Signal Processing of Random Physiological Signals presents the most widely used techniques in signal and system analysis. Specifically, the book is concerned with methods of characterizing signals and systems. Author Charles Lessard provides students and researchers an understanding of the time and frequency domain processes which may be used to evaluate random physiological signals such as brainwave, sleep, respiratory sounds, heart valve sounds, electromyograms, and electro-oculograms.Another aim of the book is to have the students evaluate actual mammalian data without spending most or all

  4. Continuous-time signals

    CERN Document Server

    Shmaliy, Yuriy

    2006-01-01

    Gives a modern description of continuous-time deterministic signals Signal formation techniquesTime vs. frequency and frequency vs. time analysisCorrelation and energy analysisNarrowband signals and sampling.

  5. Basic digital signal processing

    CERN Document Server

    Lockhart, Gordon B

    1985-01-01

    Basic Digital Signal Processing describes the principles of digital signal processing and experiments with BASIC programs involving the fast Fourier theorem (FFT). The book reviews the fundamentals of the BASIC program, continuous and discrete time signals including analog signals, Fourier analysis, discrete Fourier transform, signal energy, power. The text also explains digital signal processing involving digital filters, linear time-variant systems, discrete time unit impulse, discrete-time convolution, and the alternative structure for second order infinite impulse response (IIR) sections.

  6. Interactive Digital Signal Processor

    Science.gov (United States)

    Mish, W. H.

    1985-01-01

    Interactive Digital Signal Processor, IDSP, consists of set of time series analysis "operators" based on various algorithms commonly used for digital signal analysis. Processing of digital signal time series to extract information usually achieved by applications of number of fairly standard operations. IDSP excellent teaching tool for demonstrating application for time series operators to artificially generated signals.

  7. Signals and processing for random signal radars

    Science.gov (United States)

    Moore, G. S.

    1980-06-01

    Signals and associated processing techniques are developed which improve the performance, simplify the implementation, and are more amenable to adaptive operation for radars using the random signal concept. These goals are accomplished through the use of a signal set that is composed of a deterministic spreading function, a binary random or pseudo-random noise source, and a possibly random or pseudo-random pulsing sequence. Techniques are developed for determining the parameters of the spreading function that result in signals with desirable ambiguity functions and high effective power. These techniques are based on the use of window functions for sidelobe control and the theory of chirp waveforms for effective power enhancement.

  8. Digital signal processing laboratory

    CERN Document Server

    Kumar, B Preetham

    2011-01-01

    INTRODUCTION TO DIGITAL SIGNAL PROCESSING Brief Theory of DSP ConceptsProblem SolvingComputer Laboratory: Introduction to MATLAB®/SIMULINK®Hardware Laboratory: Working with Oscilloscopes, Spectrum Analyzers, Signal SourcesDigital Signal Processors (DSPs)ReferencesDISCRETE-TIME LTI SIGNALS AND SYSTEMS Brief Theory of Discrete-Time Signals and SystemsProblem SolvingComputer Laboratory: Simulation of Continuous Time and Discrete-Time Signals and Systems ReferencesTIME AND FREQUENCY ANALYSIS OF COMMUNICATION SIGNALS Brief Theory of Discrete-Time Fourier Transform (DTFT), Discrete Fourier Transform

  9. Multiplexing oscillatory biochemical signals.

    Science.gov (United States)

    de Ronde, Wiet; ten Wolde, Pieter Rein

    2014-04-01

    In recent years it has been increasingly recognized that biochemical signals are not necessarily constant in time and that the temporal dynamics of a signal can be the information carrier. Moreover, it is now well established that the protein signaling network of living cells has a bow-tie structure and that components are often shared between different signaling pathways. Here we show by mathematical modeling that living cells can multiplex a constant and an oscillatory signal: they can transmit these two signals simultaneously through a common signaling pathway, and yet respond to them specifically and reliably. We find that information transmission is reduced not only by noise arising from the intrinsic stochasticity of biochemical reactions, but also by crosstalk between the different channels. Yet, under biologically relevant conditions more than 2 bits of information can be transmitted per channel, even when the two signals are transmitted simultaneously. These observations suggest that oscillatory signals are ideal for multiplexing signals.

  10. The possible interaction of dopamine system in nucleus accumbens shell and glutamate system of prelimbic region on locomotor activity in rat

    Directory of Open Access Journals (Sweden)

    Hatam Ahmadi

    2013-06-01

    Full Text Available Background: Nucleus accumbens (NAc and prefrontal cortex (PFC dopaminergic and glutamatergic systems are involved in regulating of locomotor activity behaviors. This study has investigated the interaction of NAc shell dopaminergic system and prelimbic glutamatergic systems in regulating locomotor activity and related parameters. Methods: The aim of this study was the effect the drugs injection interaction in the brain of male Wistar rats on locomotor activity and related parameters, in the order of this purpose, open field apparatus that automatically recorded locomotor activity was employed. Unilateral intra-cerebral injection of drugs was done. Results: Unilateral intra-prelimbic injection of D-AP7 (N-methyl-D-aspartic acid= NMDA receptor antagonist; 0.25, 0.5 and 1μg/μl did not alter locomotor activity behaviors. However, infusion of NMDA (0.9μg/μl in this region increased locomotor activity (P<0.01, whereas decreased rearing (P<0.01 and grooming (P<0.01 which was blocked by D-AP7 (0.25μg/μl (P<0.01. Moreover, unilateral infusion of SCH23390 (dopamine D1 receptor antagonist; 0.25, 0.5 and 1μg/μl into the left NAc shell did not alter locomotor activity. However, injection of SKF38393 (dopamine D1 receptor agonist; 4μg/μl into the left NAc shell increased locomotor activity (P<0.05 which was blocked by SCH23390 (0.25μg/μl (P<0.01. Furthermore, the subthreshold dose infusion of SCH23390 (0.25μg/μl into the left NAc shell reduced the effect of intra- prelimbic NMDA on locomotor activity (P<0.01. In addition, intra-NAc shell administration of the subthreshold dose of SKF38393 (1μg/μl potentiated the middle dose (P<0.05, whereas decreased the higher dose of intra-left prelimbic NMDA response (P<0.05 on locomotor activity. Conclusion: The results suggested a modulatory effect of the NAc shell dopaminergic system on increased locomotor activity by activating glutamate system in prelimbic.

  11. ENDOCANNABINOID 2-ARACHIDONOYLGLYCEROL SELF-ADMINISTRATION BY SPRAGUE-DAWLEY RATS AND STIMULATION OF IN VIVO DOPAMINE TRANSMISSION IN THE NUCLEUS ACCUMBENS SHELL

    Directory of Open Access Journals (Sweden)

    Maria Antonietta eDe Luca

    2014-10-01

    Full Text Available 2-Arachidonoylglycerol (2-AG is the most potent endogenous ligand of brain cannabinoid CB1 receptors and is synthesized on demand from 2-arachidonate-containing phosphoinositides by the action of diacyglycerol lipase in response to increased intracellular calcium. Several studies indicate that the endocannabinoid (eCB system is involved in the mechanism of reward and that diverse drugs of abuse increase brain eCB levels. In addition, eCB are self-administered (SA by squirrel monkeys, and anandamide increases nucleus accumbens (NAc shell dopamine (DA in rats. To date, there is no evidence on the reinforcing effects of 2-AG and its effects on DA transmission in rodents. In order to fill this gap, we studied intravenous 2-AG SA and monitored the effect of 2-AG on extracellular DA in the NAc shell and core via microdialysis in male Sprague-Dawley rats. Rats were implanted with jugular catheters and trained to self-administer 2-AG (25g/kg/inf iv in single daily 1h sessions for 5 weeks under initial Fixed Ratio (FR 1 schedule. The ratio was subsequently increased to FR2. Active nose-poking increased from the 6th SA session (acquisition phase but no significant increase of nose-pokes was observed after FR2. When 2-AG was substituted for vehicle (25th SA session, extinction phase, rate responding, as well as number of injections, slowly decreased. When vehicle was replaced with 2-AG, SA behavior immediately recovered (reacquisition phase. The reinforcing effects of 2-AG in SA behavior were fully blocked by the CB1 receptor inverse agonist/antagonist rimonabant (1 mg/kg ip, 30 min before SA session. In the microdialysis studies, we observed that 2-AG (0.1-1.0 mg/kg iv preferentially stimulates NAc shell as compared to the NAc core. NAc shell DA increased by about 25% over basal value at the highest doses tested (0.5 and 1.0 mg/kg iv. The results obtained suggest that the eCB system, via 2-AG, plays an important role in reward.

  12. Inhibition of the reinstatement of morphine-induced place preference in rats by high-frequency stimulation of the bilateral nucleus accumbens

    Institute of Scientific and Technical Information of China (English)

    MA Yu; CHEN Ning; WANG Hui-min; Meng Fan-gang; ZHANG Jian-guo

    2013-01-01

    Background Opiate addiction remains intractable in a large percentage of patients,and relapse is the biggest hurdle to recovery.Many studies have identified a central role of the nucleus accumbens (NAc) in addiction.Deep brain stimulation (DBS) has the advantages of being reversible,adjustable,and minimally invasive,and it has become a potential neurobiological intervention for addiction.The purpose of our study was to investigate whether high-frequency DBS in the NAc effectively attenuates the reinstatement of morphine seeking in morphine-primed rats.Methods A morphine-dependent group of rats was given increasing doses of morphine during conditioned place preference training.A control group of rats was given equal volumes of saline.After the establishment of this model,withdrawal syndromes were precipitated in these two groups by administering naloxone,and the differences in withdrawal symptoms between the groups were analyzed.Electrodes for DBS were implanted in the bilateral shell of the NAc in the experimental group.The rats were stimulated daily in the NAc for 5 hours per day over 30 days.Changes in the conditioned place preference test and withdrawal symptoms in the rats were investigated and place navigation studies were performed using the Morris water maze.The data were assessed statistically with one-way analysis of variance (ANOVA) followed by Tukey's tests for multiple post hoc comparisons.Results High-frequency stimulation of the bilateral NAc prevented the morphine-induced reinstatement of morphine seeking in the conditioned place preference test.The time spent in the white compartment by rats following 30 days of DBS ((268.25±25.07) seconds) was not significantly different compared with the time spent in the white compartment after relapse was induced by morphine administration ((303.29±34.22) seconds).High-frequency stimulation of the bilateral NAc accelerated the innate decay of drug craving in morphine-dependent rats without significantly

  13. Influence of Volatile Anesthesia on the Release of Glutamate and other Amino Acids in the Nucleus Accumbens in a Rat Model of Alcohol Withdrawal: A Pilot Study

    Science.gov (United States)

    Seidemann, Thomas; Spies, Claudia; Morgenstern, Rudolf; Wernecke, Klaus-Dieter; Netzhammer, Nicolai

    2017-01-01

    Background Alcohol withdrawal syndrome is a potentially life-threatening condition, which can occur when patients with alcohol use disorders undergo general anesthesia. Excitatory amino acids, such as glutamate, act as neurotransmitters and are known to play a key role in alcohol withdrawal syndrome. To understand this process better, we investigated the influence of isoflurane, sevoflurane, and desflurane anesthesia on the profile of excitatory and inhibitory amino acids in the nucleus accumbens (NAcc) of alcohol-withdrawn rats (AWR). Methods Eighty Wistar rats were randomized into two groups of 40, pair-fed with alcoholic or non-alcoholic nutrition. Nutrition was withdrawn and microdialysis was performed to measure the activity of amino acids in the NAcc. The onset time of the withdrawal syndrome was first determined in an experiment with 20 rats. Sixty rats then received isoflurane, sevoflurane, or desflurane anesthesia for three hours during the withdrawal period, followed by one hour of elimination. Amino acid concentrations were measured using chromatography and results were compared to baseline levels measured prior to induction of anesthesia. Results Glutamate release increased in the alcohol group at five hours after the last alcohol intake (p = 0.002). After 140 min, desflurane anesthesia led to a lower release of glutamate (p < 0.001) and aspartate (p = 0.0007) in AWR compared to controls. GABA release under and after desflurane anesthesia was also significantly lower in AWR than controls (p = 0.023). Over the course of isoflurane anesthesia, arginine release decreased in AWR compared to controls (p < 0.001), and aspartate release increased after induction relative to controls (p20min = 0.015 and p40min = 0.006). However, amino acid levels did not differ between the groups as a result of sevoflurane anesthesia. Conclusions Each of three volatile anesthetics we studied showed different effects on excitatory and inhibitory amino acid concentrations. Under

  14. A relationship between reduced nucleus accumbens shell and enhanced lateral hypothalamic orexin neuronal activation in long-term fructose bingeing behavior.

    Directory of Open Access Journals (Sweden)

    Jacki M Rorabaugh

    Full Text Available Fructose accounts for 10% of daily calories in the American diet. Fructose, but not glucose, given intracerebroventricularly stimulates homeostatic feeding mechanisms within the hypothalamus; however, little is known about how fructose affects hedonic feeding centers. Repeated ingestion of sucrose, a disaccharide of fructose and glucose, increases neuronal activity in hedonic centers, the nucleus accumbens (NAc shell and core, but not the hypothalamus. Rats given glucose in the intermittent access model (IAM display signatures of hedonic feeding including bingeing and altered DA receptor (R numbers within the NAc. Here we examined whether substituting fructose for glucose in this IAM produces bingeing behavior, alters DA Rs and activates hedonic and homeostatic feeding centers. Following long-term (21-day exposure to the IAM, rats given 8-12% fructose solutions displayed fructose bingeing but unaltered DA D1R or D2R number. Fructose bingeing rats, as compared to chow bingeing controls, exhibited reduced NAc shell neuron activation, as determined by c-Fos-immunoreactivity (Fos-IR. This activation was negatively correlated with orexin (Orx neuron activation in the lateral hypothalamus/perifornical area (LH/PeF, a brain region linking homeostatic to hedonic feeding centers. Following short-term (2-day access to the IAM, rats exhibited bingeing but unchanged Fos-IR, suggesting only long-term fructose bingeing increases Orx release. In long-term fructose bingeing rats, pretreatment with the Ox1R antagonist SB-334867 (30 mg/kg; i.p. equally reduced fructose bingeing and chow intake, resulting in a 50% reduction in calories. Similarly, in control rats, SB-334867 reduced chow/caloric intake by 60%. Thus, in the IAM, Ox1Rs appear to regulate feeding based on caloric content rather than palatability. Overall, our results, in combination with the literature, suggest individual monosaccharides activate distinct neuronal circuits to promote feeding behavior

  15. Clinical observation of physiological and psychological reactions to electric stimulation of the amygdaloid nucleus and the nucleus accumbens in heroin addicts after detoxification

    Institute of Scientific and Technical Information of China (English)

    FANG Jun; GU Jian-wen; YANG Wen-tao; QIN Xue-ying; HU Yong-hua

    2012-01-01

    Background Stereotactic surgery has been used to treat heroin abstinence in China since 2000 by ablating the amygdaloid nucleus (AMY) and the nucleus accumbens (NAc),which also provides opportunity to identify the relationship between these nuclei and addiction.Our study aimed to explore the physiological and psychological effects of electrically stimulating the AMY and the NAc in herein addicts after detoxification by observing changes of heart rate,arterial pressure and occurrence of euphoria similar to heroin induced euphoria.Methods A total of 70 heroin addicts after detoxification were recruited,and 61 of them were eligible to be given stereotactic surgery for heroin abstinence.The operation was carried out after determining the coordinates of all target nucleuses,and stimulation was performed at the AMY and the NAc solely or jointly.Heart rate,arterial pressure and occurrence of euphoria similar to heroin induced euphoria were recorded and analyzed.Results The average heat rate was (66±10) beats/min before electric stimulation,and significantly increased to (84±14) beats/min during stimulation,and changed to (73±12) beats/min 10 minutes after stimulation.There was a significant elevation of the average arterial pressure from 83 mmHg before stimulation to 98 mmHg during the stimulation,and it then decreased to 90 mmHg after stimulation.Forty-three of the 61 patients showed intense euphoria similar to heroin induced euphoria.The largest number (118/186) of euphoric responses occurred when the AMY and the NAc were stimulated at the same time.Odds ratio was 5.4 (95% CI: 2.4-11.9,P <0.0001) to quantify the association.Results from a Logistic regression model showed a positive correlation between unilateral stimulation of either the AMY or NAC and induction of euphoria (OR >1 ),especially when the left AMY or left NAc was stimulated (P <0.05).Conclusions Our data are consistent with existing results that the AMY and the NAc are related to addiction

  16. Nucleus Accumbens MC4-R Stimulation Reduces Food and Ethanol Intake in Adult Rats Regardless of Binge-Like Ethanol Exposure during Adolescence

    Directory of Open Access Journals (Sweden)

    Francisca Carvajal

    2017-09-01

    Full Text Available The melanocortin (MC system regulates feeding and ethanol consumption. Recent evidence shows that melanocortin 4 receptor (MC4-R stimulation within the nucleus accumbens (NAc elicits anorectic responses and reduces ethanol consumption and ethanol palatability in adult rats. Ethanol exposure during adolescence causes long-lasting changes in neural pathways critically involved in neurobehavioral responses to ethanol. In this regard, binge-like ethanol exposure during adolescence reduces basal alpha-melanocyte-stimulating hormone (α-MSH and alters the levels of agouti-related peptide (AgRP in hypothalamic and limbic areas. Given the protective role of MC against excessive ethanol consumption, disturbances in the MC system induced by binge-like ethanol exposure during adolescence might contribute to excessive ethanol consumption during adulthood. In the present study, we evaluated whether binge-like ethanol exposure during adolescence leads to elevated ethanol intake and/or eating disturbance during adulthood. Toward that aim, Sprague-Dawley rats were treated with ethanol (3 g/kg i.p.; BEP group or saline (SP group for 14 days (PND 25 to PND 38. On PND73, all the groups were given access to 20% ethanol on an intermittent schedule. Our results showed that adult rats given intermittent access (IAE to 20% ethanol achieved high spontaneous ethanol intake that was not significantly enhanced by binge-like ethanol pretreatment during adolescence. However, BEP group exhibited an increase in food intake without a parallel increase in body weight (BW relative to SP group suggesting caloric efficiency disturbance. Additionally, we evaluated whether binge-like ethanol exposure during adolescence alters the expected reduction in feeding and ethanol consumption following NAc shell administration of a selective MC4-R agonist in adult rats showing high rates of ethanol consumption. For that, animals in each pretreatment condition (SP and BEP were divided into

  17. N-acetyl-S-(N,N-diethylcarbamoyl) cysteine in rat nucleus accumbens, medial prefrontal cortex, and in rat and human plasma after disulfiram administration.

    Science.gov (United States)

    Winefield, Robert D; Heemskerk, Anthonius A M; Kaul, Swetha; Williams, Todd D; Caspers, Michael J; Prisinzano, Thomas E; McCance-Katz, Elinore F; Lunte, Craig E; Faiman, Morris D

    2015-03-25

    Disulfiram (DSF), a treatment for alcohol use disorders, has shown some clinical effectiveness in treating addiction to cocaine, nicotine, and pathological gambling. The mechanism of action of DSF for treating these addictions is unclear but it is unlikely to involve the inhibition of liver aldehyde dehydrogenase (ALDH2). DSF is a pro-drug and forms a number of metabolites, one of which is N-acetyl-S-(N,N-diethylcarbamoyl) cysteine (DETC-NAC). Here we describe a LCMS/MS method on a QQQ type instrument to quantify DETC-NAC in plasma and intracellular fluid from mammalian brain. An internal standard, the N,N-di-isopropylcarbamoyl homolog (MIM: 291>128) is easily separable from DETC-NAC (MIM: 263>100) on C18 RP media with a methanol gradient. The method's linear range is 0.5-500 nM from plasma and dialysate salt solution with all precisions better than 10% RSD. DETC-NAC and internal standards were recovered at better than 95% from all matrices, perchloric acid precipitation (plasma) or formic acid addition (salt) and is stable in plasma or salt at low pH for up to 24 h. Stability is observed through three freeze-thaw cycles per day for 7 days. No HPLC peak area matrix effect was greater than 10%. A human plasma sample from a prior analysis for S-(N,N-diethylcarbamoyl) glutathione (CARB) was found to have DETC NAC as well. In other human plasma samples from 62.5 mg/d and 250 mg/d dosing, CARB concentration peaks at 0.3 and 4 nM at 3 h followed by DETC-NAC peaks of 11 and 70 nM 2 h later. Employing microdialysis sampling, DETC-NAC levels in the nucleus accumbens (NAc), medial prefrontal cortex (mPFC), and plasma of rats treated with DSF reached 1.1, 2.5 and 80 nM at 6h. The correlation between the appearance and long duration of DETC-NAC concentration in rat brain and the persistence of DSF-induced changes in neurotransmitters observed by Faiman et al. (Neuropharmacology, 2013, 75C, 95-105) is discussed.

  18. Live Imaging of Nicotine Induced Calcium Signaling and Neurotransmitter Release Along Ventral Hippocampal Axons.

    Science.gov (United States)

    Zhong, Chongbo; Talmage, David A; Role, Lorna W

    2015-06-24

    Sustained enhancement of axonal signaling and increased neurotransmitter release by the activation of pre-synaptic nicotinic acetylcholine receptors (nAChRs) is an important mechanism for neuromodulation by acetylcholine (ACh). The difficulty with access to probing the signaling mechanisms within intact axons and at nerve terminals both in vitro and in vivo has limited progress in the study of the pre-synaptic components of synaptic plasticity. Here we introduce a gene-chimeric preparation of ventral hippocampal (vHipp)-accumbens (nAcc) circuit in vitro that allows direct live imaging to analyze both the pre- and post-synaptic components of transmission while selectively varying the genetic profile of the pre- vs post-synaptic neurons. We demonstrate that projections from vHipp microslices, as pre-synaptic axonal input, form multiple, reliable glutamatergic synapses with post-synaptic targets, the dispersed neurons from nAcc. The pre-synaptic localization of various subtypes of nAChRs are detected and the pre-synaptic nicotinic signaling mediated synaptic transmission are monitored by concurrent electrophysiological recording and live cell imaging. This preparation also provides an informative approach to study the pre- and post-synaptic mechanisms of glutamatergic synaptic plasticity in vitro.

  19. Multidimensional signal processing for ultrasonic signal classification

    Science.gov (United States)

    Kim, J.; Ramuhalli, P.; Udpa, L.; Udpa, S.

    2001-04-01

    Neural network based signal classification systems are being used increasingly in the analysis of large volumes of data obtained in NDE applications. One example is in the interpretation on ultrasonic signals obtained from inspection of welds where signals can be due to porosity, slag, lack of fusion and cracks in the weld region. Standard techniques rely on differences in individual A-scans to classify the signals. This paper proposes an ultrasonic signal classification technique based on the information in a group of signals and examining the statistical characteristics of the signals. The method was 2-dimensional signal processing algorithms to analyze the information in B- and B'-scan images. In this paper, 2-dimensional transform based coefficients of the images are used as features and a multilayer perceptron is used to classify them. These results are then combined to get the final classification for the inspected region. Results of applying the technique to data obtained from the inspection of welds are presented.

  20. Dampened Mesolimbic Dopamine Function and Signaling by Saturated but not Monounsaturated Dietary Lipids.

    Science.gov (United States)

    Hryhorczuk, Cecile; Florea, Marc; Rodaros, Demetra; Poirier, Isabelle; Daneault, Caroline; Des Rosiers, Christine; Arvanitogiannis, Andreas; Alquier, Thierry; Fulton, Stephanie

    2016-02-01

    Overconsumption of dietary fat is increasingly linked with motivational and emotional impairments. Human and animal studies demonstrate associations between obesity and blunted reward function at the behavioral and neural level, but it is unclear to what degree such changes are a consequence of an obese state and whether they are contingent on dietary lipid class. We sought to determine the impact of prolonged ad libitum intake of diets rich in saturated or monounsaturated fat, separate from metabolic signals associated with increased adiposity, on dopamine (DA)-dependent behaviors and to identify pertinent signaling changes in the nucleus accumbens (NAc). Male rats fed a saturated (palm oil), but not an isocaloric monounsaturated (olive oil), high-fat diet exhibited decreased sensitivity to the rewarding (place preference) and locomotor-sensitizing effects of amphetamine as compared with low-fat diet controls. Blunted amphetamine action by saturated high-fat feeding was entirely independent of caloric intake, weight gain, and plasma levels of leptin, insulin, and glucose and was accompanied by biochemical and behavioral evidence of reduced D1R signaling in the NAc. Saturated high-fat feeding was also tied to protein markers of increased AMPA receptor-mediated plasticity and decreased DA transporter expression in the NAc but not to alterations in DA turnover and biosynthesis. Collectively, the results suggest that intake of saturated lipids can suppress DA signaling apart from increases in body weight and adiposity-related signals known to affect mesolimbic DA function, in part by diminishing D1 receptor signaling, and that equivalent intake of monounsaturated dietary fat protects against such changes.

  1. Cell signaling review series

    Institute of Scientific and Technical Information of China (English)

    Aiming Lin; Zhenggang Liu

    2008-01-01

    @@ Signal transduction is pivotal for many, if not all, fundamental cellular functions including proliferation, differentiation, transformation and programmed cell death. Deregulation of cell signaling may result in certain types of cancers and other human diseases.

  2. Retinoid signalling during embryogenesis

    NARCIS (Netherlands)

    Pijnappel, W.W.M.; Hendriks, H.F.J.; Durston, A.J.

    1996-01-01

    Conclusion: Retinoids are suspected to have multiple functions during embryogenesis, which are carried out via various different signal transduction pathways involving active retinoids and nuclear retinoid receptors. Research focuses on the identification of the retinoid signal transduction componen

  3. Biomedical signal processing

    CERN Document Server

    Akay, Metin

    1994-01-01

    Sophisticated techniques for signal processing are now available to the biomedical specialist! Written in an easy-to-read, straightforward style, Biomedical Signal Processing presents techniques to eliminate background noise, enhance signal detection, and analyze computer data, making results easy to comprehend and apply. In addition to examining techniques for electrical signal analysis, filtering, and transforms, the author supplies an extensive appendix with several computer programs that demonstrate techniques presented in the text.

  4. Danger signals in stroke.

    Science.gov (United States)

    Gelderblom, Mathias; Sobey, Christopher G; Kleinschnitz, Christoph; Magnus, Tim

    2015-11-01

    Danger molecules are the first signals released from dying tissue after stroke. These danger signals bind to receptors on immune cells that will result in their activation and the release of inflammatory and neurotoxic mediators, resulting in amplification of the immune response and subsequent enlargement of the damaged brain volume. The release of danger signals is a central event that leads to a multitude of signals and cascades in the affected and neighbouring tissue, therefore providing a potential target for therapy.

  5. Tetrapyrrole Signaling in Plants

    Science.gov (United States)

    Larkin, Robert M.

    2016-01-01

    Tetrapyrroles make critical contributions to a number of important processes in diverse organisms. In plants, tetrapyrroles are essential for light signaling, the detoxification of reactive oxygen species, the assimilation of nitrate and sulfate, respiration, photosynthesis, and programed cell death. The misregulation of tetrapyrrole metabolism can produce toxic reactive oxygen species. Thus, it is not surprising that tetrapyrrole metabolism is strictly regulated and that tetrapyrrole metabolism affects signaling mechanisms that regulate gene expression. In plants and algae, tetrapyrroles are synthesized in plastids and were some of the first plastid signals demonstrated to regulate nuclear gene expression. In plants, the mechanism of tetrapyrrole-dependent plastid-to-nucleus signaling remains poorly understood. Additionally, some of experiments that tested ideas for possible signaling mechanisms appeared to produce conflicting data. In some instances, these conflicts are potentially explained by different experimental conditions. Although the biological function of tetrapyrrole signaling is poorly understood, there is compelling evidence that this signaling is significant. Specifically, this signaling appears to affect the accumulation of starch and may promote abiotic stress tolerance. Tetrapyrrole-dependent plastid-to-nucleus signaling interacts with a distinct plastid-to-nucleus signaling mechanism that depends on GENOMES UNCUOPLED1 (GUN1). GUN1 contributes to a variety of processes, such as chloroplast biogenesis, the circadian rhythm, abiotic stress tolerance, and development. Thus, the contribution of tetrapyrrole signaling to plant function is potentially broader than we currently appreciate. In this review, I discuss these aspects of tetrapyrrole signaling.

  6. Acoustic Signals and Systems

    DEFF Research Database (Denmark)

    2008-01-01

    The Handbook of Signal Processing in Acoustics will compile the techniques and applications of signal processing as they are used in the many varied areas of Acoustics. The Handbook will emphasize the interdisciplinary nature of signal processing in acoustics. Each Section of the Handbook will pr...

  7. ACP with signals

    NARCIS (Netherlands)

    Bergstra, J.A.

    1988-01-01

    New operators are introduced on top of ACP [BK 84] in order to incorporate stable signals in process algebra. Semantically this involves assigning labels to nodes of process graphs. The labels of nodes are called signals. In combination with the operators of BPA, a signal insertion operator

  8. Optimal Signal Quality Index for Photoplethysmogram Signals

    Directory of Open Access Journals (Sweden)

    Mohamed Elgendi

    2016-09-01

    Full Text Available A photoplethysmogram (PPG is a noninvasive circulatory signal related to the pulsatile volume of blood in tissue and is typically collected by pulse oximeters. PPG signals collected via mobile devices are prone to artifacts that negatively impact measurement accuracy, which can lead to a significant number of misleading diagnoses. Given the rapidly increased use of mobile devices to collect PPG signals, developing an optimal signal quality index (SQI is essential to classify the signal quality from these devices. Eight SQIs were developed and tested based on: perfusion, kurtosis, skewness, relative power, non-stationarity, zero crossing, entropy, and the matching of systolic wave detectors. Two independent annotators annotated all PPG data (106 recordings, 60 s each and a third expert conducted the adjudication of differences. The independent annotators labeled each PPG signal with one of the following labels: excellent, acceptable or unfit for diagnosis. All indices were compared using Mahalanobis distance, linear discriminant analysis, quadratic discriminant analysis, and support vector machine with leave-one-out cross-validation. The skewness index outperformed the other seven indices in differentiating between excellent PPG and acceptable, acceptable combined with unfit, and unfit recordings, with overall F 1 scores of 86.0%, 87.2%, and 79.1%, respectively.

  9. S-(N, N-diethylcarbamoyl)glutathione (carbamathione), a disulfiram metabolite and its effect on nucleus accumbens and prefrontal cortex dopamine, GABA, and glutamate: A microdialysis study

    Science.gov (United States)

    Faiman, Morris D.; Kaul, Swetha; Latif, Shaheen A.; Williams, Todd D.; Lunte, Craig E.

    2015-01-01

    Disulfiram (DSF), used for the treatment of alcohol use disorders (AUDs) for over six decades, most recently has shown promise for treating cocaine dependence. Although DSF’s mechanism of action in alcohol abuse is due to the inhibition of liver mitochondrial aldehyde dehydrogenase (ALDH2), its mechanism of action in the treatment of cocaine dependence is unknown. DSF is a pro-drug, forming a number of metabolites each with discrete pharmacological actions. One metabolite formed during DSF bioactivation is S-(N, N-diethylcarbamoyl) glutathione (carbamathione) (carb). We previously showed that carb affects glutamate binding. In the present studies, we employed microdialysis techniques to investigate the effect of carb administration on dopamine (DA), GABA, and glutamate (Glu) in the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC), two brain regions implicated in substance abuse dependence. The effect of DSF on DA, GABA, and Glu in the NAc also was determined. Both studies were carried out in male rats. Carb (20, 50, 200 mg/kg i v) in a dose-dependent manner increased DA, decreased GABA, and had a biphasic effect on Glu, first increasing and then decreasing Glu in both the NAc and mPFC. These changes all occurred concurrently. After carb administration, NAc and mPFC carb, as well as carb in plasma, were rapidly eliminated with a half-life for each approximately 4 min, while the changes in DA, GABA, and GLu in the NAc and mPFC persisted for approximately two hours. The maximal increase in carb (Cmax) in the NAc and mPFC after carb administration was dose-dependent, as was the area under the curve (AUC). DSF (200 mg/kg i p) also increased DA, decreased GABA, and had a biphasic effect on Glu in the NAc similar to that observed in the NAc after carb administration. When the cytochrome P450 inhibitor N-benzylimidazole (NBI) (20 mg/kg i p) was administered before DSF dosing, no carb could be detected in the NAc and plasma and also no changes in NAc DA, GABA

  10. Deep brain stimulation of nucleus accumbens for refractory anorexia nervosa%脑深部电刺激治疗难治性神经性厌食症

    Institute of Scientific and Technical Information of China (English)

    孙伯民; 李殿友; 占世坤; 林国珍; 庞琦

    2012-01-01

    Objective To study the effect of deep brain stimulation (DBS) in bilateral nucleus accumbens (NAc) for patients with refractory anorexia nervosa.Methods Four patients with severe,refractory anorexia nervosa who failed to psychological,medical and behavior therapies underwent DBS of bilateral NAc.DBS electrodes were implanted by MRI guided stereotactic surgery.The body mass index (BMI) and other psychiatrist - rated scales such as Yale - Brown obsessive - compulsive rating scale (YBOCS) and Hamilton anxiety rating scale ( HAMA ) were performed as a double - blind clinical assessment before and after surgery by psychiatrists.Results All patients were followed - up from 9 to 50 months (mean 39 months).Compared with preoperative baseline condition (mean BMI =11.4),the score was gradually increased to normal ( BMI > 17.9) after stimulation for 3 - 12 months.Meanwhile,their eating behavior,OCD,anxiety symptoms were also improved slowly but steadily.The menstrual of all these patients recovered after stimulation of 3 - 12 months.The DBS devices of 2 patients were removed 30 months after the surgery because the battery were worn out and the effects were stable during the follow - up period.There was no severe side effect and complication in these patients.Conclusions NAc stimulation is very effective and safe for the treatment of refractory anorexia nervosa.It is a promising procedure to improve anorexia symptoms as well as its accompanied psychiatric symptoms.%目的 探讨脑深部电刺激(DBS)治疗难治性神经性厌食症.方法 4例经过心理及药物治疗无效的难治性神经性厌食症患者,接受磁共振导向立体定向双侧伏隔核DBS植入,术后给予持续慢性高频电刺激.采用身体质量指数(BMI)及其他精神科量表如Yale - Brown强迫症量表(YBOCS)、汉密尔顿焦虑量表(HAMA)评估DBS治疗难治性神经性厌食症的长期疗效.结果 所有患者随访9-50个月(平均39个月).经过3-12个月的慢性电

  11. Acoustic Signals and Systems

    DEFF Research Database (Denmark)

    2008-01-01

    The Handbook of Signal Processing in Acoustics will compile the techniques and applications of signal processing as they are used in the many varied areas of Acoustics. The Handbook will emphasize the interdisciplinary nature of signal processing in acoustics. Each Section of the Handbook...... will present topics on signal processing which are important in a specific area of acoustics. These will be of interest to specialists in these areas because they will be presented from their technical perspective, rather than a generic engineering approach to signal processing. Non-specialists, or specialists...

  12. Acoustic Signal Processing

    Science.gov (United States)

    Hartmann, William M.; Candy, James V.

    Signal processing refers to the acquisition, storage, display, and generation of signals - also to the extraction of information from signals and the re-encoding of information. As such, signal processing in some form is an essential element in the practice of all aspects of acoustics. Signal processing algorithms enable acousticians to separate signals from noise, to perform automatic speech recognition, or to compress information for more efficient storage or transmission. Signal processing concepts are the building blocks used to construct models of speech and hearing. Now, in the 21st century, all signal processing is effectively digital signal processing. Widespread access to high-speed processing, massive memory, and inexpensive software make signal processing procedures of enormous sophistication and power available to anyone who wants to use them. Because advanced signal processing is now accessible to everybody, there is a need for primers that introduce basic mathematical concepts that underlie the digital algorithms. The present handbook chapter is intended to serve such a purpose.

  13. Reliable Signal Transduction

    Science.gov (United States)

    Wollman, Roy

    Stochasticity inherent to biochemical reactions (intrinsic noise) and variability in cellular states (extrinsic noise) degrade information transmitted through signaling networks. We analyzed the ability of temporal signal modulation - that is dynamics - to reduce noise-induced information loss. In the extracellular signal-regulated kinase (ERK), calcium (Ca(2 +)) , and nuclear factor kappa-B (NF- κB) pathways, response dynamics resulted in significantly greater information transmission capacities compared to nondynamic responses. Theoretical analysis demonstrated that signaling dynamics has a key role in overcoming extrinsic noise. Experimental measurements of information transmission in the ERK network under varying signal-to-noise levels confirmed our predictions and showed that signaling dynamics mitigate, and can potentially eliminate, extrinsic noise-induced information loss. By curbing the information-degrading effects of cell-to-cell variability, dynamic responses substantially increase the accuracy of biochemical signaling networks.

  14. Second-hand signals

    DEFF Research Database (Denmark)

    Bergenholtz, Carsten

    2014-01-01

    Studies of signaling theory have traditionally focused on the dyadic link between the sender and receiver of the signal. Within a science‐based perspective this framing has led scholars to investigate how patents and publications of firms function as signals. I explore another important type...... of signal of firms, which is based on a formalized common practice of external, academic experts referring to firms in their peer reviewed publications. The findings provide qualitative evidence that helps explain why and how this new type of ‘second‐hand’ signal is created, validated and systematically...... used by various agents in their search for and assessment of products and firms. I conclude by arguing how this second‐hand nature of signals goes beyond a simple dyadic focus on senders and receivers of signals, and thus elucidates the more complex interrelations of the various types of agents...

  15. Altered neural reward and loss processing and prediction error signalling in depression.

    Science.gov (United States)

    Ubl, Bettina; Kuehner, Christine; Kirsch, Peter; Ruttorf, Michaela; Diener, Carsten; Flor, Herta

    2015-08-01

    Dysfunctional processing of reward and punishment may play an important role in depression. However, functional magnetic resonance imaging (fMRI) studies have shown heterogeneous results for reward processing in fronto-striatal regions. We examined neural responsivity associated with the processing of reward and loss during anticipation and receipt of incentives and related prediction error (PE) signalling in depressed individuals. Thirty medication-free depressed persons and 28 healthy controls performed an fMRI reward paradigm. Regions of interest analyses focused on neural responses during anticipation and receipt of gains and losses and related PE-signals. Additionally, we assessed the relationship between neural responsivity during gain/loss processing and hedonic capacity. When compared with healthy controls, depressed individuals showed reduced fronto-striatal activity during anticipation of gains and losses. The groups did not significantly differ in response to reward and loss outcomes. In depressed individuals, activity increases in the orbitofrontal cortex and nucleus accumbens during reward anticipation were associated with hedonic capacity. Depressed individuals showed an absence of reward-related PEs but encoded loss-related PEs in the ventral striatum. Depression seems to be linked to blunted responsivity in fronto-striatal regions associated with limited motivational responses for rewards and losses. Alterations in PE encoding might mirror blunted reward- and enhanced loss-related associative learning in depression. © The Author (2015). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

  16. Changes in the biogenic amine content of the prefrontal cortex, amygdala, dorsal hippocampus, and nucleus accumbens of rats submitted to single and repeated sessions of the elevated plus-maze test

    Directory of Open Access Journals (Sweden)

    Carvalho M.C.

    2005-01-01

    Full Text Available It has been demonstrated that exposure to a variety of stressful experiences enhances fearful reactions when behavior is tested in current animal models of anxiety. Until now, no study has examined the neurochemical changes during the test and retest sessions of rats submitted to the elevated plus maze (EPM. The present study uses a new approach (HPLC by looking at the changes in dopamine and serotonin levels in the prefrontal cortex, amygdala, dorsal hippocampus, and nucleus accumbens in animals upon single or double exposure to the EPM (one-trial tolerance. The study involved two experiments: i saline or midazolam (0.5 mg/kg before the first trial, and ii saline or midazolam before the second trial. For the biochemical analysis a control group injected with saline and not tested in the EPM was included. Stressful stimuli in the EPM were able to elicit one-trial tolerance to midazolam on re-exposure (61.01%. Significant decreases in serotonin contents occurred in the prefrontal cortex (38.74%, amygdala (78.96%, dorsal hippocampus (70.33%, and nucleus accumbens (73.58% of the animals tested in the EPM (P < 0.05 in all cases in relation to controls not exposed to the EPM. A significant decrease in dopamine content was also observed in the amygdala (54.74%, P < 0.05. These changes were maintained across trials. There was no change in the turnover rates of these monoamines. We suggest that exposure to the EPM causes reduced monoaminergic neurotransmission activity in limbic structures, which appears to underlie the "one-trial tolerance" phenomenon.

  17. Quantitation of signal transduction.

    Science.gov (United States)

    Krauss, S; Brand, M D

    2000-12-01

    Conventional qualitative approaches to signal transduction provide powerful ways to explore the architecture and function of signaling pathways. However, at the level of the complete system, they do not fully depict the interactions between signaling and metabolic pathways and fail to give a manageable overview of the complexity that is often a feature of cellular signal transduction. Here, we introduce a quantitative experimental approach to signal transduction that helps to overcome these difficulties. We present a quantitative analysis of signal transduction during early mitogen stimulation of lymphocytes, with steady-state respiration rate as a convenient marker of metabolic stimulation. First, by inhibiting various key signaling pathways, we measure their relative importance in regulating respiration. About 80% of the input signal is conveyed via identifiable routes: 50% through pathways sensitive to inhibitors of protein kinase C and MAP kinase and 30% through pathways sensitive to an inhibitor of calcineurin. Second, we quantify how each of these pathways differentially stimulates functional units of reactions that produce and consume a key intermediate in respiration: the mitochondrial membrane potential. Both the PKC and calcineurin routes stimulate consumption more strongly than production, whereas the unidentified signaling routes stimulate production more than consumption, leading to no change in membrane potential despite increased respiration rate. The approach allows a quantitative description of the relative importance of signal transduction pathways and the routes by which they activate a specific cellular process. It should be widely applicable.

  18. Signaling in the Rhizosphere.

    Science.gov (United States)

    Venturi, Vittorio; Keel, Christoph

    2016-03-01

    Signaling studies in the rhizosphere have focused on close interactions between plants and symbiotic microorganisms. However, this focus is likely to expand to other microorganisms because the rhizomicrobiome is important for plant health and is able to influence the structure of the microbial community. We discuss here the shaping of the rhizomicrobiome and define which aspects can be considered signaling. We divide signaling in the rhizosphere into three categories: (i) between microbes, (ii) from plants to microorganisms, and (iii) from microorganisms to plants. Signals act on diverse organisms including the plant. Mycorrhizal and rhizobial interkingdom signaling has revealed its pivotal role in establishing associations, and the recent discovery of signaling with non-symbiotic microorganisms indicates the important role of communication in shaping the rhizomicrobiome. Copyright © 2016 Elsevier Ltd. All rights reserved.

  19. Biomedical signals and systems

    CERN Document Server

    Tranquillo, Joseph V

    2013-01-01

    Biomedical Signals and Systems is meant to accompany a one-semester undergraduate signals and systems course. It may also serve as a quick-start for graduate students or faculty interested in how signals and systems techniques can be applied to living systems. The biological nature of the examples allows for systems thinking to be applied to electrical, mechanical, fluid, chemical, thermal and even optical systems. Each chapter focuses on a topic from classic signals and systems theory: System block diagrams, mathematical models, transforms, stability, feedback, system response, control, time

  20. Digital signal processing

    CERN Document Server

    O'Shea, Peter; Hussain, Zahir M

    2011-01-01

    In three parts, this book contributes to the advancement of engineering education and that serves as a general reference on digital signal processing. Part I presents the basics of analog and digital signals and systems in the time and frequency domain. It covers the core topics: convolution, transforms, filters, and random signal analysis. It also treats important applications including signal detection in noise, radar range estimation for airborne targets, binary communication systems, channel estimation, banking and financial applications, and audio effects production. Part II considers sel

  1. Geolocation of RF signals

    CERN Document Server

    Progri, Ilir

    2011-01-01

    ""Geolocation of RF Signals - Principles and Simulations"" offers an overview of the best practices and innovative techniques in the art and science of geolocation over the last twenty years. It covers all research and development aspects including theoretical analysis, RF signals, geolocation techniques, key block diagrams, and practical principle simulation examples in the frequency band from 100 MHz to 18 GHz or even 60 GHz. Starting with RF signals, the book progressively examines various signal bands - such as VLF, LF, MF, HF, VHF, UHF, L, S, C, X, Ku, and, K and the corresponding geoloca

  2. Slit-Robo signaling.

    Science.gov (United States)

    Blockus, Heike; Chédotal, Alain

    2016-09-01

    Slits are secreted proteins that bind to Roundabout (Robo) receptors. Slit-Robo signaling is best known for mediating axon repulsion in the developing nervous system. However, in recent years the functional repertoire of Slits and Robo has expanded tremendously and Slit-Robo signaling has been linked to roles in neurogenesis, angiogenesis and cancer progression among other processes. Likewise, our mechanistic understanding of Slit-Robo signaling has progressed enormously. Here, we summarize new insights into Slit-Robo evolutionary and system-dependent diversity, receptor-ligand interactions, signaling crosstalk and receptor activation.

  3. Brain-derived Neurotrophic Factor (BDNF)-TrkB Signaling in Inflammation-related Depression and Potential Therapeutic Targets.

    Science.gov (United States)

    Zhang, Ji-Chun; Yao, Wei; Hashimoto, Kenji

    2016-01-01

    Depression is the most prevalent and among the most debilitating of psychiatric disorders. The precise neurobiology of this illness is unknown. Several lines of evidence suggest that peripheral and central inflammation plays a role in depressive symptoms, and that anti-inflammatory drugs can improve depressive symptoms in patients with inflammation-related depression. Signaling via brain-derived neurotrophic factor (BDNF) and its receptor, tropomycin receptor kinase B (TrkB) plays a key role in the pathophysiology of depression and in the therapeutic mechanisms of antidepressants. A recent paper showed that lipopolysaccharide (LPS)-induced inflammation gave rise to depression-like phenotype by altering BDNF-TrkB signaling in the prefrontal cortex, hippocampus, and nucleus accumbens, areas thought to be involved in the antidepressant effects of TrkB agonist, 7,8-dihydroxyflavone (7,8-DHF) and TrkB antagonist, ANA-12. Here we provide an overview of the tryptophan-kynurenine pathway and BDNF-TrkB signaling in the pathophysiology of inflammation-induced depression, and propose mechanistic actions for potential therapeutic agents. Additionally, the authors discuss the putative role of TrkB agonists and antagonists as novel therapeutic drugs for inflammation-related depression.

  4. A New Insight into the Role of CART in Cocaine Reward: Involvement of CaMKII and Inhibitory G-Protein Coupled Receptor Signaling

    Directory of Open Access Journals (Sweden)

    ChengPeng Yu

    2017-08-01

    Full Text Available Cocaine- and amphetamine-regulated transcript (CART peptides are neuropeptides that are expressed in brain regions associated with reward, such as the nucleus accumbens (NAc, and play a role in cocaine reward. Injection of CART into the NAc can inhibit the behavioral effects of cocaine, and injecting CART into the ventral tegmental area (VTA reduces cocaine-seeking behavior. However, the exact mechanism of these effects is not clear. Recent research has demonstrated that Ca2+/calmodulin-dependent protein kinase II (CaMKII and inhibitory G-protein coupled receptor (GPCR signaling are involved in the mechanism of the effect of CART on cocaine reward. Hence, we review the role of CaMKII and inhibitory GPCR signaling in the effect of CART on cocaine reward and provide a new insight into the mechanism of that effect. In this article, we will first review the biological function of CART and discuss the role of CART in cocaine reward. Then, we will focus on the role of CaMKII and inhibitory GPCR signaling in cocaine reward. Furthermore, we will discuss how CaMKII and inhibitory GPCR signaling are involved in the mechanistic action of CART in cocaine reward. Finally, we will provide our opinions regarding the future directions of research on the role of CaMKII and inhibitory GPCR signaling in the effect of CART on cocaine reward.

  5. Signal sampling circuit

    NARCIS (Netherlands)

    Louwsma, S.M.; Vertregt, Maarten

    2010-01-01

    A sampling circuit for sampling a signal is disclosed. The sampling circuit comprises a plurality of sampling channels adapted to sample the signal in time-multiplexed fashion, each sampling channel comprising a respective track-and-hold circuit connected to a respective analogue to digital converte

  6. Signal sampling circuit

    NARCIS (Netherlands)

    Louwsma, S.M.; Vertregt, Maarten

    2011-01-01

    A sampling circuit for sampling a signal is disclosed. The sampling circuit comprises a plurality of sampling channels adapted to sample the signal in time-multiplexed fashion, each sampling channel comprising a respective track-and-hold circuit connected to a respective analogue to digital converte

  7. Signaling by Gasotransmitters

    OpenAIRE

    Mustafa, Asif K.; Gadalla, Moataz M.; Snyder, Solomon H

    2009-01-01

    Nitric oxide is well established as a major signaling molecule. Evidence is accumulating that carbon monoxide and hydrogen sulfide also are physiologic mediators in the cardiovascular, immune, and nervous systems. This Review focuses on mechanisms whereby they signal by binding to metal centers in metalloproteins, such as in guanylyl cyclase, or modifying sulfhydryl groups in protein targets.

  8. Ubiquitination in apoptosis signaling

    NARCIS (Netherlands)

    van de Kooij, L.W.

    2014-01-01

    The work described in this thesis focuses on ubiquitination and protein degradation, with an emphasis on how these processes regulate apoptosis signaling. More specifically, our aims were: 1. To increase the understanding of ubiquitin-mediated regulation of apoptosis signaling. 2. To identify the E3

  9. Multiresolution signal decomposition schemes

    NARCIS (Netherlands)

    J. Goutsias (John); H.J.A.M. Heijmans (Henk)

    1998-01-01

    textabstract[PNA-R9810] Interest in multiresolution techniques for signal processing and analysis is increasing steadily. An important instance of such a technique is the so-called pyramid decomposition scheme. This report proposes a general axiomatic pyramid decomposition scheme for signal analysis

  10. Multiresolution signal decomposition schemes

    NARCIS (Netherlands)

    Goutsias, J.; Heijmans, H.J.A.M.

    1998-01-01

    [PNA-R9810] Interest in multiresolution techniques for signal processing and analysis is increasing steadily. An important instance of such a technique is the so-called pyramid decomposition scheme. This report proposes a general axiomatic pyramid decomposition scheme for signal analysis and synthes

  11. SignalR blueprints

    CERN Document Server

    Ingebrigtsen, Einar

    2015-01-01

    This book is designed for software developers, primarily those with knowledge of C#, .NET, and JavaScript. Good knowledge and understanding of SignalR is assumed to allow efficient programming of core elements and applications in SignalR.

  12. MBA Quality Signals.

    Science.gov (United States)

    Chapman, Randall S.

    1998-01-01

    A study identified quality signals for master's programs in business administration (MBAs). Traditional scholarly oriented academic signals are apparently not valued as such by external customer groups. MBA academic quality appears to be a multidimensional construct, with subdimensions of real-worldness; placement; student satisfaction; and…

  13. Ubiquitination in apoptosis signaling

    NARCIS (Netherlands)

    van de Kooij, L.W.

    2014-01-01

    The work described in this thesis focuses on ubiquitination and protein degradation, with an emphasis on how these processes regulate apoptosis signaling. More specifically, our aims were: 1. To increase the understanding of ubiquitin-mediated regulation of apoptosis signaling. 2. To identify the E3

  14. Signaling in symbiosis

    NARCIS (Netherlands)

    Limpens, E.H.M.; Bisseling, T.

    2003-01-01

    In recent years, the major focus in nodulation research has been on the genetic dissection of Nod-factor signaling. Components of this pathway appear to be shared with signaling processes that are induced during the formation of mycorrhiza. With the cloning of orthologs of the NIN and DMI2 genes

  15. Signaling in symbiosis

    NARCIS (Netherlands)

    Limpens, E.H.M.; Bisseling, T.

    2003-01-01

    In recent years, the major focus in nodulation research has been on the genetic dissection of Nod-factor signaling. Components of this pathway appear to be shared with signaling processes that are induced during the formation of mycorrhiza. With the cloning of orthologs of the NIN and DMI2 genes fro

  16. Signal sampling circuit

    NARCIS (Netherlands)

    Louwsma, Simon Minze; Vertregt, Maarten

    2011-01-01

    A sampling circuit for sampling a signal is disclosed. The sampling circuit comprises a plurality of sampling channels adapted to sample the signal in time-multiplexed fashion, each sampling channel comprising a respective track-and-hold circuit connected to a respective analogue to digital converte

  17. Signal sampling circuit

    NARCIS (Netherlands)

    Louwsma, Simon Minze; Vertregt, Maarten

    2010-01-01

    A sampling circuit for sampling a signal is disclosed. The sampling circuit comprises a plurality of sampling channels adapted to sample the signal in time-multiplexed fashion, each sampling channel comprising a respective track-and-hold circuit connected to a respective analogue to digital converte

  18. Calcium signaling and epilepsy.

    Science.gov (United States)

    Steinlein, Ortrud K

    2014-08-01

    Calcium signaling is involved in a multitude of physiological and pathophysiological mechanisms. Over the last decade, it has been increasingly recognized as an important factor in epileptogenesis, and it is becoming obvious that the excess synchronization of neurons that is characteristic for seizures can be linked to various calcium signaling pathways. These include immediate effects on membrane excitability by calcium influx through ion channels as well as delayed mechanisms that act through G-protein coupled pathways. Calcium signaling is able to cause hyperexcitability either by direct modulation of neuronal activity or indirectly through calcium-dependent gliotransmission. Furthermore, feedback mechanisms between mitochondrial calcium signaling and reactive oxygen species are able to cause neuronal cell death and seizures. Unravelling the complexity of calcium signaling in epileptogenesis is a daunting task, but it includes the promise to uncover formerly unknown targets for the development of new antiepileptic drugs.

  19. Molecular and Cellular Signaling

    CERN Document Server

    Beckerman, Martin

    2005-01-01

    A small number of signaling pathways, no more than a dozen or so, form a control layer that is responsible for all signaling in and between cells of the human body. The signaling proteins belonging to the control layer determine what kinds of cells are made during development and how they function during adult life. Malfunctions in the proteins belonging to the control layer are responsible for a host of human diseases ranging from neurological disorders to cancers. Most drugs target components in the control layer, and difficulties in drug design are intimately related to the architecture of the control layer. Molecular and Cellular Signaling provides an introduction to molecular and cellular signaling in biological systems with an emphasis on the underlying physical principles. The text is aimed at upper-level undergraduates, graduate students and individuals in medicine and pharmacology interested in broadening their understanding of how cells regulate and coordinate their core activities and how diseases ...

  20. Neutron signal transfer analysis

    CERN Document Server

    Pleinert, H; Lehmann, E

    1999-01-01

    A new method called neutron signal transfer analysis has been developed for quantitative determination of hydrogenous distributions from neutron radiographic measurements. The technique is based on a model which describes the detector signal obtained in the measurement as a result of the action of three different mechanisms expressed by signal transfer functions. The explicit forms of the signal transfer functions are determined by Monte Carlo computer simulations and contain only the distribution as a variable. Therefore an unknown distribution can be determined from the detector signal by recursive iteration. This technique provides a simple and efficient tool for analysis of this type while also taking into account complex effects due to the energy dependency of neutron interaction and single and multiple scattering. Therefore this method provides an efficient tool for precise quantitative analysis using neutron radiography, as for example quantitative determination of moisture distributions in porous buil...

  1. Electrical signaling and photosynthesis

    Science.gov (United States)

    Mancuso, Stefano

    2011-01-01

    Mechanical irritation of trigger hairs and subsequent generation of action potentials have significant impact on photosynthesis and respiration in carnivorous Venus flytrap (Dionaea muscipula). Action potential-mediated inhibition of photosynthesis and stimulation of respiration is confined only to the trap and was not recorded in adjacent photosynthetic lamina. We showed that the main primary target of electrical signals on assimilation is in the dark enzymatic reaction of photosynthesis. Without doubt, the electrical signaling is costly, and the possible co-existence of such type of signals and photosynthesis in plant cell is discussed. PMID:21558815

  2. Signal flow analysis

    CERN Document Server

    Abrahams, J R; Hiller, N

    1965-01-01

    Signal Flow Analysis provides information pertinent to the fundamental aspects of signal flow analysis. This book discusses the basic theory of signal flow graphs and shows their relation to the usual algebraic equations.Organized into seven chapters, this book begins with an overview of properties of a flow graph. This text then demonstrates how flow graphs can be applied to a wide range of electrical circuits that do not involve amplification. Other chapters deal with the parameters as well as circuit applications of transistors. This book discusses as well the variety of circuits using ther

  3. Signal Station Inspection Reports

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — Handwritten reports resulting from detailed inspections of US Army Signal Service Stations, 1871-1889. Features reported included instrument exposure and condition,...

  4. Lipid signaling in plants

    NARCIS (Netherlands)

    Munnik, T.

    2010-01-01

    This book highlights the current status of plant lipid signaling. Written by leading researchers in the field, the chapters include detailed information on the measurement, regulation and function of phospholipases, lipid kinases, lipid phosphatases, inositolpolyphosphates, polyphosphoinositides, ph

  5. Ultrahigh bandwidth signal processing

    DEFF Research Database (Denmark)

    Oxenløwe, Leif Katsuo

    2016-01-01

    Optical time lenses have proven to be very versatile for advanced optical signal processing. Based on a controlled interplay between dispersion and phase-modulation by e.g. four-wave mixing, the processing is phase-preserving, an hence useful for all types of data signals including coherent multi......-level modulation founats. This has enabled processing of phase-modulated spectrally efficient data signals, such as orthogonal frequency division multiplexed (OFDM) signa In that case, a spectral telescope system was used, using two time lenses with different focal lengths (chirp rates), yielding a spectral...... regeneratio These operations require a broad bandwidth nonlinear platform, and novel photonic integrated nonlinear platform like aluminum gallium arsenide nano-waveguides used for 1.28 Tbaud optical signal processing will be described....

  6. Transmembrane Signalling: Membrane messengers

    Science.gov (United States)

    Cockroft, Scott L.

    2017-05-01

    Life has evolved elaborate means of communicating essential chemical information across cell membranes. Inspired by biology, two new artificial mechanisms have now been developed that use synthetic messenger molecules to relay chemical signals into or across lipid membranes.

  7. Acoustic MIMO signal processing

    CERN Document Server

    Huang, Yiteng; Chen, Jingdong

    2006-01-01

    A timely and important book addressing a variety of acoustic signal processing problems under multiple-input multiple-output (MIMO) scenarios. It uniquely investigates these problems within a unified framework offering a novel and penetrating analysis.

  8. Signaling in muscle contraction.

    Science.gov (United States)

    Kuo, Ivana Y; Ehrlich, Barbara E

    2015-02-02

    Signaling pathways regulate contraction of striated (skeletal and cardiac) and smooth muscle. Although these are similar, there are striking differences in the pathways that can be attributed to the distinct functional roles of the different muscle types. Muscles contract in response to depolarization, activation of G-protein-coupled receptors and other stimuli. The actomyosin fibers responsible for contraction require an increase in the cytosolic levels of calcium, which signaling pathways induce by promoting influx from extracellular sources or release from intracellular stores. Rises in cytosolic calcium stimulate numerous downstream calcium-dependent signaling pathways, which can also regulate contraction. Alterations to the signaling pathways that initiate and sustain contraction and relaxation occur as a consequence of exercise and pathophysiological conditions.

  9. Signals from the Cosmos.

    Science.gov (United States)

    Lichtman, Jeffrey M.

    1991-01-01

    Introduces the basics of radio astronomy and describes how to assemble several simple systems for receiving radio signals from the cosmos. Includes schematics, parts lists, working drawings, and contact information for radio astronomy suppliers. (11 references) (Author/JJK)

  10. Plant lipid signaling protocols

    NARCIS (Netherlands)

    Munnik, T.; Heilmann, I.

    2013-01-01

    Eukaryotic cells are surrounded by membranes consisting of various lipids, including sterols, sphingolipids, glycolipids, and phospholipids. Besides structural functions, membranes also contain lipids with regulatory and signaling roles. Such lipids include polyphosphoinositides, the low-abundant

  11. Topological signal processing

    CERN Document Server

    Robinson, Michael

    2014-01-01

    Signal processing is the discipline of extracting information from collections of measurements. To be effective, the measurements must be organized and then filtered, detected, or transformed to expose the desired information.  Distortions caused by uncertainty, noise, and clutter degrade the performance of practical signal processing systems. In aggressively uncertain situations, the full truth about an underlying signal cannot be known.  This book develops the theory and practice of signal processing systems for these situations that extract useful, qualitative information using the mathematics of topology -- the study of spaces under continuous transformations.  Since the collection of continuous transformations is large and varied, tools which are topologically-motivated are automatically insensitive to substantial distortion. The target audience comprises practitioners as well as researchers, but the book may also be beneficial for graduate students.

  12. Digital signal processing: Handbook

    Science.gov (United States)

    Goldenberg, L. M.; Matiushkin, B. D.; Poliak, M. N.

    The fundamentals of the theory and design of systems and devices for the digital processing of signals are presented. Particular attention is given to algorithmic methods of synthesis and digital processing equipment in communication systems (e.g., selective digital filtering, spectral analysis, and variation of the signal discretization frequency). Programs for the computer-aided analysis of digital filters are described. Computational examples are presented, along with tables of transfer function coefficients for recursive and nonrecursive digital filters.

  13. Nuclear localization signal in a cancer-related transcriptional regulator protein NAC1.

    Science.gov (United States)

    Okazaki, Kosuke; Nakayama, Naomi; Nariai, Yuko; Nakayama, Kentaro; Miyazaki, Kohji; Maruyama, Riruke; Kato, Hiroaki; Kosugi, Shunichi; Urano, Takeshi; Sakashita, Gyosuke

    2012-10-01

    Nucleus accumbens-associated protein 1 (NAC1) might have potential oncogenic properties and participate in regulatory networks for pluripotency. Although NAC1 is described as a transcriptional regulator, the nuclear import machinery of NAC1 remains unclear. We found, using a point mutant, that dimer formation was not committed to the nuclear localization of NAC1 and, using deletion mutants, that the amino-terminal half of NAC1 harbored a potential nuclear localization signal (NLS). Wild type, but not mutants of this region, alone was sufficient to drive the importation of green fluorescent protein (GFP) into the nucleus. Bimax1, a synthetic peptide that blocks the importin α/β pathway, impaired nuclear localization of NAC1 in cells. We also used the binding properties of importin to demonstrate that this region is an NLS. Furthermore, the transcriptional regulator function of NAC1 was dependent on its nuclear localization activity in cells. Taken together, these results show that the region with a bipartite motif constitutes a functional nuclear import sequence in NAC1 that is independent of NAC1 dimer formation. The identification of an NAC1 NLS thus clarifies the mechanism through which NAC1 translocates to the nucleus to regulate the transcription of genes involved in oncogenicity and pluripotency.

  14. Association between regulator of G protein signaling 9-2 and body weight.

    Directory of Open Access Journals (Sweden)

    Jeffrey L Waugh

    Full Text Available Regulator of G protein signaling 9-2 (RGS9-2 is a protein that is highly enriched in the striatum, a brain region that mediates motivation, movement and reward responses. We identified a naturally occurring 5 nucleotide deletion polymorphism in the human RGS9 gene and found that the mean body mass index (BMI of individuals with the deletion was significantly higher than those without. A splicing reporter minigene assay demonstrated that the deletion had the potential to significantly decrease the levels of correctly spliced RGS9 gene product. We measured the weights of rats after virally transduced overexpression of RGS9-2 or the structurally related RGS proteins, RGS7, or RGS11, in the nucleus accumbens (NAc and observed a reduction in body weight after overexpression of RGS9-2 but not RGS7 or 11. Conversely, we found that the RGS9 knockout mice were heavier than their wild-type littermates and had significantly higher percentages of abdominal fat. The constituent adipocytes were found to have a mean cross-sectional area that was more than double that of corresponding cells from wild-type mice. However, food intake and locomotion were not significantly different between the two strains. These studies with humans, rats and mice implicate RGS9-2 as a factor in regulating body weight.

  15. Reward devaluation and heroin escalation is associated with differential expression of CRF signaling genes.

    Science.gov (United States)

    McFalls, Ashley J; Imperio, Caesar G; Bixler, Georgina; Freeman, Willard M; Grigson, Patricia Sue; Vrana, Kent E

    2016-05-01

    One of the most damaging aspects of drug addiction is the degree to which natural rewards (family, friends, employment) are devalued in favor of seeking, obtaining and taking drugs. We have utilized an animal model of reward devaluation and heroin self-administration to explore the role of the coricotropin releasing factor (CRF) pathway. Given access to a saccharin cue followed by the opportunity to self-administer heroin, animals will parse into distinct phenotypes that suppress their saccharin intake (in favor of escalating heroin self-administration) or vice versa. We find that large saccharin suppressors (large heroin takers) demonstrate increased mRNA expression for elements of the CRF signaling pathway (CRF, CRF receptors and CRF binding protein) within the hippocampus, medial prefrontal cortex and the ventral tegmental area. Moreover, there were no gene expression changes of these components in the nucleus accumbens. Use of bisulfite conversion sequencing suggests that changes in CRF binding protein and CRF receptor gene expression may be mediated by differential promoter methylation.

  16. Signaling Over Distances.

    Science.gov (United States)

    Saito, Atsushi; Cavalli, Valeria

    2016-02-01

    Neurons are extremely polarized cells. Axon lengths often exceed the dimension of the neuronal cell body by several orders of magnitude. These extreme axonal lengths imply that neurons have mastered efficient mechanisms for long distance signaling between soma and synaptic terminal. These elaborate mechanisms are required for neuronal development and maintenance of the nervous system. Neurons can fine-tune long distance signaling through calcium wave propagation and bidirectional transport of proteins, vesicles, and mRNAs along microtubules. The signal transmission over extreme lengths also ensures that information about axon injury is communicated to the soma and allows for repair mechanisms to be engaged. This review focuses on the different mechanisms employed by neurons to signal over long axonal distances and how signals are interpreted in the soma, with an emphasis on proteomic studies. We also discuss how proteomic approaches could help further deciphering the signaling mechanisms operating over long distance in axons. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  17. Ultrahigh bandwidth signal processing

    Science.gov (United States)

    Oxenløwe, Leif Katsuo

    2016-04-01

    Optical time lenses have proven to be very versatile for advanced optical signal processing. Based on a controlled interplay between dispersion and phase-modulation by e.g. four-wave mixing, the processing is phase-preserving, and hence useful for all types of data signals including coherent multi-level modulation formats. This has enabled processing of phase-modulated spectrally efficient data signals, such as orthogonal frequency division multiplexed (OFDM) signals. In that case, a spectral telescope system was used, using two time lenses with different focal lengths (chirp rates), yielding a spectral magnification of the OFDM signal. Utilising such telescopic arrangements, it has become possible to perform a number of interesting functionalities, which will be described in the presentation. This includes conversion from OFDM to Nyquist WDM, compression of WDM channels to a single Nyquist channel and WDM regeneration. These operations require a broad bandwidth nonlinear platform, and novel photonic integrated nonlinear platforms like aluminum gallium arsenide nano-waveguides used for 1.28 Tbaud optical signal processing will be described.

  18. 伏隔核微注射orexin-A对大鼠摄食和活动的影响%The Effect of Orexin-A on Feeding and Locomotor Activity in the Accumbens

    Institute of Scientific and Technical Information of China (English)

    张丽娜; 冯彩华; 柴薪; 王丛丛; 董海龙

    2012-01-01

    目的:探讨伏隔核微注射orexin-A后,大鼠摄食和活动的变化.方法:采用SD大鼠(250-280g),用脑立体定位仪在伏隔核植入微量注射管.大鼠随机分组,分别微注射乳酸格林液( Ringer's),orexin-A 100pmol和500pmol.观察微注射后大鼠0-1h,1-2h,2-4h撮食和0-30min,30-60min,60-90min,90-120min活动性变化.结果:Orexin-A微注射后,大鼠0-1h,1-2h摄食量增加;30-60min,60-90min,90-120min的活动性显著增加(P<0.05 vs对照组).结论:伏隔核是orexin-A刺激大鼠增加摄食量,提高其活动性的作用点.%Objective: To investigate the effect of orexin-A on feeding and locomotor activity in the accumbens shell (Accsh). Methods: SD rats (250-280) were used and implanted a guide cannulae into the accumbens