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Sample records for accumbens dopamine release

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

    Science.gov (United States)

    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.

  2. 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...

  3. 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.

  4. Differential Dopamine Release Dynamics in the Nucleus Accumbens Core and Shell Reveal Complementary Signals for Error Prediction and Incentive Motivation

    Science.gov (United States)

    Cacciapaglia, Fabio; Wightman, R. Mark; Carelli, Regina M.

    2015-01-01

    Mesolimbic dopamine (DA) is phasically released during appetitive behaviors, though there is substantive disagreement about the specific purpose of these DA signals. For example, prediction error (PE) models suggest a role of learning, while incentive salience (IS) models argue that the DA signal imbues stimuli with value and thereby stimulates motivated behavior. However, within the nucleus accumbens (NAc) patterns of DA release can strikingly differ between subregions, and as such, it is possible that these patterns differentially contribute to aspects of PE and IS. To assess this, we measured DA release in subregions of the NAc during a behavioral task that spatiotemporally separated sequential goal-directed stimuli. Electrochemical methods were used to measure subsecond NAc dopamine release in the core and shell during a well learned instrumental chain schedule in which rats were trained to press one lever (seeking; SL) to gain access to a second lever (taking; TL) linked with food delivery, and again during extinction. In the core, phasic DA release was greatest following initial SL presentation, but minimal for the subsequent TL and reward events. In contrast, phasic shell DA showed robust release at all task events. Signaling decreased between the beginning and end of sessions in the shell, but not core. During extinction, peak DA release in the core showed a graded decrease for the SL and pauses in release during omitted expected rewards, whereas shell DA release decreased predominantly during the TL. These release dynamics suggest parallel DA signals capable of supporting distinct theories of appetitive behavior. SIGNIFICANCE STATEMENT Dopamine signaling in the brain is important for a variety of cognitive functions, such as learning and motivation. Typically, it is assumed that a single dopamine signal is sufficient to support these cognitive functions, though competing theories disagree on how dopamine contributes to reward-based behaviors. Here, we have

  5. 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

  6. 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'.

  7. 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.

  8. 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

  9. Sensitized nucleus accumbens dopamine terminal responses to methylphenidate and dopamine transporter releasers after intermittent-access self-administration.

    Science.gov (United States)

    Calipari, Erin S; Jones, Sara R

    2014-07-01

    Long-access methylphenidate (MPH) self-administration has been shown to produce enhanced amphetamine potency at the dopamine transporter and concomitant changes in reinforcing efficacy, suggesting that MPH abuse may change the dopamine system in a way that promotes future drug abuse. While long-access self-administration paradigms have translational validity for cocaine, it may not be as relevant a model of MPH abuse, as it has been suggested that people often take MPH intermittently. Although previous work outlined the neurochemical and behavioral consequences of long-access MPH self-administration, it was not clear whether intermittent access (6 h session; 5 min access/30 min) would result in similar changes. For cocaine, long-access self-administration resulted in tolerance to cocaine's effects on dopamine and behavior while intermittent-access resulted in sensitization. Here we assessed the neurochemical consequences of intermittent-access MPH self-administration on dopamine terminal function. We found increased maximal rates of uptake, increased stimulated release, and subsensitive D2-like autoreceptors. Consistent with previous work using extended-access MPH paradigms, the potencies of amphetamine and MPH, but not cocaine, were increased, demonstrating that unlike cocaine, MPH effects were not altered by the pattern of intake. Although the potency results suggest that MPH may share properties with releasers, dopamine release was increased following acute application of MPH, similar to cocaine, and in contrast to the release decreasing effects of amphetamine. Taken together, these data demonstrate that MPH exhibits properties of both blockers and releasers, and that the compensatory changes produced by MPH self-administration may increase the abuse liability of amphetamines, independent of the pattern of administration.

  10. 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.

  11. 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.

  12. Dopamine and serotonin uptake inhibitors on the release of dopamine and serotonin in the nucleus accumbens of young and aged rats.

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    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.

  13. 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.

  14. 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.

  15. 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

  16. 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

  17. 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.

  18. 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.

  19. 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.

  20. 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

  1. Actions of dopamine antagonists on stimulated striatal and limbic dopamine release: an in vivo voltammetric study.

    OpenAIRE

    Stamford, J. A.; Kruk, Z L; Millar, J.

    1988-01-01

    1. Fast cyclic voltammetry at carbon fibre microelectrodes was used to study the effects of several dopamine antagonists upon stimulated dopamine release in the rat striatum and nucleus accumbens. 2. In both nuclei, stimulated dopamine release was increased by D2-receptor-selective and mixed D1/D2-receptor antagonists. The D1-selective antagonist SCH 23390 had no effect. 3. Striatal and limbic dopamine release were elevated by cis- but not trans-flupenthixol. 4. The 'atypical' neuroleptics (c...

  2. 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.

  3. The dopamine beta-hydroxylase inhibitor nepicastat increases dopamine release and potentiates psychostimulant-induced dopamine release in the prefrontal cortex.

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    Devoto, Paola; Flore, Giovanna; Saba, Pierluigi; Bini, Valentina; Gessa, Gian Luigi

    2014-07-01

    The dopamine-beta-hydroxylase inhibitor nepicastat has been shown to reproduce disulfiram ability to suppress the reinstatement of cocaine seeking after extinction in rats. To clarify its mechanism of action, we examined the effect of nepicastat, given alone or in association with cocaine or amphetamine, on catecholamine release in the medial prefrontal cortex and the nucleus accumbens, two key regions involved in the reinforcing and motivational effects of cocaine and in the reinstatement of cocaine seeking. Nepicastat effect on catecholamines was evaluated by microdialysis in freely moving rats. Nepicastat reduced noradrenaline release both in the medial prefrontal cortex and in the nucleus accumbens, and increased dopamine release in the medial prefrontal cortex but not in the nucleus accumbens. Moreover, nepicastat markedly potentiated cocaine- and amphetamine-induced extracellular dopamine accumulation in the medial prefrontal cortex but not in the nucleus accumbens. Extracellular dopamine accumulation produced by nepicastat alone or by its combination with cocaine or amphetamine was suppressed by the α2 -adrenoceptor agonist clonidine. It is suggested that nepicastat, by suppressing noradrenaline synthesis and release, eliminated the α2 -adrenoceptor mediated inhibitory mechanism that constrains dopamine release and cocaine- and amphetamine-induced dopamine release from noradrenaline or dopamine terminals in the medial prefrontal cortex.

  4. 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

  5. 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.

  6. Excitatory amino acid receptors in the ventral tegmental area regulate dopamine release in the ventral striatum

    NARCIS (Netherlands)

    Karreman, M; Westerink, BHC; Moghaddam, B

    1996-01-01

    The role of excitatory amino acid (EAA) receptors located in the ventral tegmental area (VTA) in tonic and phasic regulation of dopamine release in the ventral striatum was investigated. Microdialysis in conscious rats was used to assess dopamine release primarily from the nucleus accumbens shell re

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

    Science.gov (United States)

    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.

  8. Selective Activation of Cholinergic Interneurons Enhances Accumbal Phasic Dopamine Release: Setting the Tone for Reward Processing

    Directory of Open Access Journals (Sweden)

    Roger Cachope

    2012-07-01

    Full Text Available Dopamine plays a critical role in motor control, addiction, and reward-seeking behaviors, and its release dynamics have traditionally been linked to changes in midbrain dopamine neuron activity. Here, we report that selective endogenous cholinergic activation achieved via in vitro optogenetic stimulation of nucleus accumbens, a terminal field of dopaminergic neurons, elicits real-time dopamine release. This mechanism occurs via direct actions on dopamine terminals, does not require changes in neuron firing within the midbrain, and is dependent on glutamatergic receptor activity. More importantly, we demonstrate that in vivo selective activation of cholinergic interneurons is sufficient to elicit dopamine release in the nucleus accumbens. Therefore, the control of accumbal extracellular dopamine levels by endogenous cholinergic activity results from a complex convergence of neurotransmitter/neuromodulator systems that may ultimately synergize to drive motivated behavior.

  9. 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.

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

    Science.gov (United States)

    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.

  11. 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

  12. 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...

  13. Local Control of Extracellular Dopamine Levels in the Medial Nucleus Accumbens by a Glutamatergic Projection from the Infralimbic Cortex.

    Science.gov (United States)

    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

  14. The Aversive Agent Lithium Chloride Suppresses Phasic Dopamine Release Through Central GLP-1 Receptors

    Science.gov (United States)

    Fortin, Samantha M; Chartoff, Elena H; Roitman, Mitchell F

    2016-01-01

    Unconditioned rewarding stimuli evoke phasic increases in dopamine concentration in the nucleus accumbens (NAc) while discrete aversive stimuli elicit pauses in dopamine neuron firing and reductions in NAc dopamine concentration. The unconditioned effects of more prolonged aversive states on dopamine release dynamics are not well understood and are investigated here using the malaise-inducing agent lithium chloride (LiCl). We used fast-scan cyclic voltammetry to measure phasic increases in NAc dopamine resulting from electrical stimulation of dopamine cell bodies in the ventral tegmental area (VTA). Systemic LiCl injection reduced electrically evoked dopamine release in the NAc of both anesthetized and awake rats. As some behavioral effects of LiCl appear to be mediated through glucagon-like peptide-1 receptor (GLP-1R) activation, we hypothesized that the suppression of phasic dopamine by LiCl is GLP-1R dependent. Indeed, peripheral pretreatment with the GLP-1R antagonist exendin-9 (Ex-9) potently attenuated the LiCl-induced suppression of dopamine. Pretreatment with Ex-9 did not, however, affect the suppression of phasic dopamine release by the kappa-opioid receptor agonist, salvinorin A, supporting a selective effect of GLP-1R stimulation in LiCl-induced dopamine suppression. By delivering Ex-9 to either the lateral or fourth ventricle, we highlight a population of central GLP-1 receptors rostral to the hindbrain that are involved in the LiCl-mediated suppression of NAc dopamine release. PMID:26211731

  15. 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...

  16. Absence of NMDA receptors in dopamine neurons attenuates dopamine release but not conditioned approach during Pavlovian conditioning.

    Science.gov (United States)

    Parker, Jones G; Zweifel, Larry S; Clark, Jeremy J; Evans, Scott B; Phillips, Paul E M; Palmiter, Richard D

    2010-07-27

    During Pavlovian conditioning, phasic dopamine (DA) responses emerge to reward-predictive stimuli as the subject learns to anticipate reward delivery. This observation has led to the hypothesis that phasic dopamine signaling is important for learning. To assess the ability of mice to develop anticipatory behavior and to characterize the contribution of dopamine, we used a food-reinforced Pavlovian conditioning paradigm. As mice learned the cue-reward association, they increased their head entries to the food receptacle in a pattern that was consistent with conditioned anticipatory behavior. D1-receptor knockout (D1R-KO) mice had impaired acquisition, and systemic administration of a D1R antagonist blocked both the acquisition and expression of conditioned approach in wild-type mice. To assess the specific contribution of phasic dopamine transmission, we tested mice lacking NMDA-type glutamate receptors (NMDARs) exclusively in dopamine neurons (NR1-KO mice). Surprisingly, NR1-KO mice learned at the same rate as their littermate controls. To evaluate the contribution of NMDARs to phasic dopamine release in this paradigm, we performed fast-scan cyclic voltammetry in the nucleus accumbens of awake mice. Despite having significantly attenuated phasic dopamine release following reward delivery, KO mice developed cue-evoked dopamine release at the same rate as controls. We conclude that NMDARs in dopamine neurons enhance but are not critical for phasic dopamine release to behaviorally relevant stimuli; furthermore, their contribution to phasic dopamine signaling is not necessary for the development of cue-evoked dopamine or anticipatory activity in a D1R-dependent Pavlovian conditioning paradigm.

  17. 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...

  18. The gamma-aminobutyric acid type B (GABAB receptor agonist baclofen inhibits morphine sensitization by decreasing the dopamine level in rat nucleus accumbens

    Directory of Open Access Journals (Sweden)

    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.

  19. 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.

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

    Directory of Open Access Journals (Sweden)

    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.

  1. 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.

  2. 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.

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

    Science.gov (United States)

    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.

  4. Dopamine release dynamics change during adolescence and after voluntary alcohol intake.

    Directory of Open Access Journals (Sweden)

    Sara Palm

    Full Text Available Adolescence is associated with high impulsivity and risk taking, making adolescent individuals more inclined to use drugs. Early drug use is correlated to increased risk for substance use disorders later in life but the neurobiological basis is unclear. The brain undergoes extensive development during adolescence and disturbances at this time are hypothesized to contribute to increased vulnerability. The transition from controlled to compulsive drug use and addiction involve long-lasting changes in neural networks including a shift from the nucleus accumbens, mediating acute reinforcing effects, to recruitment of the dorsal striatum and habit formation. This study aimed to test the hypothesis of increased dopamine release after a pharmacological challenge in adolescent rats. Potassium-evoked dopamine release and uptake was investigated using chronoamperometric dopamine recordings in combination with a challenge by amphetamine in early and late adolescent rats and in adult rats. In addition, the consequences of voluntary alcohol intake during adolescence on these effects were investigated. The data show a gradual increase of evoked dopamine release with age, supporting previous studies suggesting that the pool of releasable dopamine increases with age. In contrast, a gradual decrease in evoked release with age was seen in response to amphetamine, supporting a proportionally larger storage pool of dopamine in younger animals. Dopamine measures after voluntary alcohol intake resulted in lower release amplitudes in response to potassium-chloride, indicating that alcohol affects the releasable pool of dopamine and this may have implications for vulnerability to addiction and other psychiatric diagnoses involving dopamine in the dorsal striatum.

  5. 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.

  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. 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.

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Directory of Open Access Journals (Sweden)

    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.

  10. 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.

  11. Optical suppression of drug-evoked phasic dopamine release.

    Science.gov (United States)

    McCutcheon, James E; Cone, Jackson J; Sinon, Christopher G; Fortin, Samantha M; Kantak, Pranish A; Witten, Ilana B; Deisseroth, Karl; Stuber, Garret D; Roitman, Mitchell F

    2014-01-01

    Brief fluctuations in dopamine concentration (dopamine transients) play a key role in behavior towards rewards, including drugs of abuse. Drug-evoked dopamine transients may result from actions at both dopamine cell bodies and dopamine terminals. Inhibitory opsins can be targeted to dopamine neurons permitting their firing activity to be suppressed. However, as dopamine transients can become uncoupled from firing, it is unknown whether optogenetic hyperpolarization at the level of the soma is able to suppress dopamine transients. Here, we used in vivo fast-scan cyclic voltammetry to record transients evoked by cocaine and raclopride in nucleus accumbens (NAc) of urethane-anesthetized rats. We targeted halorhodopsin (NpHR) specifically to dopamine cells by injecting Cre-inducible virus into ventral tegmental area (VTA) of transgenic rats that expressed Cre recombinase under control of the tyrosine hydroxylase promoter (TH-Cre(+) rats). Consistent with previous work, co-administration of cocaine and raclopride led to the generation of dopamine transients in NAc shell. Illumination of VTA with laser strongly suppressed the frequency of transients in NpHR-expressing rats, but not in control rats. Laser did not have any effect on amplitude of transients. Thus, optogenetics can effectively reduce the occurrence of drug-evoked transients and is therefore a suitable approach for studying the functional role of such transients in drug-associated behavior.

  12. Optical suppression of drug-evoked phasic dopamine release

    Directory of Open Access Journals (Sweden)

    James Edgar Mccutcheon

    2014-09-01

    Full Text Available Brief fluctuations in dopamine concentration (dopamine transients play a key role in behavior towards rewards, including drugs of abuse. Drug-evoked dopamine transients may result from actions at both dopamine cell bodies and dopamine terminals. Inhibitory opsins can be targeted to dopamine neurons permitting their firing activity to be suppressed. However, as dopamine transients can become uncoupled from firing, it is unknown whether optogenetic hyperpolarization at the level of the soma is able to suppress dopamine transients. Here, we used in vivo fast-scan cyclic voltammetry to record transients evoked by cocaine and raclopride in nucleus accumbens (NAc of urethane-anesthetized rats. We targeted halorhodopsin (NpHR specifically to dopamine cells by injecting Cre-inducible virus into ventral tegmental area (VTA of transgenic rats that expressed Cre recombinase under control of the tyrosine hydroxylase promoter (TH-Cre+ rats. Consistent with previous work, co-administration of cocaine and raclopride led to the generation of dopamine transients in NAc shell. Illumination of VTA with laser strongly suppressed the frequency of transients in NpHR-expressing rats, but not in control rats. Laser did not have any effect on amplitude of transients. Thus, optogenetics can effectively reduce the occurrence of drug-evoked transients and is therefore a suitable approach for studying the functional role of such transients in drug-associated behavior.

  13. 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.

  14. 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.

  15. 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

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

    Directory of Open Access Journals (Sweden)

    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.

  17. Striatal dopamine release codes uncertainty in pathological gambling

    DEFF Research Database (Denmark)

    Linnet, Jakob; Mouridsen, Kim; Peterson, Ericka

    2012-01-01

    Two mechanisms of midbrain and striatal dopaminergic projections may be involved in pathological gambling: hypersensitivity to reward and sustained activation toward uncertainty. The midbrain—striatal dopamine system distinctly codes reward and uncertainty, where dopaminergic activation is a linear...... dopamine release, and we used performance on the Iowa Gambling Task (IGT) to determine overall reward and uncertainty. We hypothesized that we would find a linear function between dopamine release and IGT performance, if dopamine release coded reward in pathological gambling. If, on the other hand......, dopamine release coded uncertainty, we would find an inversely U-shaped function. The data supported an inverse U-shaped relation between striatal dopamine release and IGT performance if the pathological gambling group, but not in the healthy control group. These results are consistent with the hypothesis...

  18. Striatal dopamine release codes uncertainty in pathological gambling

    DEFF Research Database (Denmark)

    Linnet, Jakob; Mouridsen, Kim; Peterson, Ericka

    2012-01-01

    Two mechanisms of midbrain and striatal dopaminergic projections may be involved in pathological gambling: hypersensitivity to reward and sustained activation toward uncertainty. The midbrain-striatal dopamine system distinctly codes reward and uncertainty, where dopaminergic activation is a linear......]raclopride to measure dopamine release, and we used performance on the Iowa Gambling Task (IGT) to determine overall reward and uncertainty. We hypothesized that we would find a linear function between dopamine release and IGT performance, if dopamine release coded reward in pathological gambling. If, on the other hand......, dopamine release coded uncertainty, we would find an inversely U-shaped function. The data supported an inverse U-shaped relation between striatal dopamine release and IGT performance if the pathological gambling group, but not in the healthy control group. These results are consistent with the hypothesis...

  19. Increased amphetamine-induced locomotor activity, sensitization, and accumbal dopamine release in M5 muscarinic receptor knockout mice

    DEFF Research Database (Denmark)

    Schmidt, Lene S; Miller, Anthony D; Lester, Deranda B

    2010-01-01

    showed that M(5) receptor knockout (M (5) (-/-) ) mice are less sensitive to the reinforcing properties of addictive drugs. MATERIALS AND METHODS: Here, we investigate the role of M(5) receptors in the effects of amphetamine and cocaine on locomotor activity, locomotor sensitization, and dopamine release...... and locomotor sensitization were enhanced in M (5) (-/-) mice, while the effects of cocaine were similar in M (5) (-/-) and wild-type mice. RESULTS: Consistent with the behavioral results, amphetamine-, but not cocaine, -elicited dopamine release in nucleus accumbens was enhanced in M (5) (-/-) mice. DISCUSSION......: The different effects of amphetamine and cocaine in M (5) (-/-) mice may be due to the divergent pharmacological profile of the two drugs, where amphetamine, but not cocaine, is able to release intracellular stores of dopamine. In conclusion, we show here for the first time that amphetamine...

  20. Local control of striatal dopamine release

    Directory of Open Access Journals (Sweden)

    Roger eCachope

    2014-05-01

    Full Text Available The mesolimbic and nigrostriatal dopamine (DA systems play a key role in the physiology of reward seeking, motivation and motor control. Importantly, they are also involved in the pathophysiology of Parkinson’s and Huntington’s disease, schizophrenia and addiction. Control of DA release in the striatum is tightly linked to firing of DA neurons in the ventral tegmental area (VTA and the substantia nigra (SN. However, local influences in the striatum affect release by exerting their action directly on axon terminals. For example, endogenous glutamatergic and cholinergic activity is sufficient to trigger striatal DA release independently of cell body firing. Recent developments involving genetic manipulation, pharmacological selectivity or selective stimulation have allowed for better characterization of these phenomena. Such termino-terminal forms of control of DA release transform considerably our understanding of the mesolimbic and nigrostriatal systems, and have strong implications as potential mechanisms to modify impaired control of DA release in the diseased brain. Here, we review these and related mechanisms and their implications in the physiology of ascending DA systems.

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

    Science.gov (United States)

    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…

  2. Dopamine release in ventral striatum of pathological gamblers losing money

    DEFF Research Database (Denmark)

    Linnet, J; Peterson, E; Doudet, D J;

    2010-01-01

    Linnet J, Peterson E, Doudet DJ, Gjedde A, Møller A. Dopamine release in ventral striatum of pathological gamblers losing money. Objective: To investigate dopaminergic neurotransmission in relation to monetary reward and punishment in pathological gambling. Pathological gamblers (PG) often continue...... gambling despite losses, known as 'chasing one's losses'. We therefore hypothesized that losing money would be associated with increased dopamine release in the ventral striatum of PG compared with healthy controls (HC). Method: We used Positron Emission Tomography (PET) with [(11)C]raclopride to measure...... dopamine release in the ventral striatum of 16 PG and 15 HC playing the Iowa Gambling Task (IGT). Results: PG who lost money had significantly increased dopamine release in the left ventral striatum compared with HC. PG and HC who won money did not differ in dopamine release. Conclusion: Our findings...

  3. Influence of phasic and tonic dopamine release on receptor activation

    DEFF Research Database (Denmark)

    Dreyer, Jakob Kristoffer Kisbye; Herrik, Kjartan F; Berg, Rune W

    2010-01-01

    Tonic and phasic dopamine release is implicated in learning, motivation, and motor functions. However, the relationship between spike patterns in dopaminergic neurons, the extracellular concentration of dopamine, and activation of dopamine receptors remains unresolved. In the present study, we...... develop a computational model of dopamine signaling that give insight into the relationship between the dynamics of release and occupancy of D(1) and D(2) receptors. The model is derived from first principles using experimental data. It has no free parameters and offers unbiased estimation...

  4. 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.

  5. 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.

  6. Modulating dopamine release by optogenetics in transgenic mice reveals terminal dopaminergic dynamics.

    Science.gov (United States)

    Lu, Yao; Driscoll, Nicolette; Ozden, Ilker; Yu, Zeyang; Nurmikko, Arto V

    2015-07-01

    Dopamine (DA) release and uptake dynamics in the nucleus accumbens (NAc) have important implications for neurological diseases and mammalian animal behaviors. We demonstrate here the use of cell-type-specific optogenetic targeting in conjunction with fast-scan cyclic voltammetry applied to brain slices prepared from specifically tailored transgenic mice, which conditionally express channelrhodopsin-2 (ChR2) through dopamine transporter (DAT)-Cre. Terminal dopaminergic dynamics and the direct manipulation of induced DA release level by controlling light intensity, pulse width, and the shape of stimulation waveforms were studied. Effective cell terminal-targeting optogenetic induction of DA release at physiological levels in NAc is demonstrated and discussed. It was found that delivering more light energy by increasing stimulation intensity and length is not the only way to control DA release; the temporal shape of the stimulus waveform at light onset is also critically related to induced DA concentrations. In addition, DA uptake dynamics as well as the recovery of the presynaptic releasable DA pool are studied and modeled. More broadly, our experimental findings provide important further evidence for effectively applying optogenetics to induce neurotransmitter release in the behaviorally relevant region of the brain in a highly cell-type selective context.

  7. In vivo comparison of norepinephrine and dopamine release in rat brain by simultaneous measurements with fast-scan cyclic voltammetry.

    Science.gov (United States)

    Park, Jinwoo; Takmakov, Pavel; Wightman, R Mark

    2011-12-01

    Brain norepinephrine and dopamine regulate a variety of critical behaviors such as stress, learning, memory, and drug addiction. In this study, we demonstrate differences in the regulation of in vivo neurotransmission for dopamine in the anterior nucleus accumbens (NAc) and norepinephrine in the ventral bed nucleus of the stria terminalis (vBNST) of the anesthetized rat. Release of the two catecholamines was measured simultaneously using fast-scan cyclic voltammetry at two different carbon-fiber microelectrodes, each implanted in the brain region of interest. Simultaneous dopamine and norepinephrine release was evoked by electrical stimulation of a region where the ventral noradrenergic bundle, the pathway of noradrenergic neurons, courses through the ventral tegmental area/substantia nigra, the origin of dopaminergic cell bodies. The release and uptake of norepinephrine in the vBNST were both significantly slower than for dopamine in the NAc. Pharmacological manipulations in the same animal demonstrated that the two catecholamines are differently regulated. The combination of a dopamine autoreceptor antagonist and amphetamine significantly increased basal extracellular dopamine whereas a norepinephrine autoreceptor antagonist and amphetamine did not change basal norepinephrine concentration. α-Methyl-p-tyrosine, a tyrosine hydroxylase inhibitor, decreased electrically evoked dopamine release faster than norepinephrine. The dual-microelectrode fast-scan cyclic voltammetry technique along with anatomical and pharmacological evidence confirms that dopamine in the NAc and norepinephrine in the vBNST can be monitored selectively and simultaneously in the same animal. The high temporal and spatial resolution of the technique enabled us to examine differences in the dynamics of extracellular norepinephrine and dopamine concurrently in two different limbic structures.

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

    Science.gov (United States)

    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.

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Science.gov (United States)

    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.

  11. Blockade of Dopamine Activity in the Nucleus Accumbens Impairs Learning Extinction of Conditioned Fear

    Science.gov (United States)

    Holtzman-Assif, Orit; Laurent, Vincent; Westbrook, R. Frederick

    2010-01-01

    Three experiments used rats to investigate the role of dopamine activity in learning to inhibit conditioned fear responses (freezing) in extinction. In Experiment 1, rats systemically injected with the D2 dopamine antagonist, haloperidol, froze more across multiple extinction sessions and on a drug-free retention test than control rats. In…

  12. 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…

  13. Striatal dopamine release codes uncertainty in pathological gambling.

    Science.gov (United States)

    Linnet, Jakob; Mouridsen, Kim; Peterson, Ericka; Møller, Arne; Doudet, Doris Jeanne; Gjedde, Albert

    2012-10-30

    Two mechanisms of midbrain and striatal dopaminergic projections may be involved in pathological gambling: hypersensitivity to reward and sustained activation toward uncertainty. The midbrain-striatal dopamine system distinctly codes reward and uncertainty, where dopaminergic activation is a linear function of expected reward and an inverse U-shaped function of uncertainty. In this study, we investigated the dopaminergic coding of reward and uncertainty in 18 pathological gambling sufferers and 16 healthy controls. We used positron emission tomography (PET) with the tracer [(11)C]raclopride to measure dopamine release, and we used performance on the Iowa Gambling Task (IGT) to determine overall reward and uncertainty. We hypothesized that we would find a linear function between dopamine release and IGT performance, if dopamine release coded reward in pathological gambling. If, on the other hand, dopamine release coded uncertainty, we would find an inversely U-shaped function. The data supported an inverse U-shaped relation between striatal dopamine release and IGT performance if the pathological gambling group, but not in the healthy control group. These results are consistent with the hypothesis of dopaminergic sensitivity toward uncertainty, and suggest that dopaminergic sensitivity to uncertainty is pronounced in pathological gambling, but not among non-gambling healthy controls. The findings have implications for understanding dopamine dysfunctions in pathological gambling and addictive behaviors.

  14. 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.

  15. Presynaptic action of neurotensin on dopamine release through inhibition of D2 receptor function

    Directory of Open Access Journals (Sweden)

    Trudeau Louis-Eric

    2009-08-01

    Full Text Available Abstract Background Neurotensin (NT is known to act on dopamine (DA neurons at the somatodendritic level to regulate cell firing and secondarily enhance DA release. In addition, anatomical and indirect physiological data suggest the presence of NT receptors at the terminal level. However, a clear demonstration of the mechanism of action of NT on dopaminergic axon terminals is lacking. We hypothesize that NT acts to increase DA release by inhibiting the function of terminal D2 autoreceptors. To test this hypothesis, we used fast-scan cyclic voltammetry (FCV to monitor in real time the axonal release of DA in the nucleus accumbens (NAcc. Results DA release was evoked by single electrical pulses and pulse trains (10 Hz, 30 pulses. Under these two stimulation conditions, we evaluated the characteristics of DA D2 autoreceptors and the presynaptic action of NT in the NAcc shell and shell/core border region. The selective agonist of D2 autoreceptors, quinpirole (1 μM, inhibited DA overflow evoked by both single and train pulses. In sharp contrast, the selective D2 receptor antagonist, sulpiride (5 μM, strongly enhanced DA release triggered by pulse trains, without any effect on DA release elicited by single pulses, thus confirming previous observations. We then determined the effect of NT (8–13 (100 nM and found that although it failed to increase DA release evoked by single pulses, it strongly enhanced DA release evoked by pulse trains that lead to prolonged DA release and engage D2 autoreceptors. In addition, initial blockade of D2 autoreceptors by sulpiride considerably inhibited further facilitation of DA release generated by NT (8–13. Conclusion Taken together, these data suggest that NT enhances DA release principally by inhibiting the function of terminal D2 autoreceptors and not by more direct mechanisms such as facilitation of terminal calcium influx.

  16. Striatal cholinergic interneurons Drive GABA release from dopamine terminals.

    Science.gov (United States)

    Nelson, Alexandra B; Hammack, Nora; Yang, Cindy F; Shah, Nirao M; Seal, Rebecca P; Kreitzer, Anatol C

    2014-04-01

    Striatal cholinergic interneurons are implicated in motor control, associative plasticity, and reward-dependent learning. Synchronous activation of cholinergic interneurons triggers large inhibitory synaptic currents in dorsal striatal projection neurons, providing one potential substrate for control of striatal output, but the mechanism for these GABAergic currents is not fully understood. Using optogenetics and whole-cell recordings in brain slices, we find that a large component of these inhibitory responses derive from action-potential-independent disynaptic neurotransmission mediated by nicotinic receptors. Cholinergically driven IPSCs were not affected by ablation of striatal fast-spiking interneurons but were greatly reduced after acute treatment with vesicular monoamine transport inhibitors or selective destruction of dopamine terminals with 6-hydroxydopamine, indicating that GABA release originated from dopamine terminals. These results delineate a mechanism in which striatal cholinergic interneurons can co-opt dopamine terminals to drive GABA release and rapidly inhibit striatal output neurons.

  17. Noradrenaline-induced release of newly-synthesized accumbal dopamine: differential role of alpha- and beta-adrenoceptors

    Directory of Open Access Journals (Sweden)

    Francisca eMeyer

    2014-08-01

    Full Text Available Previous studies have shown that intra-accumbens infusion of isoproterenol (ISO, a beta-adrenoceptor-agonist, and phenylephrine (PE, an alpha-adrenoceptor-agonist, increase the release of accumbal dopamine (DA. In the present study we analyzed whether the ISO-induced release of DA is sensitive to pretreatment with the DA synthesis inhibitor alpha-methyl-para-tyrosine (AMPT. Earlier studies have shown that the PE-induced release of DA is derived from DA pools that are resistant to AMPT. In addition to PE, the alpha-adrenoceptor-antagonist phentolamine (PA was also found to increase accumbal DA release. Therefore, we investigated whether similar to the DA-increasing effect of PE, the DA increase induced by PA is resistant to AMPT. Pretreatment with AMPT prevented the ISO-induced increase of accumbal DA. The accumbal DA increase after PA was not reduced by the DA synthesis inhibitor, independently of the amount of DA released. These results show that mesolimbic beta-, but not alpha-adrenoceptors, control the release of accumbal newly-synthesized DA pools. The DA-increasing effects of PE have previously been ascribed to stimulation of presynaptic receptors located on noradrenergic terminals, whereas the DA-increasing effects of PA and ISO have been ascribed to an action of these drugs at postsynaptic receptors on dopaminergic terminals. The fact that AMPT did not affect the accumbal DA response to PE and PA, whereas it did prevent the accumbal DA increase to ISO, supports our previously reported hypothesis that the noradrenergic neurons of the nucleus accumbens containing presynaptic alpha-adrenoceptors impinge upon the dopaminergic terminals in the nucleus accumbens containing postsynaptic adrenoceptors of the alpha but not of the beta type. The putative therapeutic effects of noradrenergic agents in the treatment of DA-related disorders are shortly discussed.

  18. Imaging of dopamine release induced by pharmacologic and nonpharmacologic stimulations

    Energy Technology Data Exchange (ETDEWEB)

    Cho, Sang Soo; Kim, Sang Eun [Seoul National University College of Medicine, Seoul (Korea, Republic of)

    2007-04-15

    Technological advances in molecular imaging made it possible to image synaptic neurotransmitter concentration in living human brain. The dopaminergic system has been most intensively studied because of its importance in neurological as well as psychiatric disorders. This paper provides a brief overview of recent progress in imaging studies of dopamine release induced by pharmacologic and nonpharmacologic stimulations.

  19. 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.

  20. 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.

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

    Directory of Open Access Journals (Sweden)

    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

  2. Optogenetic control of serotonin and dopamine release in Drosophila larvae.

    Science.gov (United States)

    Xiao, Ning; Privman, Eve; Venton, B Jill

    2014-08-20

    Optogenetic control of neurotransmitter release is an elegant method to investigate neurobiological mechanisms with millisecond precision and cell type-specific resolution. Channelrhodopsin-2 (ChR2) can be expressed in specific neurons, and blue light used to activate those neurons. Previously, in Drosophila, neurotransmitter release and uptake have been studied after continuous optical illumination. In this study, we investigated the effects of pulsed optical stimulation trains on serotonin or dopamine release in larval ventral nerve cords. In larvae with ChR2 expressed in serotonergic neurons, low-frequency stimulations produced a distinct, steady-state response while high-frequency patterns were peak shaped. Evoked serotonin release increased with increasing stimulation frequency and then plateaued. The steady-state response and the frequency dependence disappeared after administering the uptake inhibitor fluoxetine, indicating that uptake plays a significant role in regulating the extracellular serotonin concentration. Pulsed stimulations were also used to evoke dopamine release in flies expressing ChR2 in dopaminergic neurons and similar frequency dependence was observed. Release due to pulsed optical stimulations was modeled to determine the uptake kinetics. For serotonin, Vmax was 0.54 ± 0.07 μM/s and Km was 0.61 ± 0.04 μM; and for dopamine, Vmax was 0.12 ± 0.03 μM/s and Km was 0.45 ± 0.13 μM. The amount of serotonin released per stimulation pulse was 4.4 ± 1.0 nM, and the amount of dopamine was 1.6 ± 0.3 nM. Thus, pulsed optical stimulations can be used to mimic neuronal firing patterns and will allow Drosophila to be used as a model system for studying mechanisms underlying neurotransmission.

  3. Dopamine control of LH release in the tench (Tinca tinca).

    Science.gov (United States)

    Podhorec, Peter; Socha, Magdalena; Sokolowska-Mikolajczyk, Miroslawa; Policar, Tomas; Svinger, Viktor W; Drozd, Borek; Kouril, Jan

    2012-01-01

    Tench (Tinca tinca) is apparently the only known member of the Cyprinidae in which ovulation is stimulated following administration of a low dose of GnRH analogue (GnRHa) without a dopamine inhibitor. This study evaluated LH release effectiveness of the most commonly used GnRHa and clarified whether LH secretion followed by ovulation is subject to inhibitory dopaminergic control in tench. Fish were intraperitoneally injected with three types of GnRHa, GnRHa with dopamine inhibitor metoclopramide (combined treatment), or the dopamine inhibitor metoclopramide alone. LH concentrations at five sampling times (0, 6, 12, 24, and 33 h) together with ovulation success and fecundity index were recorded. The combined treatment triggered an almost immediate LH release peak with a gradual decline, and resulted in a high ovulation rate. In contrast to the combined treatment, an application of GnRHa alone at 10 μg kg(-1) induced gradual increase of LH concentrations with peaks close to ovulation time, and with high ovulation success. Significant differences in LH concentrations at 6 and 12h and no differences in ovulation success were found between the combined and the GnRHa alone treatments. Metoclopramide alone induced a small increase in LH with no ovulation. The study presents clear evidence of dopaminergic control of LH release in tench, with a high ovulation rate obtained after application of GnRHa alone or in combination with dopamine inhibitor.

  4. 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.

  5. Relative Timing Between Kappa Opioid Receptor Activation and Cocaine Determines the Impact on Reward and Dopamine Release

    Science.gov (United States)

    Chartoff, Elena H; Ebner, Shayla R; Sparrow, Angela; Potter, David; Baker, Phillip M; Ragozzino, Michael E; Roitman, Mitchell F

    2016-01-01

    Negative affective states can increase the rewarding value of drugs of abuse and promote drug taking. Chronic cocaine exposure increases levels of the neuropeptide dynorphin, an endogenous ligand at kappa opioid receptors (KOR) that suppresses dopamine release in the nucleus accumbens (NAc) and elicits negative affective states upon drug withdrawal. However, there is evidence that the effects of KOR activation on affective state are biphasic: immediate aversive effects are followed by delayed increases in reward. The impact of KOR-induced affective states on reward-related effects of cocaine over time is not known. We hypothesize that the initial aversive effects of KOR activation increase, whereas the delayed rewarding effects decrease, the net effects of cocaine on reward and dopamine release. We treated rats with cocaine at various times (15 min to 48 h) after administration of the selective KOR agonist salvinorin A (salvA). Using intracranial self-stimulation and fast scan cyclic voltammetry, we found that cocaine-induced increases in brain stimulation reward and evoked dopamine release in the NAc core were potentiated when cocaine was administered within 1 h of salvA, but attenuated when administered 24 h after salvA. Quantitative real-time PCR was used to show that KOR and prodynorphin mRNA levels were decreased in the NAc, whereas tyrosine hydroxylase and dopamine transporter mRNA levels and tissue dopamine content were increased in the ventral tegmental area 24 h post-salvA. These findings raise the possibility that KOR activation—as occurs upon withdrawal from chronic cocaine—modulates vulnerability to cocaine in a time-dependent manner. PMID:26239494

  6. On the role of subsecond dopamine release in conditioned avoidance

    Directory of Open Access Journals (Sweden)

    Erik B Oleson

    2013-06-01

    Full Text Available Using shock avoidance procedures to study conditioned behavioral responses has a rich history within the field of experimental psychology. Such experiments led to the formulation of the general concept of negative reinforcement and specific theories attempting to explain escape and avoidance behavior, or why animals choose to either terminate or prevent the presentation of an aversive event. For example, the two-factor theory of avoidance holds that cues preceding an aversive event begin to evoke conditioned fear responses, and these conditioned fear responses reinforce the instrumental avoidance response. Current neuroscientific advances are providing new perspectives into this historical literature. Due to its well-established role in reinforcement processes and behavioral control, the mesolimbic dopamine system presented itself as a logical starting point in the search for neural correlates of avoidance and escape behavior. We recently demonstrated that phasic dopamine release events are inhibited by stimuli associated with aversive events but increased by stimuli preceding the successful avoidance of the aversive event. The latter observation is inconsistent with the second component of the two-factor theory of avoidance and; therefore, led us propose a new theoretical explanation of conditioned avoidance: 1 fear is initially conditioned to the warning signal and dopamine computes this fear association as a decrease in release, 2 the warning signal, now capable of producing a negative emotional state, suppresses dopamine release and behavior, 3 over repeated trials the warning signal becomes associated with safety rather than fear; dopaminergic neurons already compute safety as an increase in release and begin to encode the warning signal as the earliest predictor of safety 4 the warning signal now promotes conditioned avoidance via dopaminergic modulation of the brain’s incentive-motivational circuitry.

  7. Acute fasting increases somatodendritic dopamine release in the ventral tegmental area.

    Science.gov (United States)

    Roseberry, Aaron G

    2015-08-01

    Fasting and food restriction alter the activity of the mesolimbic dopamine system to affect multiple reward-related behaviors. Food restriction decreases baseline dopamine levels in efferent target sites and enhances dopamine release in response to rewards such as food and drugs. In addition to releasing dopamine from axon terminals, dopamine neurons in the ventral tegmental area (VTA) also release dopamine from their soma and dendrites, and this somatodendritic dopamine release acts as an autoinhibitory signal to inhibit neighboring VTA dopamine neurons. It is unknown whether acute fasting also affects dopamine release, including the local inhibitory somatodendritic dopamine release in the VTA. In these studies, I have tested whether fasting affects the inhibitory somatodendritic dopamine release within the VTA by examining whether an acute 24-h fast affects the inhibitory postsynaptic current mediated by evoked somatodendritic dopamine release (D2R IPSC). Fasting increased the contribution of the first action potential to the overall D2R IPSC and increased the ratio of repeated D2R IPSCs evoked at short intervals. Fasting also reduced the effect of forskolin on the D2R IPSC and led to a significantly bigger decrease in the D2R IPSC in low extracellular calcium. Finally, fasting resulted in an increase in the D2R IPSCs when a more physiologically relevant train of D2R IPSCs was used. Taken together, these results indicate that fasting caused a change in the properties of somatodendritic dopamine release, possibly by increasing dopamine release, and that this increased release can be sustained under conditions where dopamine neurons are highly active.

  8. Salsolinol modulation of dopamine neurons

    OpenAIRE

    Guiqin eXie; Kresimir eKrnjevic; Jiang Hong Ye

    2013-01-01

    Salsolinol, a tetrahydroisoquinoline present in the human and rat brains, is the condensation product of dopamine and acetaldehyde, the first metabolite of ethanol. Previous evidence obtained in vivo links salsolinol with the mesolimbic dopaminergic system: salsolinol is self-administered into the posterior of the ventral tegmental area (pVTA) of rats; intra-VTA administration of salsolinol induces a strong conditional place preference and increases dopamine release in the nucleus accumbens. ...

  9. Neuronal release of endogenous dopamine from corpus of guinea pig stomach.

    Science.gov (United States)

    Shichijo, K; Sakurai-Yamashita, Y; Sekine, I; Taniyama, K

    1997-11-01

    Neuronal release of endogenous dopamine was identified in mucosa-free preparations (muscle layer including intramural plexus) from guinea pig stomach corpus by measuring tissue dopamine content and dopamine release and by immunohistochemical methods using a dopamine antiserum. Dopamine content in mucosa-free preparations of guinea pig gastric corpus was one-tenth of norepinephrine content. Electrical transmural stimulation of mucosa-free preparations of gastric corpus increased the release of endogenous dopamine in a frequency-dependent (3-20 Hz) manner. The stimulated release of dopamine was prevented by either removal of external Ca2+ or treatment with tetrodotoxin. Dopamine-immunopositive nerve fibers surrounding choline acetyltransferase-immunopositive ganglion cells were seen in the myenteric plexus of whole mount preparations of gastric corpus even after bilateral transection of the splanchnic nerve proximal to the junction with the vagal nerve (section of nerves between the celiac ganglion and stomach). Domperidone and sulpiride potentiated the stimulated release of acetylcholine and reversed the dopamine-induced inhibition of acetylcholine release from mucosa-free preparations. These results indicate that dopamine is physiologically released from neurons and from possible dopaminergic nerve terminals and regulates cholinergic neuronal activity in the corpus of guinea pig stomach.

  10. Adenosine transiently modulates stimulated dopamine release in the caudate-putamen via A1 receptors.

    Science.gov (United States)

    Ross, Ashley E; Venton, B Jill

    2015-01-01

    Adenosine modulates dopamine in the brain via A1 and A2A receptors, but that modulation has only been characterized on a slow time scale. Recent studies have characterized a rapid signaling mode of adenosine that suggests a possible rapid modulatory role. Here, fast-scan cyclic voltammetry was used to characterize the extent to which transient adenosine changes modulate stimulated dopamine release (5 pulses at 60 Hz) in rat caudate-putamen brain slices. Exogenous adenosine was applied and dopamine concentration monitored. Adenosine only modulated dopamine when it was applied 2 or 5 s before stimulation. Longer time intervals and bath application of 5 μM adenosine did not decrease dopamine release. Mechanical stimulation of endogenous adenosine 2 s before dopamine stimulation also decreased stimulated dopamine release by 41 ± 7%, similar to the 54 ± 6% decrease in dopamine after exogenous adenosine application. Dopamine inhibition by transient adenosine was recovered within 10 min. The A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine blocked the dopamine modulation, whereas dopamine modulation was unaffected by the A2A receptor antagonist SCH 442416. Thus, transient adenosine changes can transiently modulate phasic dopamine release via A1 receptors. These data demonstrate that adenosine has a rapid, but transient, modulatory role in the brain. Here, transient adenosine was shown to modulate phasic dopamine release on the order of seconds by acting at the A1 receptor. However, sustained increases in adenosine did not regulate phasic dopamine release. This study demonstrates for the first time a transient, neuromodulatory function of rapid adenosine to regulate rapid neurotransmitter release.

  11. Simultaneous radioenzymatic assay of dopamine and dihydroxyphenylacetic acid: an index of in vivo dopamine release

    Energy Technology Data Exchange (ETDEWEB)

    Cheng, C.H.; Wooten, G.F.

    1981-03-01

    The relative brain tissue concentrations of dopamine (DA) and its deaminated metabolite, dihydroxyphenylacetic acid (DOPAC), appears to be a reliable index of the functional activity of dopaminergic neurons. In order to apply this approach to the assessment of dopaminergic neuronal activity in small regions of brain, we have developed a sensitive radioenzymatic assay for simultaneous measurement of DA and DOPAC. The sensitivity of the assay for DA is approximately 10 pg and for DOPAC 100 pg. In addition, the assay is highly specific, simple, and relatively inexpensive. The concurrent estimation of tissue DA and DOPAC concentrations seems to be a reliable means of evaluating the rate of DA turnover or release in behavioral, electrical stimulation, and certain drug paradigms. However, the release or turnover of DA as induced by D-amphetamine (and perhaps other indirectly-acting dopaminemimetic drugs) cannot be meaningfully assessed by measurement of DA and DOPAC alone.

  12. Socially isolated rats exhibit changes in dopamine homeostasis pertinent to schizophrenia

    DEFF Research Database (Denmark)

    Fabricius, Katrine; Steiniger-Brach, Björn; Helboe, Lone;

    2011-01-01

    an investigation of prefrontal cortical dopamine dynamics using in vivo microdialysis. Social isolation for 12 weeks after weaning caused increased locomotor activity in response to novelty and amphetamine challenge. In vivo microdialysis experiments revealed that while social isolation did not change basal...... dopamine levels in the nucleus accumbens, it did cause a significant reduction of basal dopamine release in the prefrontal cortex. In addition, social isolation lead to a significantly larger dopamine response to an amphetamine challenge, in both the nucleus accumbens and the prefrontal cortex compared...

  13. Measuring dopamine release in the human brain with PET

    Energy Technology Data Exchange (ETDEWEB)

    Volkow, N.D. [Brookhaven National Lab., Upton, NY (United States)]|[State Univ. of New York at Stony Brook, Stony Brook, NY (United States). Dept. of Psychiatry; Fowler, J.S.; Logan, J.; Wang, G.J. [Brookhaven National Lab., Upton, NY (United States)

    1995-12-01

    The dopamine system is involved in the regulation of brain regions that subserve motor, cognitive and motivational behaviors. Disruptions of dopamine (DA) function have ben implicated in neurological and psychiatric illnesses including substance abuse as well as on some of the deficits associated with aging of the human brain. This has made the DA system an important topic in research in the neurosciences and neuroimaging as well as an important molecular target for drug development. Positron Emission Tomography (PET), was the first technology that enabled direct measurement of components of the DA system in the living human brain. Imaging studies of DA in the living brain have been indirect, relying on the development of radiotracers to label DA receptors, DA transporters, compounds which have specificity for the enzymes which degrade synaptic DA. Additionally, through the use of tracers that provide information on regional brain activity (ie brain glucose metabolism and cerebral blood flow) and of appropriate pharmacological interventions, it has been possible to assess the functional consequences of changes in brain DA activity. DA specific ligands have been useful in the evaluation of patients with neuropsychiatric illnesses as well as to investigate receptor blockade by antipsychotic drugs. A limitation of strategies that rely on the use of DA specific ligands is that the measures do not necessarily reflect the functional state of the dopaminergic system and that there use to study the effects of drugs is limited to the investigation of receptor or transporter occupancy. Newer strategies have been developed in an attempt to provide with information on dopamine release and on the functional responsivity of the DA system in the human brain. This in turn allows to investigate the effects of pharmacological agent in an analogous way to what is done with microdialysis techniques.

  14. Veratridine-evoked release of dopamine from guinea pig isolated cochlea

    NARCIS (Netherlands)

    Halmos, G; Gáborján, A; Lendvai, B; Répássy, G; Szabó, L Z; Vizi, E S

    2000-01-01

    Dopamine released from the lateral olivocochlear efferent system is thought to inhibit the toxic effect of the extreme glutamate outflow from the inner hair cells during ischemia or acoustic trauma. Using in vitro microvolume superfusion, we have studied the release of [(3)H]dopamine from the latera

  15. 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.

  16. Frequency-Dependent Modulation of Dopamine Release by Nicotine and Dopamine D1 Receptor Ligands: An In Vitro Fast Cyclic Voltammetry Study in Rat Striatum.

    Science.gov (United States)

    Goutier, W; Lowry, J P; McCreary, A C; O'Connor, J J

    2016-05-01

    Nicotine is a highly addictive drug and exerts this effect partially through the modulation of dopamine release and increasing extracellular dopamine in regions such as the brain reward systems. Nicotine acts in these regions on nicotinic acetylcholine receptors. The effect of nicotine on the frequency dependent modulation of dopamine release is well established and the purpose of this study was to investigate whether dopamine D1 receptor (D1R) ligands have an influence on this. Using fast cyclic voltammetry and rat corticostriatal slices, we show that D1R ligands are able to modulate the effect of nicotine on dopamine release. Nicotine (500 nM) induced a decrease in dopamine efflux at low frequency (single pulse or five pulses at 10 Hz) and an increase at high frequency (100 Hz) electrical field stimulation. The D1R agonist SKF-38393, whilst having no effect on dopamine release on its own or on the effect of nicotine upon multiple pulse evoked dopamine release, did significantly prevent and reverse the effect of nicotine on single pulse dopamine release. Interestingly similar results were obtained with the D1R antagonist SCH-23390. In this study we have demonstrated that the modulation of dopamine release by nicotine can be altered by D1R ligands, but only when evoked by single pulse stimulation, and are likely working via cholinergic interneuron driven dopamine release.

  17. 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

  18. 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

  19. MR-DTI and PET multimodal imaging of dopamine release within subdivisions of basal ganglia

    Science.gov (United States)

    Tziortzi, A.; Searle, G.; Tsoumpas, C.; Long, C.; Shotbolt, P.; Rabiner, E.; Jenkinson, M.; Gunn, R. N.

    2011-09-01

    The basal ganglia is a group of anatomical nuclei, functionally organised into limbic, associative and sensorimotor regions, which plays a central role in dopamine related neurological and psychiatric disorders. In this study, we combine two imaging modalities to enable the measurement of dopamine release in functionally related subdivisions of the basal ganglia. [11C]-(+)-PHNO Positron Emission Tomography (PET) measurements in the living human brain pre- and post-administration of amphetamine allow for the estimation of regional dopamine release. Combined Magnetic Resonance Diffusion Tensor Imaging (MR-DTI) data allows for the definition of functional territories of the basal ganglia from connectivity information. The results suggest that there is a difference in dopamine release among the connectivity derived functional subdivisions. Dopamine release is highest in the limbic area followed by the sensorimotor and then the associative area with this pattern reflected in both striatum and pallidum.

  20. Effects of dopamine antagonists on methamphetamine-induced dopamine release in high and low alcohol preference rats.

    Science.gov (United States)

    Nishiguchi, Minori; Kinoshita, Hiroshi; Kasuda, Shogo; Takahashi, Montonori; Yamamura, Takehiko; Matsui, Kiyoshi; Ouchi, Harumi; Minami, Takako; Hishida, Shigeru; Nishio, Hajime

    2010-03-01

    The authors have previously shown that high alcohol preference rats (HAP) have a significantly higher sensitivity than low alcohol preference rats (LAP) for methamphetamine (MAP). In this study, changes in dopamine and serotonin release induced by MAP (1 mg/kg, intraperitoneally) after pre-treatment with D1 and D2 receptor antagonists were examined in the striatum of rats with different alcohol preferences to elucidate differences in receptor levels between the two rat strains. D1 receptor antagonist SCH23390 or D2 receptor antagonist haloperidol were administrated intracerebroventricularly 10 min before MAP stimulation. This study investigated the effect of methamphetamine-induced dopamine and serotonin release in striatum using microdialysis of freely moving rats coupled to ECD-HPLC. With haloperidol treatment both strains of rats showed a significantly greater maximum increase on MAP-induced dopamine release compared with respective control rats. However, after SCH23390 treatment only HAP rats showed a significantly greater increase in dopamine release compared with controls. SCH23390 blocks mainly D1 receptors only in the post-synaptic membrane, whereas haloperidol blocks D2 receptors in both the pre-synaptic and post-synaptic membranes. The MAP-induced increase in dopamine release following haloperidol pre-treatment was greater than SCH23390 pre-treatment in both strains. This result indicates that D2 receptors (autoreceptors) in the pre-synaptic membrane were blocked, leading to the elimination of the feedback function that regulates dopamine release. These data suggested that alcohol preference is associated with the action of MAP, and the dopaminergic mechanism, specifically the D1 system in the striatum, might have a different pathway dependent on alcohol preference.

  1. Dopamine release from the locus coeruleus to the dorsal hippocampus promotes spatial learning and memory.

    Science.gov (United States)

    Kempadoo, Kimberly A; Mosharov, Eugene V; Choi, Se Joon; Sulzer, David; Kandel, Eric R

    2016-12-20

    Dopamine neurotransmission in the dorsal hippocampus is critical for a range of functions from spatial learning and synaptic plasticity to the deficits underlying psychiatric disorders such as attention-deficit hyperactivity disorder. The ventral tegmental area (VTA) is the presumed source of dopamine in the dorsal hippocampus. However, there is a surprising scarcity of VTA dopamine axons in the dorsal hippocampus despite the dense network of dopamine receptors. We have explored this apparent paradox using optogenetic, biochemical, and behavioral approaches and found that dopaminergic axons and subsequent dopamine release in the dorsal hippocampus originate from neurons of the locus coeruleus (LC). Photostimulation of LC axons produced an increase in dopamine release in the dorsal hippocampus as revealed by high-performance liquid chromatography. Furthermore, optogenetically induced release of dopamine from the LC into the dorsal hippocampus enhanced selective attention and spatial object recognition via the dopamine D1/D5 receptor. These results suggest that spatial learning and memory are energized by the release of dopamine in the dorsal hippocampus from noradrenergic neurons of the LC. The present findings are critical for identifying the neural circuits that enable proper attention selection and successful learning and memory.

  2. Striatal dopamine release in the rat during a cued lever-press task for food reward and the development of changes over time measured using high-speed voltammetry.

    Science.gov (United States)

    Nakazato, Taizo

    2005-09-01

    Substantia nigra dopamine neuronal activity in the primate is thought to be related to the error in predicting reward delivery. Dopamine release in rat nucleus accumbens has been shown to increase in relation to drug/food-seeking behaviour. It is not known how the release of dopamine in the striatum corresponds to the many distinct steps of a rewarded, cued task (e.g. recognizing the cue, executing the behaviour, anticipating the reward, receiving the reward) and how dopamine release then changes over time as task performance improves. To investigate dopamine release during a rewarded, cued task and the development of changes in dopamine release over time, changes in extracellular striatal dopamine concentration during a rewarded, cued lever-press task were measured a few days every week for 5 months using high-speed in vivo voltammetry. Rats were trained to press a lever after a tone to obtain a food reward. The reaction time for the lever press decreased gradually as training continued. Changes in dopamine concentration were measured in the anterior striatum (ventral portion) during the task performance after an initial 6-day familiarization period, in which the animals learned that a lever press yielded food, and a 5-week period for surgery, recovery, and electrode preparation. During the task performance, dopamine concentration started to increase just after the cue, peaked near the time of the lever press, and returned to basal levels 1-2 s after the lever press. This pattern of changes in dopamine concentration was observed over the 5 months of testing, the peak dopamine concentration increasing steadily until peaking at week 7, at which time the task performance had not yet improved significantly from week 2. By week 13, task performance had significantly improved and peak dopamine concentration had begun to subside. Thus, the increase in dopamine concentration after the cue was highest while the task was not yet perfected and subsided toward the end of the

  3. 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.

  4. Enhanced striatal dopamine release during food stimulation in binge eating disorder

    Energy Technology Data Exchange (ETDEWEB)

    Wang, g.j.; Wang, G.-J.; Geliebter, A.; Volkow, N.D.; Telang, F.W.; Logan, Jaynbe, M.C.; Galanti, K.; Selig, P.A.; Han, H.; Zhu, W.; Wong, C.T.; Fowler, J.S.

    2011-01-13

    Subjects with binge eating disorder (BED) regularly consume large amounts of food in short time periods. The neurobiology of BED is poorly understood. Brain dopamine, which regulates motivation for food intake, is likely to be involved. We assessed the involvement of brain dopamine in the motivation for food consumption in binge eaters. Positron emission tomography (PET) scans with [{sup 11}C]raclopride were done in 10 obese BED and 8 obese subjects without BED. Changes in extracellular dopamine in the striatum in response to food stimulation in food-deprived subjects were evaluated after placebo and after oral methylphenidate (MPH), a drug that blocks the dopamine reuptake transporter and thus amplifies dopamine signals. Neither the neutral stimuli (with or without MPH) nor the food stimuli when given with placebo increased extracellular dopamine. The food stimuli when given with MPH significantly increased dopamine in the caudate and putamen in the binge eaters but not in the nonbinge eaters. Dopamine increases in the caudate were significantly correlated with the binge eating scores but not with BMI. These results identify dopamine neurotransmission in the caudate as being of relevance to the neurobiology of BED. The lack of correlation between BMI and dopamine changes suggests that dopamine release per se does not predict BMI within a group of obese individuals but that it predicts binge eating.

  5. Enhanced striatal dopamine release during food stimulation in binge eating disorder.

    Science.gov (United States)

    Wang, Gene-Jack; Geliebter, Allan; Volkow, Nora D; Telang, Frank W; Logan, Jean; Jayne, Millard C; Galanti, Kochavi; Selig, Peter A; Han, Hao; Zhu, Wei; Wong, Christopher T; Fowler, Joanna S

    2011-08-01

    Subjects with binge eating disorder (BED) regularly consume large amounts of food in short time periods. The neurobiology of BED is poorly understood. Brain dopamine, which regulates motivation for food intake, is likely to be involved. We assessed the involvement of brain dopamine in the motivation for food consumption in binge eaters. Positron emission tomography (PET) scans with [(11)C]raclopride were done in 10 obese BED and 8 obese subjects without BED. Changes in extracellular dopamine in the striatum in response to food stimulation in food-deprived subjects were evaluated after placebo and after oral methylphenidate (MPH), a drug that blocks the dopamine reuptake transporter and thus amplifies dopamine signals. Neither the neutral stimuli (with or without MPH) nor the food stimuli when given with placebo increased extracellular dopamine. The food stimuli when given with MPH significantly increased dopamine in the caudate and putamen in the binge eaters but not in the nonbinge eaters. Dopamine increases in the caudate were significantly correlated with the binge eating scores but not with BMI. These results identify dopamine neurotransmission in the caudate as being of relevance to the neurobiology of BED. The lack of correlation between BMI and dopamine changes suggests that dopamine release per se does not predict BMI within a group of obese individuals but that it predicts binge eating.

  6. Monitoring axonal and somatodendritic dopamine release using fast-scan cyclic voltammetry in brain slices.

    Science.gov (United States)

    Patel, Jyoti C; Rice, Margaret E

    2013-01-01

    Brain dopamine pathways serve wide-ranging functions including the control of movement, reward, cognition, learning, and mood. Consequently, dysfunction of dopamine transmission has been implicated in clinical conditions such as Parkinson's disease, schizophrenia, addiction, and depression. Establishing factors that regulate dopamine release can provide novel insights into dopaminergic communication under normal conditions, as well as in animal models of disease in the brain. Here we describe methods for the study of somatodendritic and axonal dopamine release in brain slice preparations. Topics covered include preparation and calibration of carbon-fiber microelectrodes for use with fast-scan cyclic voltammetry, preparation of midbrain and forebrain slices, and procedures of eliciting and recording electrically evoked dopamine release from in vitro brain slices.

  7. Real-time electrochemical recording of dopamine release under optogenetic stimulation.

    Directory of Open Access Journals (Sweden)

    Wen-Tai Chiu

    Full Text Available Dopaminergic PC12 cells can synthesize and release dopamine, providing a good cellular model for investigating dopamine regulation. Optogenetic stimulation of channelrhodopsin-2 provides high spatial and temporal precision for selective stimulation as a powerful neuromodulation tool for neuroscience studies. The aim of this study is to measure dopamine release from dopaminergic PC12 cells under optogenetic stimulation using electrochemical recording of self-assembled monolayers modified microelectrode with amperometric measurement in real time. The activation of PC12 cells under various optogenetic stimulation schemes are characterized by measuring single-cell Ca(2+ imaging. After 10 seconds of optogenetic stimulation, the evoked intracellular Ca(2+ level and dopamine current of channelrhodopsin-2-transfected PC12 cells were 1.6- and 3.5-fold higher than those of the control cells. The optogenetic stimulation effects on Ca(2+ influx and dopamine release were 81% and 63% inhibition by using a Ca(2+ channel antagonist Nifedipine. The results indicate that optogenetic stimulation can evoke voltage-gated Ca(2+ channel-dependent dopamine exocytosis from PC12 cells in a cell specific, temporally precise and dose-dependent manner. This proposed dopamine recording system can be developed to be a good cell model for dopamine regulation and drug screening in vitro, or dopaminergic cell implantation therapy in vivo using optogenetic stimulation in a precise and convenient way.

  8. Real-time electrochemical recording of dopamine release under optogenetic stimulation.

    Science.gov (United States)

    Chiu, Wen-Tai; Lin, Che-Ming; Tsai, Tien-Chun; Wu, Chun-Wei; Tsai, Ching-Lin; Lin, Sheng-Hsiang; Chen, Jia-Jin Jason

    2014-01-01

    Dopaminergic PC12 cells can synthesize and release dopamine, providing a good cellular model for investigating dopamine regulation. Optogenetic stimulation of channelrhodopsin-2 provides high spatial and temporal precision for selective stimulation as a powerful neuromodulation tool for neuroscience studies. The aim of this study is to measure dopamine release from dopaminergic PC12 cells under optogenetic stimulation using electrochemical recording of self-assembled monolayers modified microelectrode with amperometric measurement in real time. The activation of PC12 cells under various optogenetic stimulation schemes are characterized by measuring single-cell Ca(2+) imaging. After 10 seconds of optogenetic stimulation, the evoked intracellular Ca(2+) level and dopamine current of channelrhodopsin-2-transfected PC12 cells were 1.6- and 3.5-fold higher than those of the control cells. The optogenetic stimulation effects on Ca(2+) influx and dopamine release were 81% and 63% inhibition by using a Ca(2+) channel antagonist Nifedipine. The results indicate that optogenetic stimulation can evoke voltage-gated Ca(2+) channel-dependent dopamine exocytosis from PC12 cells in a cell specific, temporally precise and dose-dependent manner. This proposed dopamine recording system can be developed to be a good cell model for dopamine regulation and drug screening in vitro, or dopaminergic cell implantation therapy in vivo using optogenetic stimulation in a precise and convenient way.

  9. Membrane permeable C-terminal dopamine transporter peptides attenuate amphetamine-evoked dopamine release

    DEFF Research Database (Denmark)

    Rickhag, Karl Mattias; Owens, WA; Winkler, Marie-Therese

    2013-01-01

    The dopamine transporter (DAT) is responsible for sequestration of extracellular dopamine (DA). The psychostimulant amphetamine (AMPH) is a DAT substrate, which is actively transported into the nerve terminal, eliciting vesicular depletion and reversal of DA transport via DAT. Here, we investigate...

  10. Doped Overoxidized Polypyrrole Microelectrodes as Sensors for the Detection of Dopamine Released from Cell Populations

    DEFF Research Database (Denmark)

    Sasso, Luigi; Heiskanen, Arto; Diazzi, Francesco

    2013-01-01

    A surface modification of interdigitated gold microelectrodes (IDEs) with a doped polypyrrole (PPy) film for detection of dopamine released from populations of differentiated PC12 cells is presented. A thin PPy layer was potentiostatically electropolymerized from an 10 aqueous pyrrole solution onto...... in dopamine detection. Overoxidation of the PPy films was shown to contribute to a significant enhancement in sensitivity to dopamine. The changes caused by overoxidation in the electrochemical behavior and electrode morphology were investigated using cyclic voltammetry and SEM as well as AFM, respectively....... The optimal dopant for dopamine detection was found to be polystyrenesulfonate anion (PSS-15 ). Rat pheochromocytoma (PC12) cells, a suitable model to study exocytotic dopamine release, were differentiated on IDEs functionalized with an overoxidized PSS--doped PPy film. The modified electrodes were used...

  11. The Anorexigenic Peptide Neuromedin U (NMU Attenuates Amphetamine-Induced Locomotor Stimulation, Accumbal Dopamine Release and Expression of Conditioned Place Preference in Mice.

    Directory of Open Access Journals (Sweden)

    Daniel Vallöf

    Full Text Available Amphetamine dependence, besides its substantial economical consequence, is a serious cause of mortality and morbidity. By investigations of the neurochemical correlates through which addictive drugs, such as amphetamine, activate the mesoaccumbal dopamine system unique targets for treatment of drug addiction can be identified. This reward link consists of a dopamine projection from the ventral tegmental area to the nucleus accumbens (NAc suggesting that these brain areas are important for reward. The physiological function of gut-brain peptides has expanded beyond food intake modulation and involves regulation of drug reinforcement. A novel candidate for reward regulation is the anorexigenic peptide neuromedin U (NMU. We therefore investigated the effects of intracerebroventricular (icv administration of NMU on amphetamine's well-documented effects on the mesoaccumbal dopamine system, i.e. locomotor stimulation and accumbal dopamine release in mice. In addition, the effect of accumbal NMU administration on locomotor activity was examined. The effect of NMU, icv or intra-NAc, on the expression of conditioned place preference (CPP was elucidated. Firstly, we showed that icv administration of NMU attenuate the amphetamine-induced locomotor stimulation, accumbal dopamine release and expression of CPP in mice. Secondly, we found that a lower dose of NMU (icv reduce the amphetamine-induced locomotor stimulation in mice. Thirdly, we demonstrated that NMU administration into the NAc block the ability of amphetamine to cause a locomotor stimulation in mice. However, accumbal NMU administration did not attenuate the amphetamine-induced expression of CPP in mice. Our novel data suggest that central NMU signalling is involved in development of amphetamine dependence.

  12. Attenuated Tonic and Enhanced Phasic Release of Dopamine in Attention Deficit Hyperactivity Disorder.

    Directory of Open Access Journals (Sweden)

    Rajendra D Badgaiyan

    Full Text Available It is unclear whether attention deficit hyperactive disorder (ADHD is a hypodopaminergic or hyperdopaminergic condition. Different sets of data suggest either hyperactive or hypoactive dopamine system. Since indirect methods used in earlier studies have arrived at contradictory conclusions, we directly measured the tonic and phasic release of dopamine in ADHD volunteers. The tonic release in ADHD and healthy control volunteers was measured and compared using dynamic molecular imaging technique. The phasic release during performance of Eriksen's flanker task was measured in the two groups using single scan dynamic molecular imaging technique. In these experiments volunteers were positioned in a positron emission tomography (PET camera and administered a dopamine receptor ligand (11C-raclopride intravenously. After the injection PET data were acquired dynamically while volunteers either stayed still (tonic release experiments or performed the flanker task (phasic release experiments. PET data were analyzed to measure dynamic changes in ligand binding potential (BP and other receptor kinetic parameters. The analysis revealed that at rest the ligand BP was significantly higher in the right caudate of ADHD volunteers suggesting reduced tonic release. During task performance significantly lower ligand BP was observed in the same area, indicating increased phasic release. In ADHD tonic release of dopamine is attenuated and the phasic release is enhanced in the right caudate. By characterizing the nature of dysregulated dopamine neurotransmission in ADHD, the results explain earlier findings of reduced or increased dopaminergic activity.

  13. 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.

  14. 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

  15. Chlorpromazine, haloperidol, metoclopramide and domperidone release prolactin through dopamine antagonism at low concentrations but paradoxically inhibit prolactin release at high concentrations.

    Science.gov (United States)

    Besser, G. M.; Delitala, G.; Grossman, A.; Stubbs, W. A.; Yeo, T.

    1980-01-01

    1. The effects of chlorpromazine, haloperidol, metoclopramide and domperidone on the release of prolactin from perfused columns of dispersed rat anterior pituitary cells were studied. 2. Chlorpromazine, haloperidol, metoclopramide and domperidone antagonized the dopamine-mediated inhibition of prolactin release at low concentrations. 3. Each dopamine antagonist displaced the dose-response curve for dopamine-induced suppression of prolactin release to the right in a parallel manner. 4. At higher concentrations, the four drugs became less effective as dopamine antagonists. 5. At high concentrations in the absence of dopamine, chlorpromazine, haloperidol, metoclopramide and domperidone paradoxically suppressed prolactin secretion by an unknown mechanism. PMID:6110459

  16. Doped overoxidized polypyrrole microelectrodes as sensors for the detection of dopamine released from cell populations.

    Science.gov (United States)

    Sasso, Luigi; Heiskanen, Arto; Diazzi, Francesco; Dimaki, Maria; Castillo-León, Jaime; Vergani, Marco; Landini, Ettore; Raiteri, Roberto; Ferrari, Giorgio; Carminati, Marco; Sampietro, Marco; Svendsen, Winnie E; Emnéus, Jenny

    2013-07-07

    A surface modification of interdigitated gold microelectrodes (IDEs) with a doped polypyrrole (PPy) film for detection of dopamine released from populations of differentiated PC12 cells is presented. A thin PPy layer was potentiostatically electropolymerized from an aqueous pyrrole solution onto electrode surfaces. The conducting polymer film was doped during electropolymerization by introducing counter-ions in the monomer solution. Several counter-ions were tested and the resulting electrode modifications were characterized electrochemically to find the optimal dopant that increases sensitivity in dopamine detection. Overoxidation of the PPy films was shown to contribute to a significant enhancement in sensitivity to dopamine. The changes caused by overoxidation in the electrochemical behavior and electrode morphology were investigated using cyclic voltammetry and SEM as well as AFM, respectively. The optimal dopant for dopamine detection was found to be polystyrene sulfonate anion (PSS(-)). Rat pheochromocytoma (PC12) cells, a suitable model to study exocytotic dopamine release, were differentiated on IDEs functionalized with an overoxidized PSS(-)-doped PPy film. The modified electrodes were used to amperometrically detect dopamine released by populations of cells upon triggering cellular exocytosis with an elevated K(+) concentration. A comparison between the generated current on bare gold electrodes and gold electrodes modified with overoxidized doped PPy illustrates the clear advantage of the modification, yielding 2.6-fold signal amplification. The results also illustrate how to use cell population based dopamine exocytosis measurements to obtain biologically significant information that can be relevant in, for instance, the study of neural stem cell differentiation into dopaminergic neurons.

  17. 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.

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

    Science.gov (United States)

    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. 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.

  20. The possible interaction of dopamine system in nucleus accumbens shell and glutamate system of prelimbic region on locomotor activity in rat

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    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.

  1. Tyrosine administration enhances dopamine synthesis and release in light-activated rat retina

    Science.gov (United States)

    Gibson, C. J.; Watkins, C. J.; Wurtman, R. J.

    1983-01-01

    Exposure of dark-adapted albino rats to light (350 lux) significantly elevated retinal levels of the dopamine metabolite dihydroxyphenyl acetic acid during the next hour; their return to a dark environment caused dihydroxyphenyl acetic acid levels to fall. Retinal dopamine levels were increased slightly by light exposure, suggesting that the increase in dihydroxyphenyl acetic acid reflected accelerated dopamine synthesis. Administration of tyrosine (100 mg/kg, i.p.) further elevated retinal dihydroxyphenyl acetic acid among light-exposed animals, but failed to affect dopamine release among animals in the dark. These observations show that a physiological stimulus - light exposure - can cause catecholaminergic neurons to become tyrosine-dependent; they also suggest that food consumption may affect neurotransmitter release within the retina.

  2. BOLD and its connection to dopamine release in human striatum: a cross-cohort comparison

    Science.gov (United States)

    Lohrenz, Terry; Kishida, Kenneth T.

    2016-01-01

    Activity in midbrain dopamine neurons modulates the release of dopamine in terminal structures including the striatum, and controls reward-dependent valuation and choice. This fluctuating release of dopamine is thought to encode reward prediction error (RPE) signals and other value-related information crucial to decision-making, and such models have been used to track prediction error signals in the striatum as encoded by BOLD signals. However, until recently there have been no comparisons of BOLD responses and dopamine responses except for one clear correlation of these two signals in rodents. No such comparisons have been made in humans. Here, we report on the connection between the RPE-related BOLD signal recorded in one group of subjects carrying out an investment task, and the corresponding dopamine signal recorded directly using fast-scan cyclic voltammetry in a separate group of Parkinson's disease patients undergoing DBS surgery while performing the same task. The data display some correspondence between the signal types; however, there is not a one-to-one relationship. Further work is necessary to quantify the relationship between dopamine release, the BOLD signal and the computational models that have guided our understanding of both at the level of the striatum. This article is part of the themed issue ‘Interpreting BOLD: a dialogue between cognitive and cellular neuroscience’. PMID:27574306

  3. Glutamate stimulation of (/sup 3/H)dopamine release from dissociated cell cultures of rat ventral mesencephalon

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    Mount, H.; Welner, S.; Quirion, R.; Boksa, P.

    1989-04-01

    In dissociated cell cultures of fetal rat ventral mesencephalon preloaded with (3H)dopamine, glutamate (10(-5)-10(-3) M) stimulated the release of (3H)dopamine. Glutamate stimulation of (3H)dopamine release was Ca2+ dependent and was blocked by the glutamate antagonist, cis-2,3-piperidine dicarboxylic acid. Glutamate stimulation of (3H)dopamine release was not due to glutamate neurotoxicity because (1) glutamate did not cause release of a cytosolic marker, lactate dehydrogenase, and (2) preincubation of cultures with glutamate did not impair subsequent ability of the cells to take up or release (3H)dopamine. Thus, these dissociated cell cultures appear to provide a good model system to characterize glutamate stimulation of dopamine release. Release of (3H)dopamine from these cultures was stimulated by veratridine, an activator of voltage-sensitive Na+ channels, and this stimulation was blocked by tetrodotoxin. However, glutamate-stimulated (3H)dopamine release was not blocked by tetrodotoxin or Zn2+. Substitution of NaCl in the extracellular medium by sucrose, LiCl, or Na2SO4 had no effect on glutamate stimulation of (3H)dopamine release; however, release was inhibited when NaCl was replaced by choline chloride or N-methyl-D-glucamine HCl. Glutamate-stimulated (3H)-dopamine release was well maintained (60-82% of control) in the presence of Co2+, which blocks Ca2+ action potentials, and was unaffected by the local anesthetic, lidocaine. These results are discussed in terms of the receptor and ionic mechanisms involved in the stimulation of dopamine release by excitatory amino acids.

  4. Enhanced Dopamine Release by Dopamine Transport Inhibitors Described by a Restricted Diffusion Model and Fast-Scan Cyclic Voltammetry.

    Science.gov (United States)

    Hoffman, Alexander F; Spivak, Charles E; Lupica, Carl R

    2016-06-15

    Fast-scan cyclic voltammetry (FSCV) using carbon fiber electrodes is widely used to rapidly monitor changes in dopamine (DA) levels in vitro and in vivo. Current analytical approaches utilize parameters such as peak oxidation current amplitude and decay times to estimate release and uptake processes, respectively. However, peak amplitude changes are often observed with uptake inhibitors, thereby confounding the interpretation of these parameters. To overcome this limitation, we demonstrate that a simple five-parameter, two-compartment model mathematically describes DA signals as a balance of release (r/ke) and uptake (ku), summed with adsorption (kads and kdes) of DA to the carbon electrode surface. Using nonlinear regression, we demonstrate that our model precisely describes measured DA signals obtained in brain slice recordings. The parameters extracted from these curves were then validated using pharmacological manipulations that selectively alter vesicular release or DA transporter (DAT)-mediated uptake. Manipulation of DA release through altering the Ca(2+)/Mg(2+) ratio or adding tetrodotoxin reduced the release parameter with no effect on the uptake parameter. DAT inhibitors methylenedioxypyrovalerone, cocaine, and nomifensine significantly reduced uptake and increased vesicular DA release. In contrast, a low concentration of amphetamine reduced uptake but had no effect on DA release. Finally, the kappa opioid receptor agonist U50,488 significantly reduced vesicular DA release but had no effect on uptake. Together, these data demonstrate a novel analytical approach to distinguish the effects of manipulations on DA release or uptake that can be used to interpret FSCV data.

  5. Dopamine release from transplanted neural stem cells in Parkinsonian rat striatum in vivo.

    Science.gov (United States)

    Kang, Xinjiang; Xu, Huadong; Teng, Sasa; Zhang, Xiaoyu; Deng, Zijun; Zhou, Li; Zuo, Panli; Liu, Bing; Liu, Bin; Wu, Qihui; Wang, Li; Hu, Meiqin; Dou, Haiqiang; Liu, Wei; Zhu, Feipeng; Li, Qing; Guo, Shu; Gu, Jingli; Lei, Qian; Lü, Jing; Mu, Yu; Jin, Mu; Wang, Shirong; Jiang, Wei; Liu, Kun; Wang, Changhe; Li, Wenlin; Zhang, Kang; Zhou, Zhuan

    2014-11-01

    Embryonic stem cell-based therapies exhibit great potential for the treatment of Parkinson's disease (PD) because they can significantly rescue PD-like behaviors. However, whether the transplanted cells themselves release dopamine in vivo remains elusive. We and others have recently induced human embryonic stem cells into primitive neural stem cells (pNSCs) that are self-renewable for massive/transplantable production and can efficiently differentiate into dopamine-like neurons (pNSC-DAn) in culture. Here, we showed that after the striatal transplantation of pNSC-DAn, (i) pNSC-DAn retained tyrosine hydroxylase expression and reduced PD-like asymmetric rotation; (ii) depolarization-evoked dopamine release and reuptake were significantly rescued in the striatum both in vitro (brain slices) and in vivo, as determined jointly by microdialysis-based HPLC and electrochemical carbon fiber electrodes; and (iii) the rescued dopamine was released directly from the grafted pNSC-DAn (and not from injured original cells). Thus, pNSC-DAn grafts release and reuptake dopamine in the striatum in vivo and alleviate PD symptoms in rats, providing proof-of-concept for human clinical translation.

  6. 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.

  7. Opposing effects of narcotic gases and pressure on the striatal dopamine release in rats.

    Science.gov (United States)

    Balon, Norbert; Kriem, Badreddine; Dousset, Erick; Weiss, Michel; Rostain, Jean-Claude

    2002-08-30

    Nitrogen-oxygen breathing mixtures, for pressures higher than 0.5 MPa, decrease the release of dopamine in the rat striatum, due to the narcotic potency of nitrogen. In contrast, high pressures of helium-oxygen breathing mixtures of more than 1-2 MPa induce an increase of the striatal dopamine release and an enhancement of motor activity, referred to as the high pressure nervous syndrome (HPNS), and attributed to the effect of pressure per se. It has been demonstrated that the effect of pressure could be antagonized by narcotic gas in a ternary mixture, but most of the narcotic gas studies measuring DA release were executed below the threshold for pressure effect. To examine the effect of narcotic gases at pressure on the rat striatal dopamine release, we have used two gases, with different narcotic potency, at sublethargic pressure, nitrogen at 3 MPa and argon at 2 MPa. In addition, to dissociate the effect of the pressure, we have used nitrous oxide at 0.1 MPa to induce narcosis at very low pressure, and helium at 8 MPa to study the effect of pressure per se. In all the narcotic conditions we have recorded a decrease of the striatal dopamine release. In contrast, helium pressure induced an increase of DA release. For the pressures used, the results suggest that the decrease of dopamine release was independent of such an effect of the pressure. However, for the same narcotic gas, the measurements of the extracellular DA performed in the striatum seem to reflect an opposing effect of pressure, since the decrease in DA release is lower with increasing pressure.

  8. 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.

  9. Salsolinol modulation of dopamine neurons

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    Guiqin eXie

    2013-05-01

    Full Text Available Salsolinol, a tetrahydroisoquinoline present in the human and rat brains, is the condensation product of dopamine and acetaldehyde, the first metabolite of ethanol. Previous evidence obtained in vivo links salsolinol with the mesolimbic dopaminergic system: salsolinol is self-administered into the posterior of the ventral tegmental area (pVTA of rats; intra-VTA administration of salsolinol induces a strong conditional place preference and increases dopamine release in the nucleus accumbens. However, the underlying neuronal mechanisms are unclear. Here we present an overview of some of the recent research on this topic. Electrophysiological studies reveal that dopaminergic neurons in the posterior ventral tegmental area (pVTA are a target of salsolinol. In acute brain slices from rats, salsolinol increases the excitability and accelerates the ongoing firing of dopamine neurons in the pVTA. Intriguingly, this action of salsolinol involves multiple pre- and post-synaptic mechanisms, including: (a depolarizing the membrane potential of dopamine neurons; (b activating mu opioid receptors on the GABAergic inputs to dopamine neurons, which decreases GABAergic activity and dopamine neurons are disinhibited; and (c enhancing presynaptic glutamatergic transmission onto dopamine neurons via activation of dopamine type 1 receptors, probably situated on the glutamatergic terminals. These novel mechanisms may contribute to the rewarding/reinforcing properties of salsolinol observed in vivo.

  10. SEMICIRCADIAN RHYTHM OF DOPAMINE RELEASE IN THE MEDIOBASAL HYPOTHALAMUS IN AWAKE RATS DURING PSEUDOPREGNANCY - EVIDENCE THAT A THYROTROPIN-RELEASING-HORMONE ANALOG STIMULATES DOPAMINE RELEASE AND THEREBY INHIBITS PROLACTIN SECRETION

    NARCIS (Netherlands)

    TIMMERMAN, W; POELMAN, RT; WESTERINK, BHC; SCHUILING, GA

    1995-01-01

    The release of dopamine (DA) from tuberoinfundibular (TIDA) neurons during prolactin (PRL) surge and nonsurge periods and the effects of the thyrotropin-releasing hormone (TRH) analogue CG 3703 on DA and PRL secretion were studied in awake pseudopregnant (PSP) rats by simultaneous measurement of ext

  11. Dopamine Release and Uptake Impairments and Behavioral Alterations Observed in Mice that Model Fragile X Mental Retardation Syndrome.

    Science.gov (United States)

    Fulks, Jenny L; O'Bryhim, Bliss E; Wenzel, Sara K; Fowler, Stephen C; Vorontsova, Elena; Pinkston, Jonathan W; Ortiz, Andrea N; Johnson, Michael A

    2010-10-20

    In this study we evaluated the relationship between amphetamine-induced behavioral alterations and dopamine release and uptake characteristics in Fmr1 knockout (Fmr1 KO) mice, which model fragile X syndrome. The behavioral analyses, obtained at millisecond temporal resolution and 2 mm spatial resolution using a force-plate actometer, revealed that Fmr1 KO mice express a lower degree of focused stereotypy compared to wild type (WT) control mice after injection with 10 mg/kg (ip) amphetamine. To identify potentially related neurochemical mechanisms underlying this phenomenon, we measured electrically-evoked dopamine release and uptake using fast-scan cyclic voltammetry at carbon-fiber microelectrodes in striatal brain slices. At 10 weeks of age, dopamine release per pulse, which is dopamine release corrected for differences in uptake, was unchanged. However, at 15 (the age of behavioral testing) and 20 weeks of age, dopamine per pulse and the maximum rate of dopamine uptake was diminished in Fmr1 KO mice compared to WT mice. Dopamine uptake measurements, obtained at different amphetamine concentrations, indicated that dopamine transporters in both genotypes have equal affinities for amphetamine. Moreover, dopamine release measurements from slices treated with quinpirole, a D2-family receptor agonist, rule out enhanced D2 autoreceptor sensitivity as a mechanism of release inhibition. However, dopamine release, uncorrected for uptake and normalized against the corresponding pre-drug release peaks, increased in Fmr1 KO mice, but not in WT mice. Collectively, these data are consistent with a scenario in which a decrease in extracellular dopamine levels in the striatum result in diminished expression of focused stereotypy in Fmr1 KO mice.

  12. Simultaneous measurement of glutamate and dopamine release from isolated guinea pig cochlea

    NARCIS (Netherlands)

    Halmos, Gyorgy; Lendvai, Balázs; Gáborján, Anita; Baranyi, Mária; Szabó, László Z; Csokonai Vitéz, Lajos

    2002-01-01

    Glutamate is proved to be a neurotransmitter in the mammalian cochlea, transmitting signals between the inner hair cells and the afferent cochlear nerve terminals. The transmission in this synapse is modulated by the lateral olivocochlear efferent fibers by releasing dopamine and other neurotransmit

  13. Regionally distinct phasic dopamine release patterns in the striatum during reversal learning

    NARCIS (Netherlands)

    Klanker, Marianne; Fellinger, Lisanne; Feenstra, M.G.P.; Willuhn, Ingo; Denys, D.

    2017-01-01

    Striatal dopamine (DA) plays a central role in reward-related learning and behavioral adaptation to changing environments. Recent studies suggest that rather than being broadcast as a uniform signal throughout the entire region, DA release dynamics diverge between different striatal regions. In a pr

  14. A new aspect of aminoglycoside ototoxicity : impairment of cochlear dopamine release

    NARCIS (Netherlands)

    Gáborján, A; Halmos, G; Répássy, G; Vizi, E S

    2001-01-01

    Aminoglycoside ototoxicity is a well-documented process via several pathophysiological pathways. The protective role of cochlear dopamine, released from the lateral olivocochlear efferents, was implicated previously in case of ischemia or acoustic trauma, as it postsynaptically inhibits the effect o

  15. Intrahippocampal Infusions of Anisomycin Produce Amnesia: Contribution of Increased Release of Norepinephrine, Dopamine, and Acetylcholine

    Science.gov (United States)

    Qi, Zhenghan; Gold, Paul E.

    2009-01-01

    Intra-amygdala injections of anisomycin produce large increases in the release of norepinephrine (NE), dopamine (DA), and serotonin in the amygdala. Pretreatment with intra-amygdala injections of the beta-adrenergic receptor antagonist propranolol attenuates anisomycin-induced amnesia without reversing the inhibition of protein synthesis, and…

  16. Cocaine serves as a peripheral interoceptive conditioned stimulus for central glutamate and dopamine release.

    Directory of Open Access Journals (Sweden)

    Roy A Wise

    Full Text Available Intravenous injections of cocaine HCl are habit-forming because, among their many actions, they elevate extracellular dopamine levels in the terminal fields of the mesocorticolimbic dopamine system. This action, thought to be very important for cocaine's strong addiction liability, is believed to have very short latency and is assumed to reflect rapid brain entry and pharmacokinetics of the drug. However, while intravenous cocaine HCl has almost immediate effects on behavior and extracellular dopamine levels, recent evidence suggests that its central pharmacological effects are not evident until 10 or more seconds after IV injection. Thus the immediate effects of a given intravenous cocaine injection on extracellular dopamine concentration and behavior appear to occur before there is sufficient time for cocaine to act centrally as a dopamine uptake inhibitor. To explore the contribution of peripheral effects of cocaine to the early activation of the dopamine system, we used brain microdialysis to measure the effects of cocaine methiodide (MI--a cocaine analogue that does not cross the blood brain barrier--on glutamate (excitatory input to the dopamine cells. IP injections of cocaine MI were ineffective in cocaine-naïve animals but stimulated ventral tegmental glutamate release in rats previously trained to lever-press for cocaine HCl. This peripherally triggered glutamate input was sufficient to reinstate cocaine-seeking in previously trained animals that had undergone extinction of the habit. These findings offer an explanation for short-latency behavioral responses and immediate dopamine elevations seen following cocaine injections in cocaine-experienced but not cocaine-naïve animals.

  17. Striatal dopamine release in a schizophrenia mouse model measured by electrochemical amperometry in vivo.

    Science.gov (United States)

    Xu, Huadong; Zuo, Panli; Wang, Shirong; Zhou, Li; Sun, Xiaoxuan; Hu, Meiqin; Liu, Bin; Wu, Qihui; Dou, Haiqiang; Liu, Bing; Zhu, Feipeng; Teng, Sasa; Zhang, Xiaoyu; Wang, Li; Li, Qing; Jin, Mu; Kang, Xinjiang; Xiong, Wei; Wang, Changhe; Zhou, Zhuan

    2015-06-01

    Schizophrenia is a severely devastating mental disorder, the pathological process of which is proposed to be associated with the dysfunction of dopaminergic transmission. Our previous results have demonstrated slower kinetics of transmitter release (glutamate release in hippocampus and norepinephrine release in adrenal slice) in a schizophrenia model, dysbindin null-sandy mice. However, whether dopaminergic transmission in the nigrostriatal pathway contributes to the pathology of dysbindin-/- mice remains unknown. Here, we have provided a step-by-step protocol to be applied in the in vivo amperometric recording of dopamine (DA) release from the mouse striatum evoked by an action potential (AP) pattern. With this protocol, AP pattern-dependent DA release was recorded from dysbindin-/- mice striatum in vivo. On combining amperometric recording in slices and electrophysiology, we found that in dysbindin-/- mice, (1) presynaptically, AP-pattern dependent dopamine overflow and uptake were intact in vivo; (2) the recycling of the dopamine vesicle pool remained unchanged. (3) Postsynaptically, the excitability of medium spiny neuron (MSN) was also normal, as revealed by patch-clamp recordings in striatal slices. Taken together, in contrast to reduced norepinephrine release in adrenal chromaffin cells, the dopaminergic transmission remains unchanged in the nigrostriatal pathway in dysbindin-/- mice, providing a new insight into the functions of the schizophrenia susceptibility gene dysbindin.

  18. pH-regulated release of dopamine from well-ordered self-assembled monolayers: electrochemical studies.

    Science.gov (United States)

    Kazemi, Sayed Habib; Alizadeh, Abdolhamid; Mohamadi, Rahim; Khodaei, Mohammad Mahdi; Kordestani, Davood

    2013-12-01

    In the present work, gold electrode modified with novel aldehyde-terminated self-assembled monolayers (SAMs) was used for controllable load and release of dopamine molecules by pH triggering. Electrochemical techniques including cyclic voltammetry (CV) and electrochemcial impedance spectroscopy (EIS) were employed to investigate the SAMs characteristic on the gold electrode surface. The electrochemical experiments indicated Faradaic behavior for the electrode surface after its modification with dopamine. Notably, it was observed that decreasing the conditioning pH, results in a decrease of peak currents, presumably due to the hydrolysis of the terminal imine bonds and releasing the dopamine moiety into the solution. Moreover, the preliminary kinetics studies were done for dopamine release from the SAMs surface as a model to design future drug delivery systems. Finally, the rate constant of dopamine release from the SAMs modified surface estimated to be 0.167 day(-1) at pH=3.

  19. Striatal dopamine release and biphasic pattern of locomotor and motor activity under gas narcosis.

    Science.gov (United States)

    Balon, Norbert; Risso, Jean-Jacques; Blanc, François; Rostain, Jean-Claude; Weiss, Michel

    2003-05-02

    Inert gas narcosis is a neurological syndrome appearing when humans or animals are exposed to hyperbaric inert gases (nitrogen, argon) composed by motor and cognitive impairments. Inert gas narcosis induces a decrease of the dopamine release at the striatum level, structure involved in the regulation of the extrapyramidal motricity. We have investigated, in freely moving rats exposed to different narcotic conditions, the relationship between the locomotor and motor activity and the striatal dopamine release, using respectively a computerized device that enables a quantitative analysis of this behavioural disturbance and voltammetry. The use of 3 MPa of nitrogen, 2 MPa of argon and 0.1 MPa of nitrous oxide, revealed after a transient phase of hyperactivity, a lower level of the locomotor and motor activity, in relation with the decrease of the striatal dopamine release. It is concluded that the striatal dopamine decrease could be related to the decrease of the locomotor and motor hyperactivity, but that other(s) neurotransmitter(s) could be primarily involved in the behavioural motor disturbances induced by narcotics. This biphasic effect could be of major importance for future pharmacological investigations, and motor categorization, on the basic mechanisms of inert gas at pressure.

  20. Signaling Mechanisms in the Nitric Oxide Donor- and Amphetamine-Induced Dopamine Release in Mesencephalic Primary Cultured Neurons.

    Science.gov (United States)

    Salum, Cristiane; Schmidt, Fanny; Michel, Patrick P; Del-Bel, Elaine; Raisman-Vozari, Rita

    2016-01-01

    Previous research has shown that nitric oxide (NO) synthase inhibitors prevent rodents' sensorimotor gating impairments induced by dopamine releasing drugs, such as amphetamine (Amph) and methylphenidate. The mechanisms of this effect have not been entirely understood. In the present work, we investigated some possible mechanisms by which the NO donor, NOC-12 (3-ethyl-3-(ethylaminoethyl)-1-hydroxy-2-oxo-1-triazene), influence spontaneous and Amph-induced dopamine release, using rat mesencephalic primary cultured neurons preparations. Our results showed that NOC-12 increased dopamine release in a concentration-dependent manner and potentiated the Amph-induced one. Dopamine release induced by NOC-12 was disrupted by N-acetyl-L-cystein (NAC-a free radical scavenger) and MK-801, a NMDA (N-methyl-D-aspartate) non-competitive antagonist, and was concentration dependently affected by oxadiazolo[4,3]quinoxalin-1-one, an inhibitor of the soluble guanylate cyclase (sGC). In contrast, dopamine released by Amph was facilitated by NAC and by MK-801 and not affected by nifedipine (a L-type-Ca(+2) channel blocker), which enhanced NOC-12-induced dopamine release. The present work demonstrates that DA release induced by NOC-12 is partially dependent on sGC and on NMDA activation, and is modulated by L-type Ca(+2) channel and the antioxidant NAC. This mechanism differs from the Amph-induced one, which appears not to depend on L-type Ca(+2) channel and seems to be facilitated by NMDA channel blocking and by NAC. These results suggest that Amph and NOC-12 induce dopamine release through complementary pathways, which may explain the potentiation of Amph-induced dopamine release by NOC-12. These findings contribute to understand the involvement of NO in dopamine-related neuropsychiatric and neurodegenerative diseases.

  1. The prefrontal cortex regulates the basal release of dopamine in the limbic striatum : An effect mediated by ventral tegmental area

    NARCIS (Netherlands)

    Karreman, M; Moghaddam, B

    1996-01-01

    The present study examined whether the prefrontal cortex (PFC) exerts a tonic control over the basal release of dopamine in the limbic striatum and whether this control is mediated by glutamatergic afferents to the dopamine cell body or terminal regions. Using intracerebral microdialysis in freely m

  2. Optogenetic stimulation of VTA dopamine neurons reveals that tonic but not phasic patterns of dopamine transmission reduce ethanol self-administration

    Directory of Open Access Journals (Sweden)

    Caroline E Bass

    2013-11-01

    Full Text Available There is compelling evidence that acute ethanol exposure stimulates ventral tegmental area (VTA dopamine cell activity and that VTA-dependent dopamine release in terminal fields within the nucleus accumbens plays an integral role in the regulation of ethanol drinking behaviors. Unfortunately, due to technical limitations, the specific temporal dynamics linking VTA dopamine cell activation and ethanol self-administration are not known. In fact, establishing a causal link between specific patterns of dopamine transmission and ethanol drinking behaviors has proven elusive. Here, we sought to address these gaps in our knowledge using a newly developed viral-mediated gene delivery strategy to selectively express Channelrhodopsin-2 (ChR2 on dopamine cells in the VTA of wild-type rats. We then used this approach to precisely control VTA dopamine transmission during voluntary ethanol drinking sessions. The results confirmed that ChR2 was selectively expressed on VTA dopamine cells and delivery of blue light pulses to the VTA induced dopamine release in accumbal terminal fields with very high temporal and spatial precision. Brief high frequency VTA stimulation induced phasic patterns of dopamine release in the nucleus accumbens. Lower frequency stimulation, applied for longer periods mimicked tonic increases in accumbal dopamine. Notably, using this optogenetic approach in rats engaged in an intermittent ethanol drinking procedure, we found that tonic, but not phasic, stimulation of VTA dopamine cells selectively attenuated ethanol drinking behaviors. Collectively, these data demonstrate the effectiveness of a novel viral targeting strategy that can be used to restrict opsin expression to dopamine cells in standard outbred animals and provide the first causal evidence demonstrating that tonic activation of VTA dopamine neurons selectively decreases ethanol self-administration behaviors.

  3. Optogenetic stimulation of VTA dopamine neurons reveals that tonic but not phasic patterns of dopamine transmission reduce ethanol self-administration.

    Science.gov (United States)

    Bass, Caroline E; Grinevich, Valentina P; Gioia, Dominic; Day-Brown, Jonathan D; Bonin, Keith D; Stuber, Garret D; Weiner, Jeff L; Budygin, Evgeny A

    2013-01-01

    There is compelling evidence that acute ethanol exposure stimulates ventral tegmental area (VTA) dopamine cell activity and that VTA-dependent dopamine release in terminal fields within the nucleus accumbens plays an integral role in the regulation of ethanol drinking behaviors. Unfortunately, due to technical limitations, the specific temporal dynamics linking VTA dopamine cell activation and ethanol self-administration are not known. In fact, establishing a causal link between specific patterns of dopamine transmission and ethanol drinking behaviors has proven elusive. Here, we sought to address these gaps in our knowledge using a newly developed viral-mediated gene delivery strategy to selectively express Channelrhodopsin-2 (ChR2) on dopamine cells in the VTA of wild-type rats. We then used this approach to precisely control VTA dopamine transmission during voluntary ethanol drinking sessions. The results confirmed that ChR2 was selectively expressed on VTA dopamine cells and delivery of blue light pulses to the VTA induced dopamine release in accumbal terminal fields with very high temporal and spatial precision. Brief high frequency VTA stimulation induced phasic patterns of dopamine release in the nucleus accumbens. Lower frequency stimulation, applied for longer periods mimicked tonic increases in accumbal dopamine. Notably, using this optogenetic approach in rats engaged in an intermittent ethanol drinking procedure, we found that tonic, but not phasic, stimulation of VTA dopamine cells selectively attenuated ethanol drinking behaviors. Collectively, these data demonstrate the effectiveness of a novel viral targeting strategy that can be used to restrict opsin expression to dopamine cells in standard outbred animals and provide the first causal evidence demonstrating that tonic activation of VTA dopamine neurons selectively decreases ethanol self-administration behaviors.

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

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    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.

  5. Effects of oral exposure to mining waste on in vivo dopamine release from rat striatum.

    OpenAIRE

    1998-01-01

    Several single components of mining waste (arsenic, manganese, lead, cadmium) to which humans are exposed at the mining area of Villa de la Paz, Mexico, are known to provoke alterations of striatal dopaminergic parameters. In this study we used an animal model to examine neurochemical changes resulting from exposure to a metal mixture. We used microdialysis to compare in vivo dopamine release from adult rats subchronically exposed to a mining waste by oral route with those from a control grou...

  6. Dopamine release in organotypic cultures of foetal mouse mesencephalon: effects of depolarizing agents, pargyline, nomifensine, tetrodotoxin and calcium

    DEFF Research Database (Denmark)

    Larsen, Trine R; Rossen, Sine; Gramsbergen, Jan B

    2008-01-01

    Organotypic mesencephalic cultures provide an attractive in vitro alternative to study development of the nigrostriatal system and pathophysiological mechanisms related to Parkinson's disease. However, dopamine (DA) release mechanisms have been poorly characterized in such cultures. We report here...

  7. Intracerebroventricular administration of ouabain alters synaptic plasticity and dopamine release in rat medial prefrontal cortex.

    Science.gov (United States)

    Sui, Li; Song, Xiao-Jin; Ren, Jie; Ju, Li-Hua; Wang, Yan

    2013-08-01

    Intracerebroventricular (ICV) administration of ouabain, a specific Na-K-ATPase inhibitor, in rats mimics the manic phenotypes of bipolar disorder and thus has been proposed as one of the best animal models of mania. Bipolar mania has been known to be associated with dysfunctions of medial prefrontal cortex (mPFC), a brain area critically involved in mental functions; however, the exact mechanism underlying these dysfunctions is not yet clear. The present study investigated synaptic transmission, synaptic plasticity, and dopamine release in Sprague-Dawley rat mPFC following ICV administration of ouabain (5 μl of 1 mM ouabain). The electrophysiological results demonstrated that ouabain depressed the short- and the long-term synaptic plasticity, represented by paired-pulse facilitation and long-term potentiation, respectively, in the mPFC. These ouabain-induced alterations in synaptic plasticity can be prevented by pre-treatment with lithium (intraperitoneal injection of 47.5 mg/kg lithium, twice a day, 7 days), which acts as an effective mood stabilizer in preventing mania. The electrochemical results demonstrated that ICV administration of ouabain enhanced dopamine release in the mPFC, which did not be affected by pre-treatment with lithium. These findings suggested that alterations in synaptic plasticity and dopamine release in the mPFC might underlie the dysfunctions of mPFC accompanied with ouabain administration-induced bipolar mania.

  8. Reward-Induced Phasic Dopamine Release in the Monkey Ventral Striatum and Putamen.

    Science.gov (United States)

    Yoshimi, Kenji; Kumada, Shiori; Weitemier, Adam; Jo, Takayuki; Inoue, Masato

    2015-01-01

    In-vivo voltammetry has successfully been used to detect dopamine release in rodent brains, but its application to monkeys has been limited. We have previously detected dopamine release in the caudate of behaving Japanese monkeys using diamond microelectrodes (Yoshimi 2011); however it is not known whether the release pattern is the same in various areas of the forebrain. Recent studies have suggested variations in the dopaminergic projections to forebrain areas. In the present study, we attempted simultaneous recording at two locations in the striatum, using fast-scan cyclic voltammetry (FSCV) on carbon fibers, which has been widely used in rodents. Responses to unpredicted food and liquid rewards were detected repeatedly. The response to the liquid reward after conditioned stimuli was enhanced after switching the prediction cue. These characteristics were generally similar between the ventral striatum and the putamen. Overall, the technical application of FSCV recording in multiple locations was successful in behaving primates, and further voltammetric recordings in multiple locations will expand our knowledge of dopamine reward responses.

  9. Reward-Induced Phasic Dopamine Release in the Monkey Ventral Striatum and Putamen.

    Directory of Open Access Journals (Sweden)

    Kenji Yoshimi

    Full Text Available In-vivo voltammetry has successfully been used to detect dopamine release in rodent brains, but its application to monkeys has been limited. We have previously detected dopamine release in the caudate of behaving Japanese monkeys using diamond microelectrodes (Yoshimi 2011; however it is not known whether the release pattern is the same in various areas of the forebrain. Recent studies have suggested variations in the dopaminergic projections to forebrain areas. In the present study, we attempted simultaneous recording at two locations in the striatum, using fast-scan cyclic voltammetry (FSCV on carbon fibers, which has been widely used in rodents. Responses to unpredicted food and liquid rewards were detected repeatedly. The response to the liquid reward after conditioned stimuli was enhanced after switching the prediction cue. These characteristics were generally similar between the ventral striatum and the putamen. Overall, the technical application of FSCV recording in multiple locations was successful in behaving primates, and further voltammetric recordings in multiple locations will expand our knowledge of dopamine reward responses.

  10. Nicotine enhancement of dopamine release by a calcium-dependent increase in the size of the readily releasable pool of synaptic vesicles.

    Science.gov (United States)

    Turner, Timothy J

    2004-12-15

    A major factor underlying compulsive tobacco use is nicotine-induced modulation of dopamine release in the mesolimbic reward pathway (Wise and Rompre, 1989). An established biochemical mechanism for nicotine-enhanced dopamine release is by activating presynaptic nicotinic acetylcholine receptors (nAChRs) (Wonnacott, 1997). Prolonged application of 10(-7) to 10(-5) m nicotine to striatal synaptosomes promoted a sustained efflux of [3H]dopamine. This nicotine effect was mediated by non-alpha7 nAChRs, because it was blocked by 5 mum mecamylamine but was resistant to 100 nm alpha-bungarotoxin (alphaBgTx). Dopamine release was diminished by omitting Na+ or by applying peptide calcium channel blockers, indicating that nAChRs trigger release by depolarizing the nerve terminals. However, because alpha7 receptors rapidly desensitize in the continuous presence of agonists, a repetitive stimulation protocol was used to evaluate the possible significance of desensitization. This protocol produced a transient increase in [3H]dopamine released by depolarization and a significant increase in the response to hypertonic solutions that measure the size of the readily releasable pool (RRP) of synaptic vesicles. The nicotine-induced increase in the size of the readily releasable pool was blocked by alphaBgTx and by the calmodulin antagonist calmidazolium, suggesting that Ca2+ entry through alpha7 nAChRs specifically enhances synaptic vesicle mobilization at dopamine terminals. Thus, nicotine enhances dopamine release by two complementary actions mediated by discrete nAChR subtypes and suggest that the alpha7 nAChR-mediated pathway is tightly and specifically coupled to refilling of the RRP of vesicles in dopamine terminals.

  11. Dopamine release in ventral striatum during Iowa Gambling Task performance is associated with increased excitement levels in pathological gambling

    DEFF Research Database (Denmark)

    Linnet, Jakob; Møller, Arne; Peterson, Ericka

    2011-01-01

    Gambling excitement is believed to be associated with biological measures of pathological gambling. Here, we tested the hypothesis that dopamine release would be associated with increased excitement levels in Pathological Gamblers compared with Healthy Controls.......Gambling excitement is believed to be associated with biological measures of pathological gambling. Here, we tested the hypothesis that dopamine release would be associated with increased excitement levels in Pathological Gamblers compared with Healthy Controls....

  12. Dopamine modulates acetylcholine release via octopamine and CREB signaling in Caenorhabditis elegans.

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    Satoshi Suo

    Full Text Available Animals change their behavior and metabolism in response to external stimuli. cAMP response element binding protein (CREB is a signal-activated transcription factor that enables the coupling of extracellular signals and gene expression to induce adaptive changes. Biogenic amine neurotransmitters regulate CREB and such regulation is important for long-term changes in various nervous system functions, including learning and drug addiction. In Caenorhabditis elegans, the amine neurotransmitter octopamine activates a CREB homolog, CRH-1, in cholinergic SIA neurons, whereas dopamine suppresses CREB activation by inhibiting octopamine signaling in response to food stimuli. However, the physiological role of this activation is unknown. In this study, the effect of dopamine, octopamine, and CREB on acetylcholine signaling was analyzed using the acetylcholinesterase inhibitor aldicarb. Mutants with decreased dopamine signaling exhibited reduced acetylcholine signaling, and octopamine and CREB functioned downstream of dopamine in this regulation. This study demonstrates that the regulation of CREB by amine neurotransmitters modulates acetylcholine release from the neurons of C. elegans.

  13. Clavulanic acid increases dopamine release in neuronal cells through a mechanism involving enhanced vesicle trafficking

    Science.gov (United States)

    Kost, Gina Chun; Selvaraj, Senthil; Lee, Young Bok; Kim, Deog Joong; Ahn, Chang-Ho; Singh, Brij B

    2011-01-01

    Clavulanic acid is a CNS-modulating compound with exceptional blood-brain barrier permeability and safety profile. Clavulanic acid has been proposed to have anti-depressant activity and is currently entering Phase IIb clinical trials for the treatment of Major Depressive Disorder (MDD). Studies have also shown that clavulanic acid suppresses anxiety and enhances sexual functions in rodent and primate models by a mechanism involving central nervous system (CNS) modulation, although its detailed mechanism of action has yet to be elucidated. To further examine its potential as a CNS modulating agent as well as its mechanism of action, we investigated the effects of clavulanic acid in neuronal cells. Our results indicate that clavulanic acid enhances dopamine release in PC12 and SH-SY5Y cells without affecting dopamine synthesis. Furthermore, using affinity chromatography we were able to identify two proteins, Munc18-1 and Rab4 that potentially bind to clavulanic acid and play a critical role in neurosecretion and the vesicle trafficking process. Consistent with this result, an increase in the translocation of Munc18-1 and Rab4 from the cytoplasm to the plasma membrane was observed in clavulanic acid treated cells. Overall, these data suggest that clavulanic acid enhances dopamine release in a mechanism involving Munc18-1 and Rab4 modulation and warrants further investigation of its therapeutic use in CNS disorders, such as depression. PMID:21964384

  14. Clavulanic acid increases dopamine release in neuronal cells through a mechanism involving enhanced vesicle trafficking.

    Science.gov (United States)

    Kost, Gina Chun; Selvaraj, Senthil; Lee, Young Bok; Kim, Deog Joong; Ahn, Chang-Ho; Singh, Brij B

    2011-10-24

    Clavulanic acid is a CNS-modulating compound with exceptional blood-brain barrier permeability and safety profile. Clavulanic acid has been proposed to have anti-depressant activity and is currently entering Phase IIb clinical trials for the treatment of Major Depressive Disorder (MDD). Studies have also shown that clavulanic acid suppresses anxiety and enhances sexual functions in rodent and primate models by a mechanism involving central nervous system (CNS) modulation, although its detailed mechanism of action has yet to be elucidated. To further examine its potential as a CNS modulating agent as well as its mechanism of action, we investigated the effects of clavulanic acid in neuronal cells. Our results indicate that clavulanic acid enhances dopamine release in PC12 and SH-SY5Y cells without affecting dopamine synthesis. Furthermore, using affinity chromatography we were able to identify two proteins, Munc18-1 and Rab4 that potentially bind to clavulanic acid and play a critical role in neurosecretion and the vesicle trafficking process. Consistent with this result, an increase in the translocation of Munc18-1 and Rab4 from the cytoplasm to the plasma membrane was observed in clavulanic acid treated cells. Overall, these data suggest that clavulanic acid enhances dopamine release in a mechanism involving Munc18-1 and Rab4 modulation and warrants further investigation of its therapeutic use in CNS disorders, such as depression.

  15. Dopamine D2 receptor desensitization by dopamine or corticotropin releasing factor in ventral tegmental area neurons is associated with increased glutamate release.

    Science.gov (United States)

    Nimitvilai, Sudarat; Herman, Melissa; You, Chang; Arora, Devinder S; McElvain, Maureen A; Roberto, Marisa; Brodie, Mark S

    2014-07-01

    Neurons of the ventral tegmental area (VTA) are the source of dopaminergic (DAergic) input to important brain regions related to addiction. Prolonged exposure of these VTA neurons to moderate concentrations of dopamine (DA) causes a time-dependent decrease in DA-induced inhibition, a complex desensitization called DA inhibition reversal (DIR). DIR is mediated by conventional protein kinase C (cPKC) through concurrent stimulation of D2 and D1-like DA receptors, or by D2 stimulation concurrent with activation of some Gq-linked receptors. Corticotropin releasing factor (CRF) acts via Gq, and can modulate glutamater neurotransmission in the VTA. In the present study, we used brain slice electrophysiology to characterize the interaction of DA, glutamate antagonists, and CRF agonists in the induction and maintenance of DIR in the VTA. Glutamate receptor antagonists blocked induction but not maintenance of DIR. Putative blockers of neurotransmitter release and store-operated calcium channels blocked and reversed DIR. CRF and the CRF agonist urocortin reversed inhibition produced by the D2 agonist quinpirole, consistent with our earlier work indicating that Gq activation reverses quinpirole-mediated inhibition. In whole cell recordings, the combination of urocortin and quinpirole, but not either agent alone, increased spontaneous excitatory postsynaptic currents (sEPSCs) in VTA neurons. Likewise, the combination of a D1-like receptor agonist and quinpirole, but not either agent alone, increased sEPSCs in VTA neurons. In summary, desensitization of D2 receptors induced by dopamine or CRF on DAergic VTA neurons is associated with increased glutamatergic signaling in the VTA.

  16. Electrical release of dopamine and levodopa mediated by amphiphilic β-cyclodextrins immobilized on polycrystalline gold

    Science.gov (United States)

    Foschi, Giulia; Leonardi, Francesca; Scala, Angela; Biscarini, Fabio; Kovtun, Alessandro; Liscio, Andrea; Mazzaglia, Antonino; Casalini, Stefano

    2015-11-01

    Vesicles of cationic amphiphilic β-cyclodextrins have been immobilized on polycrystalline gold by exploiting the chemical affinity between their amino groups and Au atoms. The presence of cyclodextrins has been widely investigated by means of AFM, XPS, kelvin probe and electrochemical measurements. This multi-functional coating confers distinct electrochemical features such as pH-dependent behavior and partial/total blocking properties towards electro-active species. The host-guest properties of β-cyclodextrins have been successfully exploited in order to trap drugs, like dopamine and levodopa. The further release of these drugs was successfully achieved by providing specific electrical stimuli. This proof-of-concept led us to fabricate an electronic device (i.e. an organic transistor) capable of dispensing both dopamine and levodopa in aqueous solution.Vesicles of cationic amphiphilic β-cyclodextrins have been immobilized on polycrystalline gold by exploiting the chemical affinity between their amino groups and Au atoms. The presence of cyclodextrins has been widely investigated by means of AFM, XPS, kelvin probe and electrochemical measurements. This multi-functional coating confers distinct electrochemical features such as pH-dependent behavior and partial/total blocking properties towards electro-active species. The host-guest properties of β-cyclodextrins have been successfully exploited in order to trap drugs, like dopamine and levodopa. The further release of these drugs was successfully achieved by providing specific electrical stimuli. This proof-of-concept led us to fabricate an electronic device (i.e. an organic transistor) capable of dispensing both dopamine and levodopa in aqueous solution. Electronic supplementary information (ESI) available: Kelvin probe, AFM and electrochemical data are reported. Furthermore, the chemical backbone of both types of cyclodextrins are shown. See DOI: 10.1039/c5nr05405b

  17. A Markov State-based Quantitative Kinetic Model of Sodium Release from the Dopamine Transporter

    Science.gov (United States)

    Razavi, Asghar M.; Khelashvili, George; Weinstein, Harel

    2017-01-01

    The dopamine transporter (DAT) belongs to the neurotransmitter:sodium symporter (NSS) family of membrane proteins that are responsible for reuptake of neurotransmitters from the synaptic cleft to terminate a neuronal signal and enable subsequent neurotransmitter release from the presynaptic neuron. The release of one sodium ion from the crystallographically determined sodium binding site Na2 had been identified as an initial step in the transport cycle which prepares the transporter for substrate translocation by stabilizing an inward-open conformation. We have constructed Markov State Models (MSMs) from extensive molecular dynamics simulations of human DAT (hDAT) to explore the mechanism of this sodium release. Our results quantify the release process triggered by hydration of the Na2 site that occurs concomitantly with a conformational transition from an outward-facing to an inward-facing state of the transporter. The kinetics of the release process are computed from the MSM, and transition path theory is used to identify the most probable sodium release pathways. An intermediate state is discovered on the sodium release pathway, and the results reveal the importance of various modes of interaction of the N-terminus of hDAT in controlling the pathways of release.

  18. Effects of the NMDA receptor antagonists on deltamethrin-induced striatal dopamine release in conscious unrestrained rats.

    Science.gov (United States)

    Morikawa, Takuya; Furuhama, Kazuhisa

    2009-08-01

    To better understand the neurotoxicity caused by the pyrethroid pesticide, we examined the effects of the N-methyl-D-aspartate (NMDA) receptor antagonists MK-801, a non-competitive cation channel blocker, and 2-amino-5-phosphonovaleric acid (APV), a competitive Na(+) channel blocker, on extracellular dopamine levels in male Sprague-Dawley rats receiving the type II pyrethroid deltamethrin using an in vivo microdialysis system. Deltamethrin (60 mg/kg, i.p.) evidently increased striatal dopamine levels with a peak time of 120 min, and the local infusion (i.c.) of either MK-801(650 muM) or APV (500 muM) completely blocked these actions. The fluctuation in the dopamine metabolite 3-MT also resembled that in dopamine. Our results suggest that dopamine-releasing neurons would be modulated via the NMDA receptor by the excitatory glutamatergic neurons after deltamethrin treatment.

  19. Monitoring of dopamine release in single cell using ultrasensitive ITO microsensors modified with carbon nanotubes.

    Science.gov (United States)

    Shi, Bao-Xian; Wang, Yu; Zhang, Kai; Lam, Tin-Lun; Chan, Helen Lai-Wa

    2011-02-15

    The study of single cell dynamics has been greatly adapted in biological and medical research and applications. In this work a novel microfluidic electrochemical sensor with carbon nanotubes (CNTs) modified indium tin oxide (ITO) microelectrode was developed for single cells release monitoring. The sensitivity of the electrochemical sensor after CNTs surface modification was improved by 2.5-3 orders of magnitude. The developed CNTs modified ITO sensor was successfully employed to monitor the dopamine release from single living rat pheochromocytoma (PC 12) cells. Its ultrahigh sensitivity, transparency and need for fewer agents enable this smart electrochemical sensor to become a powerful tool in recording dynamic release from various living tissues and organs optically and electrically.

  20. Effects of oral exposure to mining waste on in vivo dopamine release from rat striatum.

    Science.gov (United States)

    Rodríguez, V M; Dufour, L; Carrizales, L; Díaz-Barriga, F; Jiménez-Capdeville, M E

    1998-01-01

    Several single components of mining waste (arsenic, manganese, lead, cadmium) to which humans are exposed at the mining area of Villa de la Paz, Mexico, are known to provoke alterations of striatal dopaminergic parameters. In this study we used an animal model to examine neurochemical changes resulting from exposure to a metal mixture. We used microdialysis to compare in vivo dopamine release from adult rats subchronically exposed to a mining waste by oral route with those from a control group and from a sodium arsenite group (25 mg/kg/day). We found that arsenic and manganese do accumulate in rat brain after 2 weeks of oral exposure. The mining waste group showed significantly decreased basal levels of dihydroxyphenylacetic acid (DOPAC; 66.7 +/- 7.53 pg/ microl) when compared to a control group (113.7 +/- 14.3 pg/ microl). Although basal dopamine release rates were comparable among groups, when the system was challenged with a long-standing depolarization through high-potassium perfusion, animals exposed to mining waste were not able to sustain an increased dopamine release in response to depolarization (mining waste group 5.5 +/- 0.5 pg/ microl versus control group 21.7 +/- 5.8 pg/ microl). Also, DOPAC and homovanillic acid levels were significantly lower in exposed animals than in controls during stimulation with high potassium. The arsenite group showed a similar tendency to that from the mining waste group. In vivo microdialysis provides relevant data about the effects of a chemical mixture. Our results indicate that this mining waste may represent a health risk for the exposed population. Images Figure 1 Figure 2 Figure 3 PMID:9681976

  1. Examining the complex regulation and drug-induced plasticity of dopamine release and uptake using voltammetry in brain slices.

    Science.gov (United States)

    Ferris, Mark J; Calipari, Erin S; Yorgason, Jordan T; Jones, Sara R

    2013-05-15

    Fast scan cyclic voltammetry in brain slices (slice voltammetry) has been used over the last several decades to increase substantially our understanding of the complex local regulation of dopamine release and uptake in the striatum. This technique is routinely used for the study of changes that occur in the dopamine system associated with various disease states and pharmacological treatments, and to study mechanisms of local circuitry regulation of dopamine terminal function. In the context of this Review, we compare the relative advantages of voltammetry using striatal slice preparations versus in vivo preparations, and highlight recent advances in our understanding of dopamine release and uptake in the striatum specifically from studies that use slice voltammetry in drug-naïve animals and animals with a history of psychostimulant self-administration.

  2. [Suppression by dopamine of GH release induced by GRF in a case of acromegaly].

    Science.gov (United States)

    Matsubara, M; Odagaki, E; Morioka, T

    1987-03-20

    Inhibition of plasma GH by dopaminergic agonists is one of the characteristics of the GH secretion in acromegaly. GRF is known to stimulate GH secretion in most patients with acromegaly. In order to elucidate the relationship between GRF and dopamine in regulating the secretion of GH in this disease, we examined plasma GH responses to dopamine (DA) infusion (4 micrograms/kg/min), GRF injection (100 micrograms i.v.), sulpiride (SP) injection (200 mg i.v.), a DA blocker, DA plus GRF and SP plus GRF in a 51-year-old male patient with acromegaly. Plasma GH was reduced to 14% of the initial level by iv infusion of DA, and was elevated to 158% by iv injection of GRF. No considerable change was observed in plasma GH by iv infusion of SP (114% of the initial level). GH release induced by GRF was remarkably reduced by simultaneous administration of DA (28% of the initial level), whereas SP administration did not affect GRF-induced GH release (154%). The marked reduction of GH release after DA plus GRF seems to suggest that the effect of DA on the GH regulation is stronger than that of GRF in this acromegalic patient. It is suggested also that endogenous DA may not play an inhibitory role in GH secretion in this case since DA blockade by SP did not raise basal GH levels and the GH response to GRF.

  3. Real-Time Chemical Measurements of Dopamine Release in the Brain

    Science.gov (United States)

    Roberts, James G.; Lugo-Morales, Leyda Z.; Loziuk, Philip L.; Sombers, Leslie A.

    2017-01-01

    Rapid changes in extracellular dopamine concentrations in freely moving or anesthetized rats can be detected using fast-scan cyclic voltammetry (FSCV). Background-subtracted FSCV is a real-time electrochemical technique that can monitor neurochemical transmission in the brain on a subsecond timescale, while providing chemical information on the analyte. Also, this voltammetric approach allows for the investigation of the kinetics of release and uptake of molecules in the brain. This chapter describes, completely, how to make these measurements and the properties of FSCV that make it uniquely suitable for performing chemical measurements of dopaminergic neurotransmission in vivo. PMID:23296789

  4. Lobelane inhibits methamphetamine-evoked dopamine release via inhibition of the vesicular monoamine transporter-2.

    Science.gov (United States)

    Nickell, Justin R; Krishnamurthy, Sairam; Norrholm, Seth; Deaciuc, Gabriela; Siripurapu, Kiran B; Zheng, Guangrong; Crooks, Peter A; Dwoskin, Linda P

    2010-02-01

    Lobeline is currently being evaluated in clinical trials as a methamphetamine abuse treatment. Lobeline interacts with nicotinic receptor subtypes, dopamine transporters (DATs), and vesicular monoamine transporters (VMAT2s). Methamphetamine inhibits VMAT2 and promotes dopamine (DA) release from synaptic vesicles, resulting ultimately in increased extracellular DA. The present study generated structure-activity relationships by defunctionalizing the lobeline molecule and determining effects on [(3)H]dihydrotetrabenazine binding, inhibition of [(3)H]DA uptake into striatal synaptic vesicles and synaptosomes, the mechanism of VMAT2 inhibition, and inhibition of methamphetamine-evoked DA release. Compared with lobeline, the analogs exhibited greater potency inhibiting DA transporter (DAT) function. Saturated analogs, lobelane and nor-lobelane, exhibited high potency (K(i) = 45 nM) inhibiting vesicular [(3)H]DA uptake, and lobelane competitively inhibited VMAT2 function. Lobeline and lobelane exhibited 67- and 35-fold greater potency, respectively, in inhibiting VMAT2 function compared to DAT function. Lobelane potently decreased (IC(50) = 0.65 microM; I(max) = 73%) methamphetamine-evoked DA overflow, and with a greater maximal effect compared with lobeline (IC(50) = 0.42 microM, I(max) = 56.1%). These results provide support for VMAT2 as a target for inhibition of methamphetamine effects. Both trans-isomers and demethylated analogs of lobelane had reduced or unaltered potency inhibiting VMAT2 function and lower maximal inhibition of methamphetamine-evoked DA release compared with lobelane. Thus, defunctionalization, cis-stereochemistry of the side chains, and presence of the piperidino N-methyl are structural features that afford greatest inhibition of methamphetamine-evoked DA release and enhancement of selectivity for VMAT2. The current results reveal that lobelane, a selective VMAT2 inhibitor, inhibits methamphetamine-evoked DA release and is a promising lead for

  5. Lobelane Inhibits Methamphetamine-Evoked Dopamine Release via Inhibition of the Vesicular Monoamine Transporter-2S⃞

    Science.gov (United States)

    Nickell, Justin R.; Krishnamurthy, Sairam; Norrholm, Seth; Deaciuc, Gabriela; Siripurapu, Kiran B.; Zheng, Guangrong; Crooks, Peter A.

    2010-01-01

    Lobeline is currently being evaluated in clinical trials as a methamphetamine abuse treatment. Lobeline interacts with nicotinic receptor subtypes, dopamine transporters (DATs), and vesicular monoamine transporters (VMAT2s). Methamphetamine inhibits VMAT2 and promotes dopamine (DA) release from synaptic vesicles, resulting ultimately in increased extracellular DA. The present study generated structure-activity relationships by defunctionalizing the lobeline molecule and determining effects on [3H]dihydrotetrabenazine binding, inhibition of [3H]DA uptake into striatal synaptic vesicles and synaptosomes, the mechanism of VMAT2 inhibition, and inhibition of methamphetamine-evoked DA release. Compared with lobeline, the analogs exhibited greater potency inhibiting DA transporter (DAT) function. Saturated analogs, lobelane and nor-lobelane, exhibited high potency (Ki = 45 nM) inhibiting vesicular [3H]DA uptake, and lobelane competitively inhibited VMAT2 function. Lobeline and lobelane exhibited 67- and 35-fold greater potency, respectively, in inhibiting VMAT2 function compared to DAT function. Lobelane potently decreased (IC50 = 0.65 μM; Imax = 73%) methamphetamine-evoked DA overflow, and with a greater maximal effect compared with lobeline (IC50 = 0.42 μM, Imax = 56.1%). These results provide support for VMAT2 as a target for inhibition of methamphetamine effects. Both trans-isomers and demethylated analogs of lobelane had reduced or unaltered potency inhibiting VMAT2 function and lower maximal inhibition of methamphetamine-evoked DA release compared with lobelane. Thus, defunctionalization, cis-stereochemistry of the side chains, and presence of the piperidino N-methyl are structural features that afford greatest inhibition of methamphetamine-evoked DA release and enhancement of selectivity for VMAT2. The current results reveal that lobelane, a selective VMAT2 inhibitor, inhibits methamphetamine-evoked DA release and is a promising lead for the development of a

  6. Effects of repeated hyperbaric nitrogen-oxygen exposures on the striatal dopamine release and on motor disturbances in rats.

    Science.gov (United States)

    Lavoute, Cécile; Weiss, Michel; Rostain, Jean-Claude

    2005-09-14

    Previous studies have demonstrated disruptions of motor activities and a decrease of extracellular dopamine level in the striatum of rats exposed to high pressure of nitrogen. Men exposed to nitrogen pressure develop also motor and cognitive disturbances related to inert gas narcosis. After repetitive exposures, adaptation to narcosis was subjectively reported. To study the effects of repetitive exposures to hyperbaric nitrogen-oxygen, male Sprague-Dawley rats were implanted in the striatum with multifiber carbon dopamine-sensitive electrodes. After recovery from surgery, free-moving rats were exposed for 2 h up to 3 MPa of nitrogen-oxygen mixture before and after one daily exposure to 1 MPa of nitrogen-oxygen, for 5 consecutive days. Dopamine release was measured by differential pulse voltammetry and motor activities were quantified using piezo-electric captor. At the first exposure to 3 MPa, the striatal dopamine level decreased during the compression (-15%) to reach -20% during the stay at 3 MPa. Motor activities were increased during compression (+15%) and the first 60 min at constant pressure (+10%). In contrast, at the second exposure to 3 MPa, an increase of dopamine of +15% was obtained during the whole exposure. However, total motor activities remained unchanged as compared to the first exposure. Our results confirm that nitrogen exposure at 3 MPa led to a decreased striatal dopamine release and increased motor disturbances in naïve rats. Repetitive exposures to 1 MPa of nitrogen induced a reversal effect on the dopamine release which suggests a neurochemical change at the level of the neurotransmitter regulation processes of the basal ganglia. In contrast, motor activity remained quantitatively unchanged, thus suggesting that dopamine is not involved alone in modulating these motor disturbances.

  7. Midbrain dopaminergic neurons generate calcium and sodium currents and release dopamine in the striatum of pups

    Directory of Open Access Journals (Sweden)

    Diana Carolina Ferrari

    2012-03-01

    Full Text Available Midbrain dopaminergic neurons (mDA neurons are essential for the control of diverse motor and cognitive behaviors. However, our understanding of the activity of immature mDA neurons is rudimentary. Rodent mDA neurons migrate and differentiate early in embryonic life and dopaminergic axons enter the striatum and contact striatal neurons a few days before birth, but when these are functional is not known. Here, we recorded Ca2+ transients and Na+ spikes from embryonic (E16-E18 and early postnatal (P0-P7 mDA neurons with dynamic two photon imaging and patch clamp techniques in slices from tyrosine hydroxylase-GFP mice, and measured evoked dopamine release in the striatum with amperometry. We show that half of identified E16-P0 mDA neurons spontaneously generate non-synaptic, intrinsically-driven Ca2+ spikes and Ca2+ plateaus mediated by N- and L-type voltage-gated Ca2+ channels. Starting from E18-P0, half of the mDA neurons also reliably generate overshooting Na+ spikes with an abrupt maturation at birth (P0 = E19. At that stage (E18-P0, dopaminergic terminals release dopamine in a calcium-dependent manner in the striatum in response to local stimulation. We propose that the intrinsic spontaneous activity of mouse mDA neurons may impact the development/activity of the striatal network from birth.

  8. Regionally distinct phasic dopamine release patterns in the striatum during reversal learning.

    Science.gov (United States)

    Klanker, Marianne; Fellinger, Lisanne; Feenstra, Matthijs; Willuhn, Ingo; Denys, Damiaan

    2017-03-14

    Striatal dopamine (DA) plays a central role in reward-related learning and behavioral adaptation to changing environments. Recent studies suggest that rather than being broadcast as a uniform signal throughout the entire region, DA release dynamics diverge between different striatal regions. In a previous study, we showed that phasic DA release patterns in the ventromedial striatum (VMS) rapidly adapt during reversal learning. However, it is unknown how DA dynamics in the dorsolateral striatum (DLS) are modulated during such adaptive behavior. Here, we used fast-scan cyclic voltammetry to measure phasic DA release in the DLS during spatial reversal learning. In the DLS, we observed minor DA release after the onset of a visual cue signaling reward availability, followed by more pronounced DA release during more proximal reward cues (e.g., lever extension) and execution of the operant response (i.e., lever press), both in rewarded and non-rewarded trials. These release dynamics (minor DA after onset of the predictive visual cue, prominent DA during the operant response) did not change significantly during or following a reversal of response-reward contingencies. Notably, the DA increase to the lever press did not reflect a general signal related to the initiation of any motivated motor response, as we did not observe DA release when rats initiated nose pokes into the food receptacle during inter-trial intervals. This suggests that DA release in the DLS occurs selectively during the initiation and execution of a learned operant response. Together with our previous results obtained in the VMS, these findings reveal distinct phasic DA release patterns during adaptation of established behavior in DLS and VMS. The VMS DA signal, which is highly sensitive to reversal of response-reward contingences, may provide a teaching signal to guide reward-related learning and facilitate behavioral adaptation, whereas DLS DA may reflect a 'response execution signal' largely

  9. Hyperbaric He but not N2 augments Ca2+-dependent dopamine release from rat striatum.

    Science.gov (United States)

    Paul, M L; Philp, R B

    1989-07-01

    Endogenous dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) were measured by high performance liquid chromatography with electrochemical detection in perfusate from continuously superfused rat brain striatal slices, and the effects of various pressures of He and N2 were determined. He at 24 and 100 atmospheres absolute (ATA) significantly (P less than 0.01 and less than 0.05) increased the release of DA evoked by a 6-min exposure to 35 mM K+, whereas He at 48 ATA did not. Experiments conducted in a Ca2+-free medium showed that only the extracellular Ca2+-dependent component of release was affected by pressure. Similar increases in DA release were observed when DA reuptake and metabolism were blocked with cocaine and pargyline, although statistical significance was not achieved. N2 did not significantly affect DA release at 12, 24, 48, or 100 ATA. The results indicate that He (= hydrostatic pressure) augments Ca2+-dependent DA release and that substitution of N2 negates this effect. The relevance of these observations to the phenomena of high pressure neurologic syndrome in divers and the anesthetic reversal of pressure effects is discussed.

  10. 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

  11. Beer Flavor Provokes Striatal Dopamine Release in Male Drinkers: Mediation by Family History of Alcoholism

    Science.gov (United States)

    Oberlin, Brandon G; Dzemidzic, Mario; Tran, Stella M; Soeurt, Christina M; Albrecht, Daniel S; Yoder, Karmen K; Kareken, David A

    2013-01-01

    Striatal dopamine (DA) is increased by virtually all drugs of abuse, including alcohol. However, drug-associated cues are also known to provoke striatal DA transmission- a phenomenon linked to the motivated behaviors associated with addiction. To our knowledge, no one has tested if alcohol's classically conditioned flavor cues, in the absence of a significant pharmacologic effect, are capable of eliciting striatal DA release in humans. Employing positron emission tomography (PET), we hypothesized that beer's flavor alone can reduce the binding potential (BP) of [11C]raclopride (RAC; a reflection of striatal DA release) in the ventral striatum, relative to an appetitive flavor control. Forty-nine men, ranging from social to heavy drinking, mean age 25, with a varied family history of alcoholism underwent two [11C]RAC PET scans: one while tasting beer, and one while tasting Gatorade. Relative to the control flavor of Gatorade, beer flavor significantly increased self-reported desire to drink, and reduced [11C]RAC BP, indicating that the alcohol-associated flavor cues induced DA release. BP reductions were strongest in subjects with first-degree alcoholic relatives. These results demonstrate that alcohol-conditioned flavor cues can provoke ventral striatal DA release, absent significant pharmacologic effects, and that the response is strongest in subjects with a greater genetic risk for alcoholism. Striatal DA responses to salient alcohol cues may thus be an inherited risk factor for alcoholism. PMID:23588036

  12. Target-specific suppression of GABA release from parvalbumin interneurons in the basolateral amygdala by dopamine.

    Science.gov (United States)

    Chu, Hong-Yuan; Ito, Wataru; Li, Jiayang; Morozov, Alexei

    2012-10-17

    Dopamine (DA) in the basolateral amygdala (BLA) promotes fear learning by disinhibiting principal neurons (PNs) and enabling synaptic plasticity in their sensory inputs. While BLA interneurons (INs) are heterogeneous, it is unclear which interneuron subtypes decrease GABAergic input to PNs in the presence of DA. Here, using cell type-selective photostimulation by channelrhodopsin 2 in BLA slices from mouse brain, we examined the role of parvalbumin-positive INs (PV-INs), the major interneuronal subpopulation in BLA, in the disinhibitory effect of DA. We found that DA selectively suppressed GABAergic transmission from PV-INs to PNs by acting on presynaptic D(2) receptors, and this effect was mimicked by Rp-cAMP, an inhibitor of cAMP-dependent signaling. In contrast, DA did not alter GABA release from PV-INs to INs. Furthermore, neither suppressing cAMP-dependent signaling by Rp-cAMP nor enhancing it by forskolin altered GABA release from PV-INs to BLA INs. Overall, DA disinhibits BLA, at least in part, by suppressing GABA release from PV-INs in the target cell-specific manner that results from differential control of this release by cAMP-dependent signaling.

  13. Mesolimbic alpha-, but not beta-adrenoceptors control the accumbal release of dopamine that is derived from reserpine-sensitive storage vesicles.

    NARCIS (Netherlands)

    Verheij, M.M.M.; Cools, A.R.

    2009-01-01

    Mesolimbic beta-, but not alpha-adrenoceptors control the accumbal release of dopamine that is derived from alpha-methyl-para-tyrosine-sensitive pools of newly synthesized neurotransmitter. The aim of this study was to investigate which of these adrenoceptors control the accumbal release of dopamine

  14. Dopamine release in ventral striatum during Iowa Gambling Task performance is associated with increased excitement levels in pathological gambling

    DEFF Research Database (Denmark)

    Linnet, Jakob; Møller, Arne; Peterson, Ericka

    2011-01-01

    Aims Gambling excitement is believed to be associated with biological measures of pathological gambling. Here, we tested the hypothesis that dopamine release would be associated with increased excitement levels in Pathological Gamblers compared with Healthy Controls. Design Pathological Gamblers...... and Healthy Controlswere experimentally compared in a non-gambling (baseline) and gambling condition. Measurements We used Positron Emission Tomography (PET) with the tracer raclopride to measure dopamine D 2/3 receptor availability in the ventral striatum during a non-gambling and gambling condition...... of the Iowa GamblingTask (IGT). After each condition participants rated their excitement level. Setting Laboratory experiment. Participants 18 Pathological Gamblers and 16 Healthy Controls. Findings Pathological Gamblers with dopamine release in the ventral striatum had significantly higher excitement levels...

  15. Effects of monoamine releasers with varying selectivity for releasing dopamine/norepinephrine versus serotonin on choice between cocaine and food in rhesus monkeys.

    Science.gov (United States)

    Banks, Matthew L; Blough, Bruce E; Negus, S Stevens

    2011-12-01

    Monoamine releasers constitute one class of candidate medications for the treatment of cocaine abuse, and concurrent cocaine-versus-food choice procedures are potentially valuable as experimental tools to evaluate the efficacy and safety of candidate medications. This study assessed the choice between cocaine and food by rhesus monkeys during treatment with five monoamine releasers that varied in selectivity to promote the release of dopamine and norepinephrine versus serotonin (5HT) [m-fluoroamphetamine, (+)-phenmetrazine, (+)-methamphetamine, napthylisopropylamine and (±)-fenfluramine]. Rhesus monkeys (n=8) responded under a concurrent-choice schedule of food delivery (1-g pellets, fixed ratio 100 schedule) and cocaine injections (0-0.1 mg/kg/injection, fixed ratio 10 schedule). Cocaine choice dose-effect curves were determined daily during continuous 7-day treatment with saline or with each test compound dose. During saline treatment, cocaine maintained a dose-dependent increase in cocaine choice, and the highest cocaine doses (0.032-0.1 mg/kg/injection) maintained almost exclusive cocaine choice. Efficacy of monoamine releasers to decrease cocaine choice corresponded to their pharmacological selectivity to release dopamine and norepinephrine versus 5HT. None of the releasers reduced cocaine choice or promoted reallocation of responding to food choice to the same extent as when saline was substituted for cocaine. These results extend the range of conditions across which dopamine and norepinephrine-selective releasers have been shown to reduce cocaine self-administration.

  16. D2 autoreceptor inhibition reveals oxygen-glucose deprivation-induced release of dopamine in guinea-pig cochlea

    NARCIS (Netherlands)

    Halmos, G; Doleviczényi, Z; Répássy, G; Kittel, A; Vizi, E S; Lendvai, B; Zelles, T

    2005-01-01

    Dopamine (DA), released from the lateral olivocochlear (LOC) efferent terminals, the efferent arm of the short-loop feedback in the cochlea, is considered as a protective factor in the inner ear since it inhibits auditory nerve dendrite firing in ischemia- or noise-induced excitotoxicity leading to

  17. Phasic dopamine release in the medial prefrontal cortex enhances stimulus discrimination.

    Science.gov (United States)

    Popescu, Andrei T; Zhou, Michael R; Poo, Mu-Ming

    2016-05-31

    Phasic dopamine (DA) release is believed to guide associative learning. Most studies have focused on projections from the ventral tegmental area (VTA) to the striatum, and the action of DA in other VTA target regions remains unclear. Using optogenetic activation of VTA projections, we examined DA function in the medial prefrontal cortex (mPFC). We found that mice perceived optogenetically induced DA release in mPFC as neither rewarding nor aversive, and did not change their previously learned behavior in response to DA transients. However, repetitive temporal pairing of an auditory conditioned stimulus (CS) with mPFC DA release resulted in faster learning of a subsequent task involving discrimination of the same CS against unpaired stimuli. Similar results were obtained using both appetitive and aversive unconditioned stimuli, supporting the notion that DA transients in mPFC do not represent valence. Using extracellular recordings, we found that CS-DA pairings increased firing of mPFC neurons in response to CSs, and administration of D1 or D2 DA-receptor antagonists in mPFC during learning impaired stimulus discrimination. We conclude that DA transients tune mPFC neurons for the recognition of behaviorally relevant events during learning.

  18. Phorbol esters potentiate rapid dopamine release from median eminence and striatal synaptosomes

    Energy Technology Data Exchange (ETDEWEB)

    Shu, C.; Selmanoff, M.

    1988-06-01

    In the present study, we investigated the ability of phorbol esters to potentiate Ca2+-dependent depolarization-induced release of tritium-labeled dopamine ((3H)DA) from median eminence and striatal synaptosomes. Phorbol esters potentiated (3H)DA release in a concentration-dependent manner in both kinds of dopaminergic nerve terminals and with a potency series similar to that reported for stimulation of protein kinase-C (PKC) activity in other cell systems. Evoked (3H)DA release was increased by 12-O-tetradecanoylphorbol-13-acetate (TPA; 10(-7) M) after 1, 3, 5, and 10 sec of depolarization. The effect of TPA was suppressed by sphingosine, a PKC inhibitor. TPA enhanced (3H)DA release evoked by high K+, veratridine or the Ca2+ ionophore A23187. Phorbol ester potentiation was found to be depolarization dependent, as it was present from 30-75 mM, but not at 5-20 mM external K+. Potentiation was seen at all external Ca2+ concentrations studied between 0.01-3 mM. However, in the absence of external free Ca2+ (i.e. with 0.1 mM EGTA), the phorbol effect was not present. These data indicate that an increase in intrasynaptosomal Ca2+ concentration is necessary for the enhancement of (3H)DA release by phorbol esters to occur. The combination of TPA and the Ca2+ ionophore A23187 does not show the marked synergism observed in some other systems, that is maximal release was not reinstated. This suggests that in dopaminergic nerve terminals, activation of PKC has a modulatory, rather than a mediating, effect on release. Recently, we have shown that hyperprolactinemia stimulated (3H)DA release from median eminence synaptosomes by an external Ca2+-independent mechanism which might involve the PKC pathway. However, in the present work we found that the TPA and PRL effects on evoked (3H)DA release were additive, suggesting that two independent mechanisms are involved.

  19. Direct monitoring of dopamine and 5-HT release in substantia nigra and ventral tegmental area in vitro

    DEFF Research Database (Denmark)

    Rice, M E; Richards, C D; Nedergaard, S;

    1994-01-01

    Fast-scan cyclic voltammetry with carbon fibre microelectrodes was used to detect endogenous dopamine (DA) and 5-hydroxytryptamine (5-HT) release from three distinct regions of guinea-pig mid-brain in vitro: rostral and caudal substantia nigra (SN) and the ventral tegmental area (VTA). Previous...... these regions with in situ electrodes and demonstrates the utility of fast-scan cyclic voltammetry to investigate the mechanisms and possible non-classical functions of somato-dendritic DA release....

  20. Treatment of Parkinson’s disease: nanostructured sol–gel silica–dopamine reservoirs for controlled drug release in the central nervous system

    Science.gov (United States)

    López, Tessy; Bata-García, José L; Esquivel, Dulce; Ortiz-Islas, Emma; Gonzalez, Richard; Ascencio, Jorge; Quintana, Patricia; Oskam, Gerko; Álvarez-Cervera, Fernando J; Heredia-López, Francisco J; Góngora-Alfaro, José L

    2011-01-01

    Introduction We have evaluated the use of silica–dopamine reservoirs synthesized by the sol–gel approach with the aim of using them in the treatment of Parkinson’s disease, specifically as a device for the controlled release of dopamine in the striatum. Theoretical calculations illustrate that dopamine is expected to assume a planar structure and exhibit weak interactions with the silica surface. Methods Several samples were prepared by varying the wt% of dopamine added during the hydrolysis of tetraethyl orthosilicate. The silica–dopamine reservoirs were characterized by N2 adsorption, scanning and transmission electron microscopy, and Fourier transform infrared spectroscopy. The in vitro release profiles were determined using ultraviolet visible absorbance spectroscopy. The textural analyses showed a maximum value for the surface area of 620 m2/g nanostructured silica materials. The stability of dopamine in the silica network was confirmed by infrared and 13C-nuclear magnetic resonance spectroscopy. The reservoirs were evaluated by means of apomorphine-induced rotation behavior in hemiparkisonian rats. Results The in vitro dopamine delivery profiles indicate two regimes of release, a fast and sustained dopamine delivery was observed up to 24 hours, and after this time the rate of delivery became constant. Histologic analysis of formalin-fixed brains performed 24–32 weeks after reservoir implantation revealed that silica–dopamine implants had a reddish-brown color, suggesting the presence of oxidized dopamine, likely caused by the fixation procedure, while implants without dopamine were always translucent. Conclusion The major finding of the study was that intrastriatal silica–dopamine implants reversed the rotational asymmetry induced by apomorphine, a dopamine agonist, in hemiparkinsonian rats. No dyskinesias or other motor abnormalities were observed in animals implanted with silica or silica–dopamine. PMID:21289978

  1. Iptkalim inhibits cocaine challenge—induced enhancement of dopamine levels in nucleus accumbens and striatum of rats by up—regulating Kir6.1 and Kir6.2 mRNA expression

    Institute of Scientific and Technical Information of China (English)

    HEHai-Rong; DINGJian-Hua; GUBing; WANGHai; HUGang; LIUYun

    2003-01-01

    AIM:To investigate the effect and mechanism of novel ATP-sensitive potassium channel opener (KCO) iptkalim (IPT) on acute and cocaine challenge-induced alterations in the levels of dopamine (DA) and glutamate (Glu) from nucleus accumbens (NAc), striatum, and prefrontal cortex (PFC) in rats. METHODS: The levels of DA and Glu were assayed using high performance liquid chromatography (HPLC) combined with amperometric and fluorescent detection, respectively. The mRNA levels of Kir6.1, Kir6.2, SUR1, and SUR2 were measured by semiquantitative reverse transcription polymerase chain reaction (RT-PCR). RESULTS: IPT did not affect acute cocaine (30mg/kg,ip)-induced elevations in either DA levels from NAc and striatum or Glu levels from NAc and PFC. An acute cocaine challenge (30mg/kg,ip) on d 21 after withdrawal caused an elevation in DA levels in NAc and striatum. Moreover, the same treatment also increased Gluo levels in PFC and NAc of cocaine-pretreated rats. Repeated IPT injections reversed cocaine challenge-induced DA increase in NAc and striatum. Cocaine challenge increased Kir6.1 and Kir6.2 mRNA expression in striatum and NAc and only elevate Kir6.2 expression in PFC in both cocainepretreated rats and rats pretreated with IPT plus cocaine. Moreover, expression of Kir6.1 and Kir6.2 mRNA was augmented in rats pretreated with IPT plus cocaine compared to rats pretreated with cocaine alone. No significant change was found in the SUR1 and SUR2 expression of all four groups. CONCLUSION:IPT inhibited cocaine challenge-induced enhancement of DA levels in NAc and striatum by up-regulating Kir6.1 and Kir6.2 mRNA expression.

  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. Studies, using in vivo microdialysis, on the effect of the dopamine uptake inhibitor GBR 12909 on 3,4-methylenedioxymethamphetamine ('ecstasy')-induced dopamine release and free radical formation in the mouse striatum.

    Science.gov (United States)

    Camarero, Jorge; Sanchez, Veronica; O'Shea, Esther; Green, A Richard; Colado, M Isabel

    2002-06-01

    The present study examined the mechanisms by which 3,4-methylenedioxymethamphetamine (MDMA) produces long-term neurotoxicity of striatal dopamine neurones in mice and the protective action of the dopamine uptake inhibitor GBR 12909. MDMA (30 mg/kg, i.p.), given three times at 3-h intervals, produced a rapid increase in striatal dopamine release measured by in vivo microdialysis (maximum increase to 380 +/- 64% of baseline). This increase was enhanced to 576 +/- 109% of baseline by GBR 12909 (10 mg/kg, i.p.) administered 30 min before each dose of MDMA, supporting the contention that MDMA enters the terminal by diffusion and not via the dopamine uptake site. This, in addition to the fact that perfusion of the probe with a low Ca(2+) medium inhibited the MDMA-induced increase in extracellular dopamine, indicates that the neurotransmitter may be released by a Ca(2+) -dependent mechanism not related to the dopamine transporter. MDMA (30 mg/kg x 3) increased the formation of 2,3-dihydroxybenzoic acid (2,3-DHBA) from salicylic acid perfused through a probe implanted in the striatum, indicating that MDMA increased free radical formation. GBR 12909 pre-treatment attenuated the MDMA-induced increase in 2,3-DHBA formation by approximately 50%, but had no significant intrinsic radical trapping activity. MDMA administration increased lipid peroxidation in striatal synaptosomes, an effect reduced by approximately 60% by GBR 12909 pre-treatment. GBR 12909 did not modify the MDMA-induced changes in body temperature. These data suggest that MDMA-induced toxicity of dopamine neurones in mice results from free radical formation which in turn induces an oxidative stress process. The data also indicate that the free radical formation is probably not associated with the MDMA-induced dopamine release and that MDMA does not induce dopamine release via an action at the dopamine transporter.

  4. Circadian-related heteromerization of adrenergic and dopamine D₄ receptors modulates melatonin synthesis and release in the pineal gland.

    Directory of Open Access Journals (Sweden)

    Sergio González

    Full Text Available The role of the pineal gland is to translate the rhythmic cycles of night and day encoded by the retina into hormonal signals that are transmitted to the rest of the neuronal system in the form of serotonin and melatonin synthesis and release. Here we describe that the production of both melatonin and serotonin by the pineal gland is regulated by a circadian-related heteromerization of adrenergic and dopamine D₄ receptors. Through α(₁B-D₄ and β₁-D₄ receptor heteromers dopamine inhibits adrenergic receptor signaling and blocks the synthesis of melatonin induced by adrenergic receptor ligands. This inhibition was not observed at hours of the day when D₄ was not expressed. These data provide a new perspective on dopamine function and constitute the first example of a circadian-controlled receptor heteromer. The unanticipated heteromerization between adrenergic and dopamine D₄ receptors provides a feedback mechanism for the neuronal hormone system in the form of dopamine to control circadian inputs.

  5. Dopamine release in human striatum induced by repetitive transcranial magnetic stimulation over dorsolateral prefrontal cortex

    Energy Technology Data Exchange (ETDEWEB)

    Cho, Sang Soo; Yoon, Eun Jin; Kim, Yu Kyeong; Lee, Won Woo; Kim, Sang Eun [Seoul National University College of Medicine, Seoul (Korea, Republic of)

    2005-07-01

    Animal study suggests that prefrontal cortex plays an important Animal studies suggest that prefrontal cortex plays an important role in the modulation of dopamine (DA) release in subcortical areas. However, little is known about the relationship between DA release and prefrontal activation in human. We investigated whether repetitive transcranial magnetic stimulation (rTMS) over left dorsolateral prefrontal cortex (DLPFC) influences DA release in human striatum with SPECT measurements of striatal binding of [123I)iodobenzamide (IBZM), a DA D2 receptor radioligand that is sensitive to endogenous DA. Five healthy male volunteers (age, 25{+-}2 yr) were studied with brain [123I]IBZM SPECT under three conditions (resting, Sham stimulation, and active rTMS over left DLPFC), while receiving a bolus plus constant infusion of [123I]IBZM DLPFC was defined as a 6 cm anterior and 1cm lateral from the primary motor cortex. rTMS session consisted of three blocks, in each block, 15 trains of 2 see duration were delivered with 10 Hz stimulation frequency, 100% motor threshold, and between-train intervals of 10 sec. Striatal V3', calculated as (striatal - occipital) / occipital activity ratio, was measured under equilibrium condition, at baseline and after sham and active rTMS. Sham stimulation did not affect striatal V3'. rTMS over DLPFC induced reduction of V3' in the ipsilateral and contralateral striatum by 9.7% {+-} 1.3% and 10.6% {+-} 3.2%, respectively, compared with sham procedures (P < 0.01 and P < 0.01, respectively), indicating striatal DA release elicited by rTMS over DLPFC. V3' reduction in the ipsilateral caudate nucleus was greater than that in the contralateral caudate nucleus (9.9% {+-} 4.5% vs. 6.6% {+-} 3.1%, P < 0.05). These data demonstrate DA release in human striatum induced by rTMS over DLPFC, supporting that cortico-striatal fibers originating in prefrontal cortex are involved in local DA release.

  6. Sulpiride in combination with fluvoxamine increases in vivo dopamine release selectively in rat prefrontal cortex.

    Science.gov (United States)

    Ago, Yukio; Nakamura, Shigeo; Baba, Akemichi; Matsuda, Toshio

    2005-01-01

    Coadministration of atypical antipsychotics and selective serotonin reuptake inhibitors (SSRIs) enhances the release of monoamines such as dopamine (DA), norepinephrine (NE), and serotonin (5-HT) in the prefrontal cortex. To clarify the role of DA-D2/3 receptors in the combination effect, we examined the effects of coadministration of the selective DA-D2/3 antagonist sulpiride and the SSRI fluvoxamine on amine neurotransmitter release in rat prefrontal cortex. Sulpiride (10 mg/kg, i.p.) and fluvoxamine (10 mg/kg, i.p.) alone did not affect extracellular DA levels, while their coadministration caused a significant increase in DA levels. Sulpiride alone did not affect extracellular levels of 5-HT and NE in the prefrontal cortex, while fluvoxamine alone caused a marked increase in 5-HT levels and a slight increase in NE levels. Sulpiride did not affect the fluvoxamine-induced increases in extracellular levels of 5-HT and NE. The DA-D2/3 antagonist haloperidol (0.1 mg/kg) in combination with fluvoxamine also caused a selective increase in extracellular DA levels in the cortex. Coadministration of sulpiride and fluvoxamine did not affect extracellular DA levels in the striatum. Combination of systemic sulpiride and local fluvoxamine did not increase the DA levels, but that of systemic fluvoxamine with local sulpiride increased. The combination effect in increasing prefrontal DA levels was antagonized systemically, but not locally, by the 5-HT1A antagonist WAY100635 at a low dose. These findings suggest that the combination of prefrontal DA-D2/3 receptor blockade and 5-HT1A receptor activation in regions other than the cortex plays an important role in sulpiride and fluvoxamine-induced increase in prefrontal DA release.

  7. Long-term but not short-term blockade of dopamine release in Drosophila impairs orientation during flight in a visual attention paradigm.

    Science.gov (United States)

    Ye, Yizhou; Xi, Wang; Peng, Yueqing; Wang, Yizheng; Guo, Aike

    2004-08-01

    Dopamine is a major neuromodulator in both vertebrates and invertebrates and has profound effects on many physiological processes, including the regulation of attention. Most studies of the functions of dopamine use models with long-term blockade of dopamine release and few effects of transient blockade have yet been reported. The goal of the present study was to determine the role of dopamine in attention-like behavior in Drosophila by taking advantage of the fly's orientation behavior during flight. The examination of several different transgenic flies in a single-target visual attention paradigm showed that flies lost their orientation ability if dopamine release was blocked from the beginning of the development of dopaminergic neurons. This is similar to the attention loss in mammals. However, if the blockade of dopamine release was induced during the experimental procedure, flies performed normally. Statistical analysis of the behavioral assessment showed a significant difference between long-term and transient blockade. Using the RNA interference approach, we generated flies with down-regulated J-domain protein, which is a potential cochaperone in synaptic vesicle release, to make an alternative form of long-term dopamine-blockade mutant. Behavioral assays revealed that flies with permanent J-domain protein down-regulation specifically in dopaminergic neurons have an attention defect similar to that induced by long-term blockade of dopamine release. Furthermore, dopamine depletion beginning at eclosion also caused an attention deficit. Our results indicate that prolonged but not transient blockade of dopamine release impairs visual attention-like behavior in Drosophila.

  8. On the release of catecholamines and dopamine-beta-hydroxylase evoked by ouabain in the perfused cat adrenal gland.

    OpenAIRE

    Garcia, A. G.; Hernandez, M.; Horga, J. F.; Sanchez-Garcia, P.

    1980-01-01

    1 Secretion of catecholamines (CA) and dopamine-beta-hydroxylase (DBH) activity from the retrogradely perfused cat adrenal gland was studied following ouabain infusion. Perfusion with ouabain (10(-4) M) for 10 min caused a gradual release of CA in the effluent which reached its peak 30 min after the ouabain pulse, and was maintained constant for at least 1 h. The effect of ouabain seemed to be irreversible. 2 Mecamylamine, while blocking the CA secretory effects of acetylcholine (ACh) perfusi...

  9. Native CB1 receptor affinity, intrinsic activity and accumbens shell dopamine stimulant properties of third generation SPICE/K2 cannabinoids: BB-22, 5F-PB-22, 5F-AKB-48 and STS-135.

    Science.gov (United States)

    De Luca, Maria Antonietta; Castelli, M Paola; Loi, Barbara; Porcu, Alessandra; Martorelli, Mariella; Miliano, Cristina; Kellett, Kathryn; Davidson, Colin; Stair, Jacqueline L; Schifano, Fabrizio; Di Chiara, Gaetano

    2016-06-01

    In order to investigate the in vivo dopamine (DA) stimulant properties of selected 3rd generation Spice/K2 cannabinoids, BB-22, 5F-PB-22, 5F-AKB-48 and STS-135, their in vitro affinity and agonist potency at native rat and mice CB1 receptors was studied. The compounds bind with high affinity to CB1 receptors in rat cerebral cortex homogenates and stimulate CB1-induced [(35)S]GTPγS binding with high potency and efficacy. BB-22 and 5F-PB-22 showed the lowest Ki of binding to CB1 receptors (0.11 and 0.13 nM), i.e., 30 and 26 times lower respectively than that of JWH-018 (3.38 nM), and a potency (EC50, 2.9 and 3.7 nM, respectively) and efficacy (Emax, 217% and 203%, respectively) as CB1 agonists higher than JWH-018 (EC50, 20.2 nM; Emax, 163%). 5F-AKB-48 and STS-135 had higher Ki for CB1 binding, higher EC50 and lower Emax as CB1 agonists than BB-22 and 5F-PB-22 but still comparatively more favourable than JWH-018. The agonist properties of all the compounds were abolished or drastically reduced by the CB1 antagonist/inverse agonist AM251 (0.1 μM). No activation of G-protein was observed in CB1-KO mice. BB-22 (0.003-0.01 mg/kg i.v.) increased dialysate DA in the accumbens shell but not in the core or in the medial prefrontal cortex, with a bell shaped dose-response curve and an effect at 0.01 mg/kg and a biphasic time-course. Systemic AM251 (1.0 mg/kg i.p.) completely prevented the stimulant effect of BB-22 on dialysate DA in the NAc shell. All the other compounds increased dialysate DA in the NAc shell at doses consistent with their in vitro affinity for CB1 receptors (5F-PB-22, 0.01 mg/kg; 5F-AKB-48, 0.1 mg/kg; STS-135, 0.15 mg/kg i.v.). 3rd generation cannabinoids can be even more potent and super-high CB1 receptor agonists compared to JWH-018. Future research will try to establish if these properties can explain the high toxicity and lethality associated with these compounds.

  10. Striatal dopamine release induced by repetitive transcranial magnetic stimulation over dorsolateral prefrontal cortex: effect of aging

    Energy Technology Data Exchange (ETDEWEB)

    Bang, Seong Ae; Cho, Sang Soo; Yoon, Eun Jin; Kim, Ji Sun; Lee, Byung Chul; Kim, Yu Kyeong; Kim, Sang Eun [Seoul National Univ. College of Medicine, Seoul (Korea, Republic of)

    2007-07-01

    We previously demonstrated dopamine (DA) release in the bilateral striatal regions following prefrontal repetitive transcranial magnetic stimulation (rTMS) in young subjects. Several lines of evidence support substantial age-related changes in human dopaminergic neurotransmission. One possible explanation is alteration of cortico striatal neural connection with aging. Therefore, we investigated how frontal activation by rTMS influences striatal DA release in the elderly with SPECT measurements of striatal binding of [123I]iodobenzamide (lBZM), a DA D2 receptor radioligand that is sensitive to endogenous DA. Five healthy elderly male subjects (age, 64 3 y) were studied with brain [123I]IBZM SPECT under three conditions (resting, sham stimulation, and active rTMS over left dorsolateral prefrontal cortex (DLPFC)), while receiving a bolus plus constant infusion of [123I]IBZM. rTMS session consisted of three blocks. In each block, 15 trains of 2 sec duration were delivered with 10 Hz stimulation frequency and 100% motor threshold. Striatal V3', calculated as (striatal - occipital)/occipital radioactivity, was measured under equilibrium condition at baseline and after sham and active rTMS. Sham stimulation did not affect striatal V3'. rTMS over left DLPFC induced no significant change in V3' in the right striatum compared with baseline condition (0.91 0.25 vs. 0.96 0.25, P = NS). Interestingly, left striatal V3' showed a significant increase after rTMS over left DLPFC compared with sham condition (1.09 0.33 vs. 0.93 0.27, P < 0.05; 17.0 11.1% increase). These results are discrepant from previous ones from young subjects, who showed frontal rTMS-induced reduction of striatal V3', indicating rTMS-induced striatal DA release. We found no significant striatal DA release induced by rTMS over DLPFC in healthy elderly subjects using in vivo binding competition techniques. These results may support an altered cortico striatal circuit in normal aging.

  11. Conductor compounds of phenylpentane in Mycoleptodonoides aitchisonii mycelium enhance the release of dopamine from rat brain striatum slices.

    Science.gov (United States)

    Okuyama, Satoshi; Sawasaki, Emi; Yokogoshi, Hidehiko

    2004-04-01

    Monoterpene compound is a major component of essential oils in various aromatic species. Previous reports about the monoterpene compound linalool and its effect on the brain neurotransmitters glutamic acid, GABA and acetylcholine, but not catecholamines, have been reported. In this study, we investigated the effect of linalool or conductor compounds of phenylpentane, including 1-phenyl-3-pentanol and 1-phenyl-3-pentanone, on dopamine release using rat striatal slices. The edible mushroom Mycoleptodonoides aitchisonii belongs to the Climacodontaceae family, and its cultivate medium or mycelium contains derivatives of the fragrant conductor compound, phenylpentane. Compared to basal levels, 2.5 microg linalool increased dopamine from striatal slices 3-fold. A 4-fold increase in dopamine release resulted from 2.5 microg 1-phenyl-3-pentanol administration, while a half dose of this compound induced a 2.5-fold increase. A greater than 2-fold increase resulted with 2.5 microg 1-phenyl-3-pentanone. These data indicate that striatum has sensitivity for these fragrant compounds and different releasing effects result with differ structures. These actions may affect other neurotransmitters and influence brain function.

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

    Science.gov (United States)

    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. A glutamatergic reward input from the dorsal raphe to ventral tegmental area dopamine neurons.

    Science.gov (United States)

    Qi, Jia; Zhang, Shiliang; Wang, Hui-Ling; Wang, Huikun; de Jesus Aceves Buendia, Jose; Hoffman, Alexander F; Lupica, Carl R; Seal, Rebecca P; Morales, Marisela

    2014-11-12

    Electrical stimulation of the dorsal raphe (DR) and ventral tegmental area (VTA) activates the fibres of the same reward pathway but the phenotype of this pathway and the direction of the reward-relevant fibres have not been determined. Here we report rewarding effects following activation of a DR-originating pathway consisting of vesicular glutamate transporter 3 (VGluT3) containing neurons that form asymmetric synapses onto VTA dopamine neurons that project to nucleus accumbens. Optogenetic VTA activation of this projection elicits AMPA-mediated synaptic excitatory currents in VTA mesoaccumbens dopaminergic neurons and causes dopamine release in nucleus accumbens. Activation also reinforces instrumental behaviour and establishes conditioned place preferences. These findings indicate that the DR-VGluT3 pathway to VTA utilizes glutamate as a neurotransmitter and is a substrate linking the DR-one of the most sensitive reward sites in the brain--to VTA dopaminergic neurons.

  14. Histamine H3 receptor activation prevents dopamine D1 receptor-mediated inhibition of dopamine release in the rat striatum: a microdialysis study.

    Science.gov (United States)

    Alfaro-Rodriguez, Alfonso; Alonso-Spilsbury, María; Arch-Tirado, Emilio; Gonzalez-Pina, Rigoberto; Arias-Montaño, José-Antonio; Bueno-Nava, Antonio

    2013-09-27

    Histamine H3 receptors (H3Rs) co-localize with dopamine (DA) D1 receptors (D1Rs) on striatal medium spiny neurons and functionally antagonize D1R-mediated responses. The intra-striatal administration of D1R agonists reduces DA release whereas D1R antagonists have the opposite effect. In this work, a microdialysis method was used to study the effect of co-activating D1 and H3 receptors on the release of DA from the rat dorsal striatum. Infusion of the D1R agonist SKF-38393 (0.5 and 1 μM) significantly reduced DA release (26-58%), and this effect was prevented by co-administration of the H3R agonist immepip (10 μM). In turn, the effect of immepip was blocked by the H3R antagonist thioperamide (10 μM). Our results indicate that co-stimulation of post-synaptic D1 and H3 receptors may indirectly regulate basal DA release in the rat striatum and provide in vivo evidence for a functional interaction between D1 and H3 receptors in the basal ganglia.

  15. Concentration-dependent activation of dopamine receptors differentially modulates GABA release onto orexin neurons

    Science.gov (United States)

    Linehan, Victoria; Trask, Robert B.; Briggs, Chantalle; Rowe, Todd M.; Hirasawa, Michiru

    2017-01-01

    Dopamine (DA) and orexin neurons play important roles in reward and food intake. There are anatomical and functional connections between these two cell groups, where orexin peptides stimulate DA neurons in the ventral tegmental area and DA inhibits orexin neurons in the hypothalamus. However, the cellular mechanisms underlying DA action on orexin neurons remain incompletely understood. Therefore, the effect of DA on inhibitory transmission to orexin neurons was investigated in rat brain slices using whole cell patch clamp technique. We found that DA modulated the frequency of spontaneous and miniature IPSCs (mIPSCs) in a concentration dependent, bidirectional manner. Low (1 μM) and high concentrations (100 μM) of DA decreased and increased IPSC frequency, respectively. These effects did not accompany a change in mIPSC amplitude and persisted in the presence of G protein signaling inhibitor GDPβS in the pipette, suggesting that DA acts presynaptically. The decrease in mIPSC frequency was mediated by D2 receptors, whereas the increase required co-activation of D1 and D2 receptors and subsequent activation of phospholipase C. In summary, our results suggest that DA has complex effects on GABAergic transmission to orexin neurons, involving cooperation of multiple receptor subtypes. The direction of dopaminergic influence on orexin neurons is dependent on the level of DA in the hypothalamus. At low levels DA disinhibits orexin neurons whereas at high levels it facilitates GABA release, which may act as negative feedback to curb the excitatory orexinergic output to DA neurons. These mechanisms may have implications for consummatory and motivated behaviours. PMID:26036709

  16. Concentration-dependent activation of dopamine receptors differentially modulates GABA release onto orexin neurons.

    Science.gov (United States)

    Linehan, Victoria; Trask, Robert B; Briggs, Chantalle; Rowe, Todd M; Hirasawa, Michiru

    2015-08-01

    Dopamine (DA) and orexin neurons play important roles in reward and food intake. There are anatomical and functional connections between these two cell groups: orexin peptides stimulate DA neurons in the ventral tegmental area and DA inhibits orexin neurons in the hypothalamus. However, the cellular mechanisms underlying the action of DA on orexin neurons remain incompletely understood. Therefore, the effect of DA on inhibitory transmission to orexin neurons was investigated in rat brain slices using the whole-cell patch-clamp technique. We found that DA modulated the frequency of spontaneous and miniature IPSCs (mIPSCs) in a concentration-dependent bidirectional manner. Low (1 μM) and high (100 μM) concentrations of DA decreased and increased IPSC frequency, respectively. These effects did not accompany a change in mIPSC amplitude and persisted in the presence of G-protein signaling inhibitor GDPβS in the pipette, suggesting that DA acts presynaptically. The decrease in mIPSC frequency was mediated by D2 receptors whereas the increase required co-activation of D1 and D2 receptors and subsequent activation of phospholipase C. In summary, our results suggest that DA has complex effects on GABAergic transmission to orexin neurons, involving cooperation of multiple receptor subtypes. The direction of dopaminergic influence on orexin neurons is dependent on the level of DA in the hypothalamus. At low levels DA disinhibits orexin neurons whereas at high levels it facilitates GABA release, which may act as negative feedback to curb the excitatory orexinergic output to DA neurons. These mechanisms may have implications for consummatory and motivated behaviours.

  17. Dopamine regulation of gonadotropin-releasing hormone neuron excitability in male and female mice.

    Science.gov (United States)

    Liu, Xinhuai; Herbison, Allan E

    2013-01-01

    Numerous in vivo studies have shown that dopamine is involved in the regulation of LH secretion in mammals. However, the mechanisms through which this occurs are not known. In this study, we used green fluorescent protein-tagged GnRH neurons to examine whether and how dopamine may modulate the activity of adult GnRH neurons in the mouse. Bath-applied dopamine (10-80 μm) potently inhibited the firing of approximately 50% of GnRH neurons. This resulted from direct postsynaptic inhibitory actions through D1-like, D2-like, or both receptors. Further, one third of GnRH neurons exhibited an increase in their basal firing rate after administration of SCH23390 (D1-like antagonist) and/or raclopride (D2-like antagonist) indicating tonic inhibition by endogenous dopamine in the brain slice. The role of dopamine in presynaptic modulation of the anteroventral periventricular nucleus (AVPV) γ-aminobutyric acid/glutamate input to GnRH neurons was examined. Exogenous dopamine was found to presynaptically inhibit AVPV-evoked γ-aminobutyric acid /glutamate postsynaptic currents in about 50% of GnRH neurons. These effects were, again, mediated by both D1- and D2-like receptors. Neither postsynaptic nor presynaptic actions of dopamine were found to be different between diestrous, proestrous, and estrous females, or males. Approximately 20% of GnRH neurons were shown to receive a dopaminergic input from AVPV neurons in male and female mice. Together, these observations show that dopamine is one of the most potent inhibitors of GnRH neuron excitability and that this is achieved through complex pre- and postsynaptic actions that each involve D1- and D2-like receptor activation.

  18. D4 and D1 dopamine receptors modulate [3H] GABA release in the substantia nigra pars reticulata of the rat.

    Science.gov (United States)

    Acosta-García, Jacqueline; Hernández-Chan, Nancy; Paz-Bermúdez, Francisco; Sierra, Arturo; Erlij, David; Aceves, Jorge; Florán, Benjamín

    2009-12-01

    Neurons of the globus pallidus express dopamine D4 receptors that can modulate transmitter release by their axon terminals. Indeed, GABA release from pallidal terminals in the subthalamic nucleus and in the reticular nucleus of the thalamus is inhibited by activation of D4 receptors. Here we investigated whether GABA release by pallidal projections to the substantia nigra reticulate (SNr) is also modulated by D4 receptors. Dopamine-stimulated depolarization-induced GABA release in slices of the SNr; however, after selective blockade of D1 receptors, dopamine inhibited release. The selective D4 agonist PD 168,077 (IC(50) = 5.30 nM) mimicked the inhibition of release while the selective D4 antagonist L-745,870 blocked the inhibition. To identify the source of D1 and D4 modulated terminals, we unilaterally injected kainic acid in either the GP or the striatum. After lesions of the pallidum, the D4 induced inhibition of release was blocked while the D1 induced stimulation was still significant. Lesions of the striatum had the converse effects. We conclude that release of dopamine in the SNr enhances GABA release mainly through activation of D1 receptors in striatonigral projections and inhibits release mainly through activation of D4 receptors in pallidonigral projections. Because deficient D4 receptor signaling in globus pallidus terminals will lead to disinhibition of impulse traffic through the thalamus we speculate that the D4 abnormalities observed in ADHD patients may be important in the generation of the syndrome.

  19. Effects of cysteamine on dopamine-mediated behaviors: evidence for dopamine-somatostatin interactions in the striatum

    Energy Technology Data Exchange (ETDEWEB)

    Martin-Iverson, M.T.; Radke, J.M.; Vincent, S.R.

    1986-06-01

    The effects of prior treatment with cysteamine, a drug which appears to deplete selectively the neuropeptide somatostatin, on apomorphine-induced stereotypy and amphetamine-induced locomotor activity and conditioned place preferences were investigated. Twelve hours following systemic cysteamine injections apomorphine-induced stereotypy was attenuated and striatal somatostatin levels were reduced by half. Systemic cysteamine also decreased the motor stimulant effects of amphetamine, without influencing the rewarding properties as determined by the conditioned place preference procedure. Direct injections of cysteamine into the nucleus accumbens also decreased the locomotor response to amphetamine, and produced a local reduction in somatostatin levels in the accumbens. Cysteamine did not appear to alter monoamine turnover in the striatum after either systemic or intra-accumbens injections. These results suggest that somatostatin in the nucleus accumbens and caudate-putamen modulates the motor, but not the reinforcing properties of dopaminergic drugs, possibly via an action postsynaptic to dopamine-releasing terminals. Furthermore, it is evident from these results that cysteamine is an important tool with which to study the central actions of somatostatin.

  20. Differential behavioral reinforcement effects of dopamine receptor agonists in the rat with bilateral lesion of the posterior ventral tegmental area.

    Science.gov (United States)

    Ouachikh, Omar; Dieb, Wisam; Durif, Franck; Hafidi, Aziz

    2013-09-01

    Dopamine dysregulation syndrome in Parkinson's disease has been attributed to dopamine replacement therapies and/or a lesion of the dopaminergic system. The dopaminergic neuronal loss targets the substantia nigra and the ventral tegmental area (VTA). We hypothesize that dopamine replacement therapy is responsible for the potential reinforcement effect in Parkinson's disease by acting on the neuronal reward circuitry. Therefore this study was designed to explore the potential motivational effect of dopamine replacement therapy in bilateral VTA-lesioned animals. The posterior (p)VTA, which project to the nucleus accumbens (NAc) constitutes the major dopamine neuronal circuitry implicated in addictive disorders. Using the conditioned place preference (CPP) behavioral paradigm, we investigated the motivational effects of dopamine receptor agonists, and cocaine in rat with a 6-OHDA bilateral lesion of the pVTA. Amongst the dopamine receptor agonists used in this study only the D2R and D3R agonists (bromocriptine, PD128907 and pramipexole), induced a significant CPP in pVTA-lesioned animals. Dopamine receptor agonists did not induce behavioral sensitization in sham animals. Moreover, confocal D2R immunostaining analysis showed a significant increase in the number of D2R per cell body in the NAc shell of pVTA lesioned rats compared to sham. This result correlated, for the first time, the dopamine receptor agonists effect with DR2 overexpression in the NAc shell of pVTA-lesioned rats. In addition, cocaine, which is known to increase dopamine release, induced behavioral sensitization in sham group but not in dopamine deprived group. Thus, the later result highlighted the importance of pVTA-NAc dopaminergic pathway in positive reinforcements. Altogether these data suggested that the implication of the dopamine replacement therapy in the appearance of dopamine dysregulation syndrome in Parkinson's disease is probably due to both neuronal degeneration in the posterior VTA and

  1. 5-HT modulation of dopamine release in basal ganglia in psilocybin-induced psychosis in man--a PET study with [11C]raclopride.

    Science.gov (United States)

    Vollenweider, F X; Vontobel, P; Hell, D; Leenders, K L

    1999-05-01

    The modulating effects of serotonin on dopamine neurotransmission are not well understood, particularly in acute psychotic states. Positron emission tomography was used to examine the effect of psilocybin on the in vivo binding of [11C]raclopride to D2-dopamine receptors in the striatum in healthy volunteers after placebo and a psychotomimetic dose of psilocybin (n = 7). Psilocybin is a potent indoleamine hallucinogen and a mixed 5-HT2A and 5-HT1A receptor agonist. Psilocybin administration (0.25 mg/kg p.o.) produced changes in mood, disturbances in thinking, illusions, elementary and complex visual hallucinations and impaired ego-functioning. Psilocybin significantly decreased [11C]raclopride receptor binding potential (BP) bilaterally in the caudate nucleus (19%) and putamen (20%) consistent with an increase in endogenous dopamine. Changes in [11C]raclopride BP in the ventral striatum correlated with depersonalization associated with euphoria. Together with previous reports of 5-HT receptor involvement in striatal dopamine release, it is concluded that stimulation of both 5-HT2A and 5-HT1A receptors may be important for the modulation of striatal dopamine release in acute psychoses. The present results indirectly support the hypothesis of a serotonin-dopamine dysbalance in schizophrenia and suggest that psilocybin is a valuable tool in the analysis of serotonin-dopamine interactions in acute psychotic states.

  2. 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

  3. Dopamine-associated cached values are not sufficient as the basis for action selection.

    Science.gov (United States)

    Hollon, Nick G; Arnold, Monica M; Gan, Jerylin O; Walton, Mark E; Phillips, Paul E M

    2014-12-23

    Phasic dopamine transmission is posited to act as a critical teaching signal that updates the stored (or "cached") values assigned to reward-predictive stimuli and actions. It is widely hypothesized that these cached values determine the selection among multiple courses of action, a premise that has provided a foundation for contemporary theories of decision making. In the current work we used fast-scan cyclic voltammetry to probe dopamine-associated cached values from cue-evoked dopamine release in the nucleus accumbens of rats performing cost-benefit decision-making paradigms to evaluate critically the relationship between dopamine-associated cached values and preferences. By manipulating the amount of effort required to obtain rewards of different sizes, we were able to bias rats toward preferring an option yielding a high-value reward in some sessions and toward instead preferring an option yielding a low-value reward in others. Therefore, this approach permitted the investigation of dopamine-associated cached values in a context in which reward magnitude and subjective preference were dissociated. We observed greater cue-evoked mesolimbic dopamine release to options yielding the high-value reward even when rats preferred the option yielding the low-value reward. This result identifies a clear mismatch between the ordinal utility of the available options and the rank ordering of their cached values, thereby providing robust evidence that dopamine-associated cached values cannot be the sole determinant of choices in simple economic decision making.

  4. Effects of NMDA administration in the substantia nigra pars compacta on the striatal dopamine release before and after repetitive exposures to nitrogen narcosis in rats.

    Science.gov (United States)

    Lavoute, C; Weiss, M; Rostain, J C

    2006-01-01

    Hyperbaric nitrogen-oxygen exposure developed in rats a decrement of the striatal dopamine release, which was reversed by repetitive exposures. This dopamine decrease could be the result of the antagonistic effect of nitrogen on NMDA receptors. The increment of the dopamine release, following repetitive exposures to nitrogen, could be attributed to a desensitisation of NMDA receptors to the effects of nitrogen. To test these hypotheses, male Sprague-Dawley rats were implanted with electrodes in the striatum to measure dopamine release by voltammetry and cannula in the substantia nigra pars compacta for NMDA injection. Free-moving rats were exposed up to 3MPa of nitrogen-oxygen mixture before and after 5 exposures to 1MPa. At the first exposure to 3MPa, the dopamine level decreased (-15%) but is counteracted by NMDA administration. In contrast, after repetitive exposure, the second exposure to 3MPa, induces a 10% dopamine increase. NMDA administration significantly potentiated this increase. Our results neither support the hypothesis of an antagonist effect of nitrogen on NMDA receptors at the first exposure, nor that of a NMDA receptor desensitization following repetitive exposures to hyperbaric nitrogen.

  5. The pharmacological effect of positive KCNQ (Kv7) modulators on dopamine release from striatal slices

    DEFF Research Database (Denmark)

    Jensen, Majbrit M; Lange, Sofie Cecilie; Thomsen, Morten Skøtt;

    2011-01-01

    Retigabine is an anti-epileptic drug that inhibits neuronal firing by stabilizing the membrane potential through positive modulation of voltage-dependent KCNQ potassium channels in cortical neurons and in mesencephalic dopamine (DA) neurons. The purpose of this study was to compare the effect of ...

  6. THE REGULATION OF DOPAMINE RELEASE FROM NIGROSTRIATAL NEURONS IN CONSCIOUS RATS - THE ROLE OF SOMATODENDRITIC AUTORECEPTORS

    NARCIS (Netherlands)

    SANTIAGO, M; WESTERINK, BHC

    1991-01-01

    Drugs were infused into the substantia nigra of the rat brain via a microdialysis probe, and the extracellular concentration of dopamine (DA) and 3,4-dihydroxyphenylacetic acid was recorded from a second dialysis probe implanted in the ipsilateral striatum. This approach allowed the evaluation of th

  7. Direct monitoring of dopamine and 5-HT release in substantia nigra and ventral tegmental area in vitro

    DEFF Research Database (Denmark)

    Rice, M E; Richards, C D; Nedergaard, S;

    1994-01-01

    Fast-scan cyclic voltammetry with carbon fibre microelectrodes was used to detect endogenous dopamine (DA) and 5-hydroxytryptamine (5-HT) release from three distinct regions of guinea-pig mid-brain in vitro: rostral and caudal substantia nigra (SN) and the ventral tegmental area (VTA). Previous......-HT. Release signals were monitored every 250 ms with a spatial resolution of less than 50 microns.l DA release was calcium-dependent and was not detectable in a catecholamine-poor area such as the cerebellum, or in mid-brain tissue pre-treated with reserpine. Within the normal mid-brain, the amount...... of DA released was correlated with tissue content in that it was higher in the VTA than in either region of SN. It is concluded that DA released from somato-dendritic parts of mid-brain neurons exhibits site-specific variation. This is the first report of direct monitoring of DA and 5-HT release from...

  8. Effect of pressure on the release of endogenous dopamine from rat striatum and the role of sodium-calcium exchange.

    Science.gov (United States)

    Paul, M L; Philp, R B

    1992-01-01

    Exposure to environmental pressures in excess of 20 atm abs can precipitate a hyperexcitability state known as high pressure neurologic syndrome (HPNS). Little is known about the underlying neurochemical basis of this syndrome. An in vitro model of the synthesis and release of endogenous dopamine (DA) from rat striatal slices has been used to examine the mechanism underlying the effects of high pressures of He. He at 100 atm abs produced changes in DA release which were strikingly similar to those of the cardiac glycoside, ouabain. Neither pressure nor ouabain (1-10 microM) had any significant effects on the spontaneous (nonevoked) release of DA or its metabolite 3,4-dihydroxyphenylacetic acid, but both pressure and ouabain significantly enhanced the stimulated release of DA which was evoked by a 6-min exposure to 35 mM KCl (P less than 0.05 and P less than 0.001). In both cases, this effect was dependent on the presence of extracellular Ca2+. Augmentation of evoked DA release by both ouabain and He pressure was reversed (P less than 0.05) by 3,4-dichlorobenzamil, a selective antagonist of the membrane Na+/Ca2+ exchange mechanism. The results suggest that pressure exerts its effects on DA release by increasing intracellular-free Ca2+ exchange after pressure-inhibition of the activity of the membrane Na,K-ATPase.

  9. Presentation of smoking-associated cues does not elicit dopamine release after one-hour smoking abstinence: A [11C]-(+-PHNO PET study.

    Directory of Open Access Journals (Sweden)

    Lina Chiuccariello

    Full Text Available The presentation of drug-associated cues has been shown to elicit craving and dopamine release in the striatum of drug-dependent individuals. Similarly, exposure to tobacco-associated cues induces craving and increases the propensity to relapse in tobacco- dependent smokers. However, whether exposure to tobacco-associated cues elicits dopamine release in the striatum of smokers remains to be investigated. We hypothesized that presentation of smoking-related cues compared to neutral cues would induce craving and elevation of intrasynaptic dopamine levels in subregions of the striatum and that the magnitude of dopamine release would be correlated with subjective levels of craving in briefly abstinent tobacco smokers. Eighteen participants underwent two [(11C]-(+-PHNO positron emission tomography (PET scans after one-hour abstinence period: one during presentation of smoking-associated images and one during presentation of neutral images. Smoking cues significantly increased craving compared to neutral cues on one, but not all, craving measures; however, this increase in craving was not associated with overall significant differences in [(11C]-(+-PHNO binding potential (BPND (an indirect measure of dopamine release between the two experimental conditions in any of the brain regions of interest sampled. Our findings suggest that presentation of smoking cues does not elicit detectable (by PET overall increases in dopamine in humans after one-hour nicotine abstinence. Future research should consider studying smoking cue-induced dopamine release at a longer abstinence period, since recent findings suggest the ability of smoking-related cues to induce craving is associated with a longer duration of smoking abstinence.

  10. Pharmacological characterization of dopamine, norepinephrine and serotonin release in the rat prefrontal cortex by neuronal nicotinic acetylcholine receptor agonists.

    Science.gov (United States)

    Rao, Tadimeti S; Correa, Lucia D; Adams, Pamala; Santori, Emily M; Sacaan, Aida I

    2003-11-14

    Neuronal nicotinic acetylcholine receptors (nAChRs) modulate synaptic transmission by regulating neurotransmitter release, an action that involves multiple nAChRs. The effects of four nAChR agonists, nicotine (NIC), 1,1-dimethyl-4-phenylpiperzinium iodide (DMPP), cytisine (CYT) and epibatidine (EPI) were investigated on [3H]-norepinephrine (NE), [3H]-dopamine (DA) and [3H]-serotonin (5-HT) release from rat prefrontal cortical (PFC) slices. All four agonists evoked [3H]-DA release to a similar magnitude but with a differing rank order of potency of EPI>DMPP approximately NIC approximately CYT. Similarly, all four agonists also increased [3H]-NE release, but with a differing rank order of potency of EPI>CYT approximately DMPP>NIC. NIC-induced [3H]-NE and [3H]-DA release responses were both calcium-dependent and attenuated by the sodium channel antagonist, tetrodotoxin (TTX) and by the nAChR antagonists mecamylamine (MEC) and dihydro-beta-erythroidine (DHbetaE), but not by D-tubocurare (D-TC). The modulation of [3H]-5-HT release by nAChR agonists was distinct from that seen for catecholamines. DMPP produced robust increases with minimal release observed with other agonists. DMPP-induced [3H]-5-HT release was neither sensitive to known nAChR antagonists nor dependent on external calcium. The differences between nicotinic agonist induced catecholamine and serotonin release suggest involvement of distinct nAChRs.

  11. Effects of morphine on hypothalamic corticotropin-releasing factor (CRF, norepinephrine and dopamine in non-stressed and stressed rats.

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    Suemaru,Shuso

    1985-12-01

    Full Text Available The effects of morphine on the hypothalamic corticotropin-releasing factor (CRF, norepinephrine (NE and dopamine (DA concentrations were investigated in non-stressed and stressed rats. Acutely administered morphine stimulated both the synthesis and release of CRF in the hypothalamus, thereby activating the pituitary-adrenocortical system in non-stressed rats, but inhibited the stress-induced CRF synthesis and ACTH-corticosterone secretion. Either a morphine or ether-laparotomy stress reduced NE and DA concentrations in the hypothalamus. A pretreatment with morphine inhibited the stress-induced reduction in the hypothalamic NE and DA concentrations, and induced a significant increase in the DA concentration. These observations suggest that hypothalamic NE and DA are involved in morphine-induced changes in hypothalamo-pituitary-adrenocortical (HPA activity and that endogenous opiates have a role in regulating CRF secretion by interacting with hypothalamic biogenic amines.

  12. Effects of extracerebral dopamine on salsolinol- or thyrotropin-releasing hormone-induced prolactin (PRL) secretion in goats.

    Science.gov (United States)

    Inaba, Yuki; Kato, Yuki; Itou, Azumi; Chiba, Aoi; Sawai, Ken; Fülöp, Ferenc; Nagy, György Miklos; Hashizume, Tsutomu

    2016-12-01

    The aim of the present study was to clarify the effect of extracerebral dopamine (DA) on salsolinol (SAL)-induced prolactin (PRL) secretion in goats. An intravenous injection of SAL or thyrotropin-releasing hormone (TRH) was given to female goats before and after treatment with an extracerebral DA receptor antagonist, domperidone (DOM), and the PRL-releasing response to SAL was compared with that to TRH. DOM alone increased plasma PRL concentrations and the PRL-releasing response to DOM alone was greater than that to either SAL alone or TRH alone. The PRL-releasing response to DOM plus SAL was similar to that to DOM alone, and no additive effect of DOM and SAL on the secretion of PRL was observed. In contrast, the PRL-releasing response to DOM plus TRH was greater than that to either TRH alone or DOM alone and DOM synergistically increased TRH-induced PRL secretion. The present results demonstrate that the mechanism involved in PRL secretion by SAL differs from that by TRH, and suggest that the extracerebral DA might be associated in part with the modulation of SAL-induced PRL secretion in goats.

  13. Role of glutamate receptors and nitric oxide on the effects of glufosinate ammonium, an organophosphate pesticide, on in vivo dopamine release in rat striatum.

    Science.gov (United States)

    Faro, Lilian R F; Ferreira Nunes, Brenda V; Alfonso, Miguel; Ferreira, Vania M; Durán, Rafael

    2013-09-15

    The purpose of the present work was to assess the possible role of glutamatergic receptors and nitric oxide (NO) production on effects of glufosinate ammonium (GLA), an organophosphate pesticide structurally related to glutamate, on in vivo striatal dopamine release in awake and freely moving rats. For this, we used antagonists of NMDA (MK-801 and AP5) or AMPA/kainate (CNQX) receptors, or nitric oxide synthase (NOS) inhibitors (l-NAME and 7-NI), to study the effects of GLA on release of dopamine from rat striatum. So, intrastriatal infusion of 10mM GLA significantly increased dopamine levels (1035±140%, compared with basal levels) and administration of GLA to MK-801 (250μM) or AP5 (650μM) pretreated animals, produced increases in dopamine overflow that were ∼40% and ∼90% smaller than those observed in animals not pretreated with MK-801 or AP5. Administration of GLA to CNQX (500μM) pretreated animals produced an effect that was not significantly different from the one produced in animals not pretreated with CNQX. On the other hand, administration of GLA to l-NAME (100μM) or 7-NI (100μM) pretreated animals, produced increases in dopamine overflow that were ∼80% and ∼75% smaller than those observed in animals not pretreated with these inhibitors. In summary, GLA appears to act, at least in part, through an overstimulation of NMDA (and not AMPA/kainate) receptors with possible NO production to induce in vivo dopamine release. Administration of NMDA receptor antagonists and NOS inhibitors partially blocks the release of dopamine from rat striatum.

  14. Changes in the kinetics of ( sup 3 H)dopamine release from median eminence and striatal synaptosomes during aging

    Energy Technology Data Exchange (ETDEWEB)

    Gregerson, K.A.; Selmanoff, M. (Univ. of Maryland School of Medicine, Baltimore (USA))

    1990-01-01

    The release of preaccumulated tritium-labeled dopamine was examined in isolated nerve terminals prepared from the median eminence (ME) and corpus striatum (CS) of young, middle-aged, and old male rats. Fractional release of (3H)DA was measured over 1- to 10-sec time intervals under basal and depolarizing conditions in the presence of calcium. No differences in the rate of basal efflux between the age groups were observed in either ME or CS preparations. Fast-phase evoked (3H)DA release from CS synaptosomes was unchanged from young to middle-aged, but was decreased in old preparations. These data demonstrate that the nigrostriatal nerve terminal has a diminished ability to respond fully to depolarizing stimuli in advanced age. Mean serum PRL levels in old rats were 2.3-fold greater than those in both young and middle-aged rats, while serum LH levels were decreased 2.0-fold in middle-aged and old compared with those in young rats. The fact that LH levels were already decreased in middle-aged rats while PRL levels had not yet increased suggests that decreased gonadotropin titers in old rats do not result from the coincident hyperprolactinemia. In ME synaptosomes, depolarization-induced (3H)DA release was decreased at all time points in middle-aged preparations compared to that in young preparations. The reduced fractional release from the middle-aged ME synaptosomes was due to a depressed rate of release during the initial second of depolarization. Evoked release from ME terminals of old rats was comparable to that measured in the young group. Thus, there occurred an age-related biphasic change in the initial rate of evoked DA release from ME synaptosomes. Diminished response of ME dopaminergic terminals to depolarizing stimuli during middle age may be important in the later development of hyperprolactinemia in aging male rats.

  15. Novel bis-, tris-, and tetrakis-tertiary amino analogs as antagonists at neuronal nicotinic receptors that mediate nicotine-evoked dopamine release.

    Science.gov (United States)

    Zhang, Zhenfa; Zheng, Guangrong; Pivavarchyk, Marharyta; Deaciuc, A Gabriela; Dwoskin, Linda P; Crooks, Peter A

    2011-01-01

    A series of tertiary amine analogs derived from lead azaaromatic quaternary ammonium salts has been designed and synthesized. The preliminary structure-activity relationships of these new analogs suggest that such tertiary amine analogs, which potently inhibit nicotine-evoked dopamine release from rat striatum, represent drug-like inhibitors of α6-containing nicotinic acetylcholine receptors. The bis-tertiary amine analog 7 exhibited an IC(50) of 0.95 nM, while the tris-tertiary amine analog 19 had an IC(50) of 0.35 nM at nAChRs mediating nicotine-evoked dopamine release.

  16. Striatal dopamine release in reading and writing measured with [123I]iodobenzamide and single photon emission computed tomography in right handed human subjects.

    Science.gov (United States)

    Schommartz, B; Larisch, R; Vosberg, H; Müller-Gärtner, H M

    2000-09-29

    Competition between endogenous dopamine and a radioligand for postsynaptic dopamine D(2) receptor binding was examined in two groups of eight subjects each who had to read or write off a text, respectively, and in a control group. Single photon emission computed tomography (SPECT) and the ligand [(123)I]iodobenzamide (IBZM) were used for in vivo imaging. Subjects commenced reading or writing immediately before IBZM injection and continued for 30min thereafter. SPECT images were acquired 60min later. Striatum-to-parietal-cortex IBZM uptake ratios were lower in subjects who wrote off the text than in controls indicating competition of IBZM and dopamine. There was no difference between subjects who read the text and controls. Thus, dopamine release occurs as a consequence of the motoric activity involved in writing rather than of cognitive functions necessary for reading the text.

  17. Opposing effects of APP/PS1 and TrkB.T1 genotypes on midbrain dopamine neurons and stimulated dopamine release in vivo.

    Science.gov (United States)

    Kärkkäinen, E; Yavich, L; Miettinen, P O; Tanila, H

    2015-10-01

    Brain derived neurotrophic factor (BDNF) signaling disturbances in Alzheimer׳s disease (AD) have been demonstrated. BDNF levels fall in AD, but the ratio between truncated and full-length BDNF receptors TrkB.T1 and TrkB.TK, respectively, increases in brains of AD patients and APPswe/PS1dE9 (APP/PS1) AD model mice. Dopaminergic (DAergic) system disturbances in AD and detrimental effects of BDNF signaling deficits on DAergic system functions have also been indicated. Against this, we investigated changes in nigrostriatal dopamine (DA) system in mice carrying APP/PS1 and/or TrkB.T1 transgenes, the latter line modeling the TrkB.T1/TK ratio change in AD. Employing in vivo voltammetry, we found normal short-term DA release in caudate-putamen of mice carrying APP/PS1 or TrkB.T1 transgenes but impaired capacity to recruit more DA upon prolonged stimulation. However, mice carrying both transgenes did not differ from wild-type controls. Immunohistochemistry revealed normal density of tyrosine hydroxylase positive axon terminals in caudate-putamen in all genotypes and intact presynaptic machinery for DA release and reuptake, as shown by unchanged levels of SNAP-25, α-synuclein and DA transporter. However, we observed increased DAergic neurons in substantia nigra of TrkB.T1 mice resulting in decreased tyrosine hydroxylase per neuron in TrkB.T1 mice. The finding of unchanged nigral DAergic neurons in APP/PS1 mice largely confirms earlier reports, but the unexpected increase in midbrain DA neurons in TrkB.T1 mice is a novel finding. We suggest that both APP/PS1 and TrkB.T1 genotypes disrupt DAergic signaling, but via separate mechanisms.

  18. Effect of MK-801 on methamphetamine-induced dopaminergic neurotoxicity: long-term attenuation of methamphetamine-induced dopamine release

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Sang Eun; Kim, Yu Ri; Hwang, Se Hwan [Sungkyunkwan Univ., School of Medicine, Seoul (Korea, Republic of)

    2001-08-01

    Repeated administration of methamphetamine (METH) produces high extracellular levels of dopamine (DA) and subsequent striatal DA terminal damage. The effect of MK-801, a noncompetitive N-methyl-D-aspartate receptor antagonist, on METH-induced changes in DA transporter (DAT) and DA release evoked by an acute METH challenge was evaluated in rodent striatum using [{sup 3}H] WIN 38,428 ex vivo auto-radiography and in vivo microdialysis. Four injections of METH (10 mg/kg, i.p.), each given 2 h apart, produced 71% decrease in DAT levels in mouse striatum 3 d after administration. Pretreatment with MK-801 (2.5 g/kg, i.p.) 15 min before each of the four METH injections protected completely against striatal DAT depletions. Four injections of MK-801 alone did not significantly change striatal DAT levels. Striatal DA release evoked by an acute METH challenge (4mg/kg, i.p.) at 3 d after repeated administration of METH in rats was decreased but significant compared with controls, which was attenuated by repeated pretreatment with MK-801. Also, repeated injections of MK-801 alone attenuated acute METH-induced striatal DA release 3 d after administration. These results suggest that repeated administration of MK-801 may exert a preventive effect against METH-induced DA terminal injury through long-term attenuation of DA release induced by METH and other stimuli.

  19. Pharmacokinetics and dopamine/acetylcholine releasing effects of ginsenoside Re in hippocampus and mPFC of freely moving rats

    Institute of Scientific and Technical Information of China (English)

    Jing SHI; Wei XUE; Wen-jie ZHAO; Ke-xin LI

    2013-01-01

    Aim: To investigate the pharmacokinetics and dopamine/acetylcholine-releasing effects of ginsenoside Re (Re) in brain regions related to learning and memory,and to clarify the neurochemical mechanisms underlying its anti-dementia activity.Methods: Microdialysis was conducted on awake,freely moving adult male SD rats with dialysis probes implanted into the hippocampus,medial prefrontal cortex (mPFC) or the third ventricle.The concentrations of Re,dopamine (DA) and acetylcholine (ACh) in dialysates were determined using LC-MS/MS.Results: Subcutaneous administration of a single dose of Re (12.5,25 or 50 mg/kg) rapidly distributed to the cerebrospinal fluid and exhibited linear pharmacokinetics.The peak concentration (Cmax) occurred at 60 min for all doses.Re was not detectable after 240 min in the dialysates for the low dose of 12.5 mg/kg.At the same time,Re dose-dependently increased extracellular levels of DA and ACh in the hippocampus and mPFC,and more prominent effects were observed in the hippocampus.Conclusion: The combined study of the pharmacokinetics and pharmacodynamics of Re demonstrate that increase of extracellular levels of DA and ACh,particularly in the hippocampus,may contribute,at least in part,to the anti-dementia activity of Re.

  20. Dopamine dysregulation syndrome in Parkinson's disease patients with unsatisfactory switching from immediate to extended release pramipexole: a further clue to incentive sensitization mechanisms?

    Science.gov (United States)

    Solla, Paolo; Cannas, Antonino; Corona, Marta; Marrosu, Maria Giovanna; Marrosu, Francesco

    2013-01-01

    A small proportion of patients with Parkinson's disease (PD), chronically under dopamine replacement therapy, may undergo an addiction-like behavioral disturbance, named dopamine dysregulation syndrome (DDS). This behavioral disorder is characterized by the increase of doses beyond those required for motor control, and its management remains difficult; thus, early recognition and careful monitoring of at-risk individuals are crucial. We report the cases of two PD patients with a previous unsatisfactory switching from an immediate release (IR) to an extended release (ER) pramipexole formulation who developed DDS. PD patients unsatisfactorily switched from an IR to an ER formulation of dopamine agonists should be considered as at-risk individuals for DDS development.

  1. 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.

  2. Aspects of dopamine and acetylcholine release induced by glutamate receptors; Aspectos das liberacoes de dopamina e acetilcolina mediadas por receptores de glutamato

    Energy Technology Data Exchange (ETDEWEB)

    Paes, Paulo Cesar de Arruda

    2002-07-01

    The basal ganglia play an important role in the motor control of rats and humans. This control involves different neurotransmitters and the mutual control of these key elements has been subject to several studies. In this work we determined the role of glutamate on the release of radioactively labelled dopamine and acetylcholine from chopped striatal tissue in vitro. The values of Effective Concentration 50% for glutamate, NMDA, kainic, quisqualic acids and AMPA on the release of dopamine and acetylcholine were obtained. The inhibitory effects of magnesium, tetrodotoxin, MK-801, AP5 and MCPG, as well as the effects of glycin were evaluated. The results suggested that dopamine is influenced by the NMDA type glutamate receptor while acetylcholine seems to be influenced by NMDA, kainate and AMPA receptors. Tetrodotoxin experiments suggested that kainate receptors are both present in cholinergic terminals and cell bodies while AMPA and NMDA receptors are preferentially distributed in cell bodies. Magnesium effectively blocked the NMDA stimulation and unexpectedly also AMPA- and quisqualate-induced acetylcholine release. The latter could not be blocked by MCPG ruling out the participation of methabotropic receptors. MK-801 also blocked NMDA-receptors. Results point out the importance of the glutamic acid control of dopamine and acetylcholine release in striatal tissue. (author)

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

    Science.gov (United States)

    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

  4. Indolizidine (-)-235B' and related structural analogs: discovery of nicotinic receptor antagonists that inhibit nicotine-evoked [3H]dopamine release.

    Science.gov (United States)

    Pivavarchyk, Marharyta; Smith, Andrew M; Zhang, Zhenfa; Zhou, Dejun; Wang, Xu; Toyooka, Naoki; Tsuneki, Hiroshi; Sasaoka, Toshiyasu; McIntosh, J Michael; Crooks, Peter A; Dwoskin, Linda P

    2011-05-11

    Although several therapeutic agents are available to aid in tobacco smoking cessation, relapse rates continue to be high, warranting the development of alternative pharmacotherapies. Nicotine-evoked dopamine release from its presynaptic terminals in the central nervous system leads to reward which maintains continued tobacco use. The ability of indolizidine (-)-235B' and a sub-library of structurally related analogs to inhibit nicotine-evoked [(3)H]dopamine release from rat striatal slices was determined in the current study. Indolizidine (-)-235B' inhibited nicotine-evoked [(3)H]dopamine release in a concentration-dependent manner (IC(50)=42 nM, I(max)=55%). Compound (-)-237D, the double bond-reduced analog, afforded the greatest inhibitory potency (IC(50)=0.18 nM, I(max)=76%), and was 233-fold more potent than indolizidine (-)-235B'. The des-8-methyl aza-analog of indolizidine (-)-235B', ZZ-272, also inhibited nicotine-evoked [(3)H]dopamine release (IC(50)=413 nM, I(max)=59%). Concomitant exposure to maximally effective concentrations of indolizidine (-)-235B', ZZ-272 or (-)-237D with a maximally effective concentration of α-conotoxin MII, a selective antagonist for α6β2-containing nicotinic receptors, resulted in inhibition of nicotine-evoked [(3)H]dopamine release no greater than that produced by each compound alone. The latter results suggest that indolizidine (-)-235B', (-)-237D, ZZ-272 and α-conotoxin MII inhibit the same α-conotoxin MII-sensitive nicotinic receptor subtypes. Thus, indolizidine (-)-235B' and its analogs act as antagonists of α6β2-nicotinic receptors and constitute a novel structural scaffold for the discovery of pharmacotherapies for smoking cessation.

  5. Dopamine, behavioral economics, and effort.

    Science.gov (United States)

    Salamone, John D; Correa, Merce; Farrar, Andrew M; Nunes, Eric J; Pardo, Marta

    2009-01-01

    There are numerous problems with the hypothesis that brain dopamine (DA) systems, particularly in the nucleus accumbens, directly mediate the rewarding or primary motivational characteristics of natural stimuli such as food. Research and theory related to the functions of mesolimbic DA are undergoing a substantial conceptual restructuring, with the traditional emphasis on hedonia and primary reward yielding to other concepts and lines of inquiry. The present review is focused upon the involvement of nucleus accumbens DA in behavioral activation and effort-related processes. Viewed from the framework of behavioral economics, the effects of accumbens DA depletions and antagonism on food-reinforced behavior are highly dependent upon the work requirements of the instrumental task, and DA depleted rats are more sensitive to increases in response costs (i.e., ratio requirements). Moreover, interference with accumbens DA transmission exerts a powerful influence over effort-related choice behavior. Rats with accumbens DA depletions or antagonism reallocate their instrumental behavior away from food-reinforced tasks that have high response requirements, and instead these rats select a less-effortful type of food-seeking behavior. Nucleus accumbens DA and adenosine interact in the regulation of effort-related functions, and other brain structures (anterior cingulate cortex, amygdala, ventral pallidum) also are involved. Studies of the brain systems regulating effort-based processes may have implications for understanding drug abuse, as well as energy-related disorders such as psychomotor slowing, fatigue or anergia in depression and other neurological disorders.

  6. Dopamine, behavioral economics, and effort

    Directory of Open Access Journals (Sweden)

    John D Salamone

    2009-09-01

    Full Text Available Abstract. There are numerous problems with the hypothesis that brain dopamine (DA systems, particularly in the nucleus accumbens, directly mediate the rewarding or primary motivational characteristics of natural stimuli such as food. Research and theory related to the functions of mesolimbic DA are undergoing a substantial conceptual restructuring, with the traditional emphasis on hedonia and primary reward yielding to other concepts and lines of inquiry. The present review is focused upon the involvement of nucleus accumbens DA in behavioral activation and effort-related processes. Viewed from the framework of behavioral economics, the effects of accumbens DA depletions and antagonism on food-reinforced behavior are highly dependent upon the work requirements of the instrumental task, and DA depleted rats are more sensitive to increases in response costs (i.e., ratio requirements. Moreover, interference with accumbens DA transmission exerts a powerful influence over effort-related choice behavior. Rats with accumbens DA depletions or antagonism reallocate their instrumental behavior away from food-reinforced tasks that have high response requirements, and instead these rats select a less-effortful type of food-seeking behavior. Nucleus accumbens DA and adenosine interact in the regulation of effort-related functions, and other brain structures (anterior cingulate cortex, amygdala, ventral pallidum also are involved. Studies of the brain systems regulating effort-based processes may have implications for understanding drug abuse, as well as energy-related disorders such as psychomotor slowing, fatigue or anergia in depression and other neurological disorders.

  7. Patterns of renal dopamine release to regulate diuresis and natriuresis during volume expansion. Role of renal monoamine-oxidase.

    Science.gov (United States)

    de Luca Sarobe, Verónica; Di Ciano, Luis; Carranza, Andrea M; Levin, Gloria; Arrizurieta, Elvira E; Ibarra, Fernando R

    2010-01-01

    Diuretic and natriuretic effects of renal dopamine (DA) are well established. However, in volume expansion the pattern of renal DA release into urine (UDAV) and the role of enzymes involved in DA synthesis/degradation have not yet been defined. The objective was to determine the pattern of UDAV during volume expansion and to characterize the involvement of monoamine-oxidase (MAO) and aromatic amino-acid decarboxylase (AADC) in this response. In this study male Wistar rats were expanded with NaCl 0.9% at a rate of 5% BWt per hour. At the beginning of expansion three groups received a single drug injection as follows: C (vehicle, Control), IMAO (MAO inhibitor Pargyline, 20 mg/kg BWt, i.v.) and BNZ (AADC inhibitor Benserazide, 25 mg/kg BWt, i.v.). Results revealed that in C rats UDAV (ng/30 min/100g BWt) increased in the first 30 min expansion from 11.5 +/- 1.20 to 21.8 +/- 3.10 (p diuresis and natriuresis over controls. BNZ abolished the early UDAV peak to 3.2+/-0.72 (p diuresis were diminished by BNZ treatment. Results indicate that an increment in renal DA release into urine occurs early in expansion and in a peak-shaped way. In this response MAO plays a predominant role.

  8. Angiotensin AT1 and AT2 receptor antagonists modulate nicotine-evoked [³H]dopamine and [³H]norepinephrine release.

    Science.gov (United States)

    Narayanaswami, Vidya; Somkuwar, Sucharita S; Horton, David B; Cassis, Lisa A; Dwoskin, Linda P

    2013-09-01

    Tobacco smoking is the leading preventable cause of death in the United States. A major negative health consequence of chronic smoking is hypertension. Untoward addictive and cardiovascular sequelae associated with chronic smoking are mediated by nicotine-induced activation of nicotinic receptors (nAChRs) within striatal dopaminergic and hypothalamic noradrenergic systems. Hypertension involves both brain and peripheral angiotensin systems. Activation of angiotensin type-1 receptors (AT1) release dopamine and norepinephrine. The current study determined the role of AT1 and angiotensin type-2 (AT2) receptors in mediating nicotine-evoked dopamine and norepinephrine release from striatal and hypothalamic slices, respectively. The potential involvement of nAChRs in mediating effects of AT1 antagonist losartan and AT2 antagonist, 1-[[4-(dimethylamino)-3-methylphenyl]methyl]-5-(diphenylacetyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid (PD123319) was evaluated by determining their affinities for α4β2* and α7* nAChRs using [³H]nicotine and [³H]methyllycaconitine binding assays, respectively. Results show that losartan concentration-dependently inhibited nicotine-evoked [³H]dopamine and [³H]norepinephrine release (IC₅₀: 3.9 ± 1.2 and 2.2 ± 0.7 μM; Imax: 82 ± 3 and 89 ± 6%, respectively). In contrast, PD123319 did not alter nicotine-evoked norepinephrine release, and potentiated nicotine-evoked dopamine release. These results indicate that AT1 receptors modulate nicotine-evoked striatal dopamine and hypothalamic norepinephrine release. Furthermore, AT1 receptor activation appears to be counteracted by AT2 receptor activation in striatum. Losartan and PD123319 did not inhibit [³H]nicotine or [³H]methyllycaconitine binding, indicating that these AT1 and AT2 antagonists do not interact with the agonist recognition sites on α4β2* and α7* nAChRs to mediate these effects of nicotine. Thus, angiotensin receptors contribute to the effects of

  9. GBR12909 attenuates amphetamine-induced striatal dopamine release as measured by [(11)C]raclopride continuous infusion PET scans.

    Science.gov (United States)

    Villemagne, V L; Wong, D F; Yokoi, F; Stephane, M; Rice, K C; Matecka, D; Clough, D J; Dannals, R F; Rothman, R B

    1999-09-15

    Major neurochemical effects of methamphetamine include release of dopamine (DA), serotonin (5-HT), and norepinephrine (NE) via a carrier-mediated exchange mechanism. Preclinical research supports the hypothesis that elevations of mesolimbic DA mediate the addictive and reinforcing effects of methamphetamine and amphetamine. This hypothesis has not been adequately tested in humans. Previous in vivo rodent microdialysis demonstrated that the high affinity DA uptake inhibitor, GBR12909, attenuates cocaine- and amphetamine-induced increases in mesolimbic DA. The present study determined the ability of GBR12909 to attenuate amphetamine-induced increases in striatal DA as measured by [(11)C]raclopride continuous infusion positron emission tomography (PET) scans in two Papio anubis baboons. [(11)C]Raclopride was given in a continuous infusion paradigm resulting in a flat volume of distribution vs. time for up to 45 min postinjection. At that time, a 1.5 mg/kg amphetamine i.v. bolus was administered which caused a significant (30.3%) reduction in the volume of distribution (V(3)"). The percent reduction in the volume of distribution and, hence, a measure of the intrasynaptic DA release ranged between 22-41%. GBR12909 (1 mg/kg, slow i.v. infusion) was administered 90 min before the administration of the radiotracer. The comparison of the volume of distribution before and after administration of GBR12909 showed that GBR12909 inhibited amphetamine-induced DA release by 74%. These experiments suggest that GBR12909 is an important prototypical medication to test the hypothesis that stimulant-induced euphoria is mediated by DA and, if the DA hypothesis is correct, a potential treatment agent for cocaine and methamphetamine abuse. Furthermore, this quantitative approach demonstrates a way of testing various treatment medications, including other forms of GBR12909 such as a decanoate derivative.

  10. The potential role of dopamine D₃ receptor neurotransmission in cognition.

    Science.gov (United States)

    Nakajima, Shinichiro; Gerretsen, Philip; Takeuchi, Hiroyoshi; Caravaggio, Fernando; Chow, Tiffany; Le Foll, Bernard; Mulsant, Benoit; Pollock, Bruce; Graff-Guerrero, Ariel

    2013-08-01

    Currently available treatments have limited pro-cognitive effects for neuropsychiatric disorders, such as schizophrenia, Parkinson's disease and Alzheimer's disease. The primary objective of this work is to review the literature on the role of dopamine D₃ receptors in cognition, and propose dopamine D₃ receptor antagonists as possible cognitive enhancers for neuropsychiatric disorders. A literature search was performed to identify animal and human studies on D₃ receptors and cognition using PubMed, MEDLINE and EMBASE. The search terms included "dopamine D₃ receptor" and "cognition". The literature search identified 164 articles. The results revealed: (1) D₃ receptors are associated with cognitive functioning in both healthy individuals and those with neuropsychiatric disorders; (2) D₃ receptor blockade appears to enhance while D₃ receptor agonism seems to impair cognitive function, including memory, attention, learning, processing speed, social recognition and executive function independent of age; and (3) D₃ receptor antagonists may exert their pro-cognitive effect by enhancing the release of acetylcholine in the prefrontal cortex, disinhibiting the activity of dopamine neurons projecting to the nucleus accumbens or prefrontal cortex, or activating CREB signaling in the hippocampus. These findings suggest that D₃ receptor blockade may enhance cognitive performance in healthy individuals and treat cognitive dysfunction in individuals with a neuropsychiatric disorder. Clinical trials are needed to confirm these effects.

  11. Programming of Dopaminergic Neurons by Neonatal Sex Hormone Exposure: Effects on Dopamine Content and Tyrosine Hydroxylase Expression in Adult Male Rats

    Science.gov (United States)

    Espinosa, Pedro; Silva, Roxana A.; Sanguinetti, Nicole K.; Venegas, Francisca C.; Riquelme, Raul; González, Luis F.; Cruz, Gonzalo; Renard, Georgina M.; Moya, Pablo R.; Sotomayor-Zárate, Ramón

    2016-01-01

    We sought to determine the long-term changes produced by neonatal sex hormone administration on the functioning of midbrain dopaminergic neurons in adult male rats. Sprague-Dawley rats were injected subcutaneously at postnatal day 1 and were assigned to the following experimental groups: TP (testosterone propionate of 1.0 mg/50 μL); DHT (dihydrotestosterone of 1.0 mg/50 μL); EV (estradiol valerate of 0.1 mg/50 μL); and control (sesame oil of 50 μL). At postnatal day 60, neurochemical studies were performed to determine dopamine content in substantia nigra-ventral tegmental area and dopamine release in nucleus accumbens. Molecular (mRNA expression of tyrosine hydroxylase) and cellular (tyrosine hydroxylase immunoreactivity) studies were also performed. We found increased dopamine content in substantia nigra-ventral tegmental area of TP and EV rats, in addition to increased dopamine release in nucleus accumbens. However, neonatal exposure to DHT, a nonaromatizable androgen, did not affect midbrain dopaminergic neurons. Correspondingly, compared to control rats, levels of tyrosine hydroxylase mRNA and protein were significantly increased in TP and EV rats but not in DHT rats, as determined by qPCR and immunohistochemistry, respectively. Our results suggest an estrogenic mechanism involving increased tyrosine hydroxylase expression, either by direct estrogenic action or by aromatization of testosterone to estradiol in substantia nigra-ventral tegmental area. PMID:26904299

  12. Programming of Dopaminergic Neurons by Neonatal Sex Hormone Exposure: Effects on Dopamine Content and Tyrosine Hydroxylase Expression in Adult Male Rats

    Directory of Open Access Journals (Sweden)

    Pedro Espinosa

    2016-01-01

    Full Text Available We sought to determine the long-term changes produced by neonatal sex hormone administration on the functioning of midbrain dopaminergic neurons in adult male rats. Sprague-Dawley rats were injected subcutaneously at postnatal day 1 and were assigned to the following experimental groups: TP (testosterone propionate of 1.0 mg/50 μL; DHT (dihydrotestosterone of 1.0 mg/50 μL; EV (estradiol valerate of 0.1 mg/50 μL; and control (sesame oil of 50 μL. At postnatal day 60, neurochemical studies were performed to determine dopamine content in substantia nigra-ventral tegmental area and dopamine release in nucleus accumbens. Molecular (mRNA expression of tyrosine hydroxylase and cellular (tyrosine hydroxylase immunoreactivity studies were also performed. We found increased dopamine content in substantia nigra-ventral tegmental area of TP and EV rats, in addition to increased dopamine release in nucleus accumbens. However, neonatal exposure to DHT, a nonaromatizable androgen, did not affect midbrain dopaminergic neurons. Correspondingly, compared to control rats, levels of tyrosine hydroxylase mRNA and protein were significantly increased in TP and EV rats but not in DHT rats, as determined by qPCR and immunohistochemistry, respectively. Our results suggest an estrogenic mechanism involving increased tyrosine hydroxylase expression, either by direct estrogenic action or by aromatization of testosterone to estradiol in substantia nigra-ventral tegmental area.

  13. Voltammetric characterization of the effect of monoamine uptake inhibitors and releasers on dopamine and serotonin uptake in mouse caudate-putamen and substantia nigra slices

    OpenAIRE

    John, Carrie E.; Jones, Sara R

    2007-01-01

    Fast scan cyclic voltammetry is an electrochemical technique used to measure dynamics of transporter-mediated monoamine uptake in real time and provides a tool to evaluate the detailed effects of monoamine uptake inhibitors and releasers on dopamine and serotonin transporter function. We measured the effects of cocaine, methylphenidate, 2β-propanoyl–3β-(4tolyl) tropane (PTT), fluoxetine, amphetamine, methamphetamine, 3,4-methylenedioxymethamphetamine (MDMA), phentermine and fenfluramine on do...

  14. Stimulated serotonin release from hyperinnervated terminals subsequent to neonatal dopamine depletion regulates striatal tachykinin, but not enkephalin gene expression.

    Science.gov (United States)

    Basura, G J; Walker, P D

    2000-09-30

    Dopamine (DA) depletion in neonatal rodents results in depressed tachykinin and elevated enkephalin gene expression in the adult striatum (STR). Concurrently, serotonin (5-HT) fibers sprout to hyperinnervate the DA-depleted anterior striatum (A-STR). The present study was designed to determine if increased 5-HT release from sprouted terminals influences dysregulated preprotachykinin (PPT) and preproenkephalin (PPE) mRNA expression in the DA-depleted STR. Three-day-old Sprague-Dawley rat pups received bilateral intracerebroventricular injections of vehicle or the DA neurotoxin 6-hydroxydopamine (6-OHDA, 100 microg). Two months later, rats received a single intraperitoneal injection of vehicle or the acute 5-HT releasing agent p-chloroamphetamine (PCA; 10 mg/kg). Rats were killed 4 h later and striata processed for monoamine content by HPLC-ED and mRNA expression by in situ hybridization within specific subregions of the A-STR and posterior striatum (P-STR). 6-OHDA treatment severely (>98%) reduced striatal DA levels, while 5-HT content in the A-STR was significantly elevated (doubled), indicative of 5-HT hyperinnervation. Following 6-OHDA, PPT mRNA levels were depressed 60-66% across three subregions of the A-STR and 52-59% across two subregions of the P-STR, while PPE mRNA expression was elevated in both the A-STR (50-62%) and P-STR (55-82%). PCA normalized PPT mRNA levels in all regions of the DA-depleted A-STR and P-STR, yet did not alter PPE levels in either dorsal central or medial regions from 6-OHDA alone, but reduced PPE to control levels in the dorsal lateral A-STR. These data indicate that increased 5-HT neurotransmission, following neonatal 6-OHDA treatment, primarily influences PPT-containing neurons of the direct striatal output pathway.

  15. Antipsychotic drugs classified by their effects on the release of dopamine and noradrenaline in the prefrontal cortex and striatum

    NARCIS (Netherlands)

    Westerink, B.H.C.; Kawahara, Y; de Boer, P; Geels, C; de Vries, J.B; Wikström, H.V; van Kalkeren, A; van Vliet, B; Kruse, C.H; Long, S.K

    2001-01-01

    Dose-effect curves were established for the effects of the antipsychotic drugs haloperidol, clozapine, olanzapine, risperidone and ziprasidone on extracellular levels of dopamine and noradrenaline in the medial prefrontal cortex, and of dopamine in the striatum. Haloperidol was more effective in sti

  16. Single versus multiple impulse control disorders in Parkinson's disease: an ¹¹C-raclopride positron emission tomography study of reward cue-evoked striatal dopamine release.

    Science.gov (United States)

    Wu, Kit; Politis, Marios; O'Sullivan, Sean S; Lawrence, Andrew D; Warsi, Sarah; Bose, Subrata; Lees, Andrew J; Piccini, Paola

    2015-06-01

    Impulse control disorders (ICDs) are reported in Parkinson's disease (PD) in association with dopaminergic treatment. Approximately 25 % of patients with ICDs have multiple co-occurring ICDs (i.e. more than one diagnosed ICD). The extent to which dopaminergic neurotransmission in PD patients with multiple ICDs differs from those with only one diagnosed ICD is unknown. The aims of this study are: (1) to investigate dopamine neurotransmission in PD patients diagnosed with multiple ICDs, single ICDs and non-ICD controls in response to reward-related visual cues using positron emission tomography with (11)C-raclopride. (2) to compare clinical features of the above three groups. PD individuals with mulitple ICDs (n = 10), single ICD (n = 7) and no ICDs (n = 9) were recruited and underwent two positron emission tomography (PET) scans with (11)C-raclopride: one where they viewed neutral visual cues and the other where they viewed a range of visual cues related to different rewards. Individuals with both multiple ICDs and single ICDs showed significantly greater ventral striatal dopamine release compared to non-ICD PD individuals in response to reward cues, but the two ICD groups did not differ from each other in the extent of dopamine release. Subjects with multiple ICDs were, however, significantly more depressed, and had higher levels of impulsive sensation-seeking compared to subjects with single ICDs and without ICDs. This is the first study to compare dopamine neurotransmission using PET neuroimaging in PD subjects with multiple vs. single ICDs. Our results suggest that striatal dopamine neurotransmission is not directly related to the co-occurrence of ICDs in PD, potentially implicating non-dopaminergic mechanisms linked to depression; and suggest that physicians should be vigilant in managing depression in PD patients with ICDs.

  17. Ventral tegmental area glutamate neurons co-release GABA and promote positive reinforcement.

    Science.gov (United States)

    Yoo, Ji Hoon; Zell, Vivien; Gutierrez-Reed, Navarre; Wu, Johnathan; Ressler, Reed; Shenasa, Mohammad Ali; Johnson, Alexander B; Fife, Kathryn H; Faget, Lauren; Hnasko, Thomas S

    2016-12-15

    In addition to dopamine neurons, the ventral tegmental area (VTA) contains GABA-, glutamate- and co-releasing neurons, and recent reports suggest a complex role for the glutamate neurons in behavioural reinforcement. We report that optogenetic stimulation of VTA glutamate neurons or terminals serves as a positive reinforcer on operant behavioural assays. Mice display marked preference for brief over sustained VTA glutamate neuron stimulation resulting in behavioural responses that are notably distinct from dopamine neuron stimulation and resistant to dopamine receptor antagonists. Whole-cell recordings reveal EPSCs following stimulation of VTA glutamate terminals in the nucleus accumbens or local VTA collaterals; but reveal both excitatory and monosynaptic inhibitory currents in the ventral pallidum and lateral habenula, though the net effects on postsynaptic firing in each region are consistent with the observed rewarding behavioural effects. These data indicate that VTA glutamate neurons co-release GABA in a projection-target-dependent manner and that their transient activation drives positive reinforcement.

  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. Dopamine D1 Receptor-Mediated Transmission Maintains Information Flow Through the Cortico-Striato-Entopeduncular Direct Pathway to Release Movements.

    Science.gov (United States)

    Chiken, Satomi; Sato, Asako; Ohta, Chikara; Kurokawa, Makoto; Arai, Satoshi; Maeshima, Jun; Sunayama-Morita, Tomoko; Sasaoka, Toshikuni; Nambu, Atsushi

    2015-12-01

    In the basal ganglia (BG), dopamine plays a pivotal role in motor control, and dopamine deficiency results in severe motor dysfunctions as seen in Parkinson's disease. According to the well-accepted model of the BG, dopamine activates striatal direct pathway neurons that directly project to the output nuclei of the BG through D1 receptors (D1Rs), whereas dopamine inhibits striatal indirect pathway neurons that project to the external pallidum (GPe) through D2 receptors. To clarify the exact role of dopaminergic transmission via D1Rs in vivo, we developed novel D1R knockdown mice in which D1Rs can be conditionally and reversibly regulated. Suppression of D1R expression by doxycycline treatment decreased spontaneous motor activity and impaired motor ability in the mice. Neuronal activity in the entopeduncular nucleus (EPN), one of the output nuclei of the rodent BG, was recorded in awake conditions to examine the mechanism of motor deficits. Cortically evoked inhibition in the EPN mediated by the cortico-striato-EPN direct pathway was mostly lost during suppression of D1R expression, whereas spontaneous firing rates and patterns remained unchanged. On the other hand, GPe activity changed little. These results suggest that D1R-mediated dopaminergic transmission maintains the information flow through the direct pathway to appropriately release motor actions.

  20. Regulation of dopamine release by CASK-β modulates locomotor initiation in Drosophila melanogaster

    Directory of Open Access Journals (Sweden)

    Justin eSlawson

    2014-11-01

    Full Text Available CASK is an evolutionarily conserved scaffolding protein that has roles in many cell types. In Drosophila, loss of the entire CASK gene or just the CASK-β transcript causes a complex set of adult locomotor defects. In this study, we show that the motor initiation component of this phenotype is due to loss of CASK-β in dopaminergic neurons and can be specifically rescued by expression of CASK-β within this subset of neurons. Functional imaging demonstrates that mutation of CASK-β disrupts coupling of neuronal activity to vesicle fusion. Consistent with this, locomotor initiation can be rescued by artificially driving activity in dopaminergic neurons. The molecular mechanism underlying this role of CASK-β in dopaminergic neurons involves interaction with Hsc70-4, a molecular chaperone previously shown to regulate calcium-dependent vesicle fusion. These data suggest that there is a novel CASK-β-dependent regulatory complex in dopaminergic neurons that serves to link activity and neurotransmitter release.

  1. Acute intraperitoneal injection of caffeine improves endurance exercise performance in association with increasing brain dopamine release during exercise.

    Science.gov (United States)

    Zheng, Xinyan; Takatsu, Satomi; Wang, Hongli; Hasegawa, Hiroshi

    2014-07-01

    The purpose of this study was to examine changes of thermoregulation, neurotransmitters in the preoptic area and anterior hypothalamus (PO/AH), which is the thermoregulatory center, and endurance exercise performance after the intraperitoneal injection of caffeine in rats. Core body temperature (Tcore), oxygen consumption (VO₂) and tail skin temperature (Ttail) were measured. A microdialysis probe was inserted in the PO/AH, and samples for the measurements of extracellular dopamine (DA), noradrenaline (NA) and serotonin (5-HT) levels were collected. During the rest experiment, 1 h after baseline collections in the chamber (23 °C), the rats were intraperitoneally injected with saline, or 3 mg kg(-1) or 10 mg kg(-1) caffeine. The duration of the test was 4 h. During the exercise experiment, baseline collections on the treadmill were obtained for 1 h. One hour before the start of exercise, rats were intraperitoneally injected with either 10 mg kg(-1) caffeine (CAF) or saline (SAL). Animals ran until fatigue at a speed of 18 m min(-1), at a 5% grade, on the treadmill in a normal environment (23 °C). At rest, 3 mg kg(-1) caffeine did not influence Tcore, Ttail, VO₂, extracellular DA, NA and 5-HT. 10 mg kg(-1) caffeine caused significant increases in Tcore, VO₂, Ttail and extracellular DA in the PO/AH. In addition, 10 mg kg(-1) caffeine increased the run time to fatigue (SAL: 104.4 ± 30.9 min, CAF: 134.0 ± 31.1 min, pexercise increased Tcore, VO₂, Ttail and extracellular DA in the PO/AH. NA increased during exercise, while neither caffeine nor exercise changed 5-HT. These results indicate that caffeine has ergogenic and hyperthermic effects, and these effects may be related to changes of DA release in the brain.

  2. 5-HT6/7 receptor antagonists facilitate dopamine release in the cochlea via a GABAergic disinhibitory mechanism

    NARCIS (Netherlands)

    Doleviczenyi, Zoltan; Vizi, E. Sylvester; Gacsalyi, Istvan; Pallagi, Katalin; Volk, Balazs; Harsing, Laszlo G.; Halmos, Gyorgy; Lendvai, Balazs; Zelles, Tibor

    2008-01-01

    In humans, serotonin (5-HT) has been implicated in numerous physiological and pathological processes in the peripheral auditory system. Dopamine (DA), another transmitter of the lateral olivocochlear (LOC) efferents making synapses on cochlear nerve dendrites, controls auditory nerve activation and

  3. Neurons of human nucleus accumbens

    Directory of Open Access Journals (Sweden)

    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.

  4. Effects of dopamine on leptin release and leptin gene (OB expression in adipocytes from obese and hypertensive patients

    Directory of Open Access Journals (Sweden)

    Alvarez-Aguilar C

    2013-11-01

    gene messenger ribonucleic acid expression under different doses of DA was observed in adipocytes from obese hypertensive patients. Whereas prolactin treatment elicited a significant increase of both leptin release and OB gene expression, NE reduced these parameters. Although similar effects of DA and NE were observed in adipocytes from controls, baseline values in controls were reduced to 20% of the value in adipocytes from obese hypertensive patients. Conclusion: These results suggest that DAergic deficiency contributes to metabolic disorders linked to hyperleptinemia in obese and hypertensive patients. Keywords: dopamine, leptin, cultured adipocytes, obesity, hypertension

  5. Mathematical model of dopamine autoreceptors and uptake inhibitors and their influence on tonic and phasic dopamine signaling

    DEFF Research Database (Denmark)

    Dreyer, Jakob Kristoffer Kisbye; Hounsgaard, Jørn Dybkjær

    2013-01-01

    Dopamine (DA) D2-like autoreceptors are an important component of the DA system, but their influence on postsynaptic DA signaling is not well understood. They are, directly or indirectly, involved in drug abuse and in treatment of schizophrenia and attention deficit hyperactive disorder: DA...... autoreceptors influence the behavioral effect of cocaine and methylphenidate and may be the target of antipsychotic medications such as haloperidol. DA autoreceptors are active at two levels: Somatodendritic autoreceptors mainly influence firing rate of DA neurons, and presynaptic autoreceptors control release...... to phasic DA signaling. This effect had remarkable regional specificity: While high-affinity DA receptors saturated at low levels of uptake inhibition in nucleus accumbens, they only saturated at higher levels of uptake inhibition in dorsal striatum. Based on high-affinity receptor saturation, the model...

  6. Effects of the triple monoamine uptake inhibitor amitifadine on pain-related depression of behavior and mesolimbic dopamine release in rats.

    Science.gov (United States)

    Miller, Laurence L; Leitl, Michael D; Banks, Matthew L; Blough, Bruce E; Negus, S Stevens

    2015-01-01

    Pain-related depression of behavior and mood is a key therapeutic target in the treatment of pain. Clinical evidence suggests a role for decreased dopamine (DA) signaling in pain-related depression of behavior and mood. Similarly, in rats, intraperitoneal injection of dilute lactic acid (IP acid) serves as a chemical noxious stimulus to produce analgesic-reversible decreases in both (1) extracellular DA levels in nucleus accumbens (NAc) and (2) intracranial self-stimulation (ICSS), an operant behavior reliant on NAc DA. Intraperitonial acid-induced depression of ICSS is blocked by DA transporter (DAT) inhibitors, but clinical viability of selective DAT inhibitors as analgesics is limited by abuse potential. Drugs that produce combined inhibition of both DA and serotonin transporters may retain efficacy to block pain-related behavioral depression with reduced abuse liability. Amitifadine is a "triple uptake inhibitor" that inhibits DAT with approximately 5- to 10-fold weaker potency than it inhibits serotonin and norepinephrine transporters. This study compared amitifadine effects on IP acid-induced depression of NAc DA and ICSS and IP acid-stimulated stretching in male Sprague-Dawley rats. Amitifadine blocked IP acid-induced depression of both NAc DA and ICSS and IP acid-stimulated stretching. In the absence of the noxious stimulus, amitifadine increased NAc levels of both DA and serotonin, and behaviorally, amitifadine produced significant but weak abuse-related ICSS facilitation. Moreover, amitifadine was more potent to block IP acid-induced depression of ICSS than to facilitate control ICSS. These results support consideration of amitifadine and related monoamine uptake inhibitors as candidate analgesics for treatment of pain-related behavioral depression.

  7. THE EFFECT OF INTRASTRIATAL APPLICATION OF DIRECTLY AND INDIRECTLY ACTING DOPAMINE AGONISTS AND ANTAGONISTS ON THE INVIVO RELEASE OF ACETYLCHOLINE MEASURED BY BRAIN MICRODIALYSIS - THE IMPORTANCE OF THE POSTSURGERY INTERVAL

    NARCIS (Netherlands)

    DEBOER, P; DAMSMA, G; SCHRAM, Q; STOOF, JC; ZAAGSMA, J; WESTERINK, BHC

    1992-01-01

    The effect of intrastriatal application of D-1, D-2 and indirect dopaminergic drugs on the release of striatal acetylcholine as a function of the post-implantation intervals was studied using in vivo microdialysis. The dopamine D-2 agonists LY 171555 and (-)N0437 inhibited the release of striatal ac

  8. Partial agonist properties of the antipsychotics SSR181507, aripiprazole and bifeprunox at dopamine D2 receptors: G protein activation and prolactin release.

    Science.gov (United States)

    Cosi, Cristina; Carilla-Durand, Elisabeth; Assié, Marie Bernadette; Ormiere, Anne Marie; Maraval, Mireille; Leduc, Nathalie; Newman-Tancredi, Adrian

    2006-03-27

    Dopamine D2 receptor antagonists induce hyperprolactinemia depending on the extent of D2 receptor blockade. We compared the effects of the new antipsychotic agents SSR181507 ((3-exo)-8-benzoyl-N-[[(2 s)7-chloro-2,3-dihydro-1,4-benzodioxin-1-yl]methyl]-8-azabicyclo[3.2.1]octane-3-methanamine monohydrochloride), bifeprunox (DU127090: 1-(2-Oxo-benzoxazolin-7-yl)-4-(3-biphenyl)methylpiperazinemesylate) and SLV313 (1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-4-[5-(4-fluorophenyl)-pyridin-3-ylmethyl]-piperazine) with those of aripiprazole (7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]-butyloxy)-3,4-dihydro-2(1 H)-quinolinone), clozapine and haloperidol, on functional measures of dopamine D2 receptor activity in vitro and in vivo: [35S]-GTPgammaS binding to membranes from Sf9 insect cells expressing human dopamine D2 Long (hD2 L) receptors, and serum prolactin levels in the rat. All compounds antagonized apomorphine-induced G protein activation at dopamine hD2 L receptors. Antagonist potencies of aripiprazole, bifeprunox and SLV313 were similar to haloperidol (pK(b) = 9.12), whereas SSR181507 (8.16) and clozapine (7.35) were less potent. Haloperidol, SLV313 and clozapine were silent antagonists but SSR181507, bifeprunox and aripiprazole stimulated [35S]-GTPgammaS binding by 17.5%, 26.3% and 25.6%, respectively, relative to 100 microM apomorphine (Emax = 100%). pEC50s were: SSR181507, 8.08; bifeprunox, 8.97; aripiprazole, 8.56. These effects were antagonized by raclopride. Following oral administration in vivo, the drugs increased prolactin release to different extents. SLV313 and haloperidol potently (ED50 0.12 and 0.22 mg/kg p.o., respectively) stimulated prolactin release up to 86 and 83 ng/ml. Aripiprazole potently (ED50 0.66 mg/kg p.o.) but partially (32 ng/ml) induced prolactin release. SSR181507 (ED50 4.9 mg/kg p.o.) also partially (23 ng/ml) enhanced prolactin release. Bifeprunox only weakly increased prolactin at high doses (13 ng/ml at 40 mg/kg) and clozapine only

  9. 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.

  10. Protection from inorganic mercury effects on the in vivo dopamine release by ionotropic glutamate receptor antagonists and nitric oxide synthase inhibitors.

    Science.gov (United States)

    Vidal, Lucía; Durán, Rafael; Faro, Lilian F; Campos, Francisco; Cervantes, Rosa C; Alfonso, Miguel

    2007-09-05

    The possible role of ionotropics glutamate receptors on the HgCl(2)-induced dopamine (DA) release from rat striatum was investigated by using in vivo brain microdialysis technique after administration of selective NMDA and AMPA/Kainate receptors antagonists dizocilpine (MK-801), D (-)-2-amino-5-phoshonopentanoic acid (AP5), and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). Moreover, we have also studied the effects of nitric oxide synthase (NOS) inhibitors L-nitro-arginine methyl ester (L-NAME) and 7-nitro-indazol (7-NI) on HgCl(2)-induced DA release. Intraestriatal infusion of 1mM HgCl(2) increased striatal DA to 1717.2+/-375.4% respect to basal levels. Infusion of 1mM HgCl(2) in 400 microM MK-801 pre-treated animals produced an increase on striatal DA levels 61% smaller than that induced in non-pre-treated animals. In the case of AP5, this treatment reduced 92% the increase produced by HgCl(2) as compared to non-pre-treated rats. Nevertheless, the administration of CNQX did not produce any effect on HgCl(2)-induced dopamine release. Intrastriatal infusion of 1mM HgCl(2) in 100 microM L-NAME pre-treated animals produced an increase on extracellular DA levels 82% smaller than produced by HgCl(2) alone. In addition, the pre-treatment with 7-NI reduced 90% the increase produced by infusion of HgCl(2) alone in rats. Thus, HgCl(2)-induced DA release could be produced at last in part, by overstimulation of NMDA receptors with NO production, since administration of NMDA receptor antagonists and NOS inhibitors protected against HgCl(2) effects on DA release.

  11. CHARACTERIZATION AND PHARMACOLOGICAL RESPONSIVENESS OF DOPAMINE RELEASE RECORDED BY MICRODIALYSIS IN THE SUBSTANTIA-NIGRA OF CONSCIOUS RATS

    NARCIS (Netherlands)

    SANTIAGO, M; WESTERINK, BHC

    1991-01-01

    The extracellular concentration of dopamine (DA) and 3,4-dihydroxyphenylacetic acid in the substantia nigra (SN) and striatum was estimated by microdialysis. The dialysate content of DA from the SN was recorded during infusion of a DA uptake blocker (nomifensine; 5-mu-mol/L) dissolved in the perfusi

  12. High-Fat-Diet-Induced Deficits in Dopamine Terminal Function Are Reversed by Restoring Insulin Signaling.

    Science.gov (United States)

    Fordahl, Steve C; Jones, Sara R

    2017-02-15

    Systemically released insulin crosses the blood-brain barrier and binds to insulin receptors on several neural cell types, including dopaminergic neurons. Insulin has been shown to decrease dopamine neuron firing in the ventral tegmental area (VTA), but potentiate release and reuptake at dopamine terminals in the nucleus accumbens (NAc). Here we show that prolonged consumption of a high fat diet blocks insulin's effects in the NAc, but insulin's effects are restored by inhibiting protein tyrosine phosphatase 1B, which supports insulin receptor signaling. Mice fed a high fat diet (60% kcals from fat) displayed significantly higher fasting blood glucose 160 mg/dL, compared to 101 mg/dL for control-diet-fed mice, and high-fat-diet-fed mice showed reduced blood glucose clearance after an intraperitoneal glucose tolerance test. Using fast scan cyclic voltammetry to measure electrically evoked dopamine in brain slices containing the NAc core, high-fat-diet-fed mice exhibited slower dopamine reuptake compared to control-diet-fed mice (2.2 ± 0.1 and 2.67 ± 0.15 μM/s, respectively). Moreover, glucose clearance rate was negatively correlated with Vmax. Insulin (10 nM to 1 μM) dose dependently increased reuptake rates in control-diet-fed mice compared with in the high-fat-diet group; however, the small molecule insulin receptor sensitizing agent, TCS 401 (300 nM), restored reuptake in high-fat-diet-fed mice to control-diet levels, and a small molecule inhibitor of the insulin receptor, BMS 536924 (300 nM), attenuated reuptake, similar to high-fat-diet-fed mice. These data show that a high-fat diet impairs dopamine reuptake by attenuating insulin signaling at dopamine terminals.

  13. QSAR study on maximal inhibition (Imax) of quaternary ammonium antagonists for S-(-)-nicotine-evoked dopamine release from dopaminergic nerve terminals in rat striatum.

    Science.gov (United States)

    Zheng, Fang; McConnell, Matthew J; Zhan, Chang-Guo; Dwoskin, Linda P; Crooks, Peter A

    2009-07-01

    Maximal inhibition (I(max)) of the agonist effect is an important pharmacological property of inhibitors that interact with multiple receptor subtypes that are activated by the same agonist and which elicit the same functional response. This report represents the first QSAR study on a set of 66 mono- and bis-quaternary ammonium salts that act as antagonists at neuronal nicotinic acetylcholine receptors mediating nicotine-evoked dopamine release, conducted using multi-linear regression (MLR) and neural network (NN) analysis with the maximal inhibition (I(max)) values of the antagonists as target values. The statistical results for the generated MLR model were: r(2)=0.89, rmsd=9.01, q(2)=0.83 and loormsd=11.1; the statistical results for the generated NN model were: r(2)=0.89, rmsd=8.98, q(2)=0.83 and loormsd=11.2. The maximal inhibition values of the compounds exhibited a good correlation with the predictions made by the QSAR models developed, which provide a basis for rationalizing selection of compounds for synthesis in the discovery of effective and selective second generation inhibitors of nAChRs mediating nicotine-evoked dopamine release.

  14. CyPPA, a Positive SK3/SK2 Modulator, Reduces Activity of Dopaminergic Neurons, Inhibits Dopamine Release, and Counteracts Hyperdopaminergic Behaviors Induced by Methylphenidate

    DEFF Research Database (Denmark)

    Herrik, Kjartan F; Redrobe, John P; Holst, Dorte

    2012-01-01

    Dopamine (DA) containing midbrain neurons play critical roles in several psychiatric and neurological diseases, including schizophrenia and attention deficit hyperactivity disorder, and the substantia nigra pars compacta neurons selectively degenerate in Parkinson's disease. Pharmacological...... modulation of DA receptors and transporters are well established approaches for treatment of DA-related disorders. Direct modulation of the DA system by influencing the discharge pattern of these autonomously firing neurons has yet to be exploited as a potential therapeutic strategy. Small conductance Ca(2...... mouse and rat midbrain slices. Using an immunocytochemically and pharmacologically validated DA release assay employing cultured DA neurons from rats, we show that CyPPA repressed DA release in a concentration-dependent manner with a maximal effect equal to the D2 receptor agonist quinpirole. In vivo...

  15. 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…

  16. The potential role of dopamine D3 receptor neurotransmission in cognition

    Science.gov (United States)

    Nakajima, Shinichiro; Gerretsen, Philip; Takeuchi, Hiroyoshi; Caravaggio, Fernando; Chow, Tiffany; Le Foll, Bernard; Mulsant, Benoit; Pollock, Bruce; Graff-Guerrero, Ariel

    2013-01-01

    Currently available treatments have limited pro-cognitive effects for neuropsychiatric disorders, such as schizophrenia, Parkinson’s disease and Alzheimer’s disease. The primary objective of this work is to review the literature on the role of dopamine D3 receptors in cognition, and propose dopamine D3 receptor antagonists as possible cognitive enhancers for neuropsychiatric disorders. A literature search was performed to identify animal and human studies on D3 receptors and cognition using PubMed, MEDLINE and EMBASE. The search terms included “dopamine D3 receptor” and “cognition”. The literature search identified 164 articles. The results revealed: (1) D3 receptors are associated with cognitive functioning in both healthy individuals and those with neuropsychiatric disorders; (2) D3 receptor blockade appears to enhance while D3 receptor agonism seems to impair cognitive function, including memory, attention, learning, processing speed, social recognition and executive function independent of age; and (3) D3 receptor antagonists may exert their pro-cognitive effect by enhancing the release of acetylcholine in the prefrontal cortex, disinhibiting the activity of dopamine neurons projecting to the nucleus accumbens or prefrontal cortex, or activating CREB signaling in the hippocampus. These findings suggest that D3 receptor blockade may enhance cognitive performance in healthy individuals and treat cognitive dysfunction in individuals with a neuropsychiatric disorder. Clinical trials are needed to confirm these effects. PMID:23791072

  17. The effects of endomorphins and diprotin A on striatal dopamine release induced by electrical stimulation-an in vitro superfusion study in rats.

    Science.gov (United States)

    Bagosi, Zsolt; Jászberényi, Miklós; Bujdosó, Erika; Szabó, Gyula; Telegdy, Gyula

    2006-12-01

    The endomorphins (EM1: Tyr-Pro-Trp-Phe-NH2, and EM2: Tyr-Pro-Phe-Phe-NH2) are recently discovered endogenous ligands for mu-opioid receptors (MORs) with role of neurotransmitters or neuromodulators in mammals. Cessation of their physiological action may be effected through rapid enzymatic degradation by the dipeptidyl-peptidase IV (DPPIV) found in the brain synaptic membranes. An in vitro superfusion system was utilized to investigate the actions of EM1, EM2 and specific DPPIV inhibitor diprotin A on the striatal release of dopamine (DA) induced by electrical stimulation in rats. The involvement of the different MORs (MOR1 and MOR2) in this process was studied by pretreatment with MOR antagonists beta-funaltrexamine (a MOR1 and MOR2 antagonist) and naloxonazine (a MOR1 antagonist). EM1 significantly increased the tritium-labelled dopamine DA release induced by electrical stimulation. EM2 was effective only when the slices were pretreated with diprotin A. beta-Funaltrexamine antagonized the stimulatory effects of both EM1 and EM2. The administration of naloxonazine did not appreciably influence the action of EM1, but blocked the action of EM2, at least when the slices were pretreated with diprotin A. These data suggest that both EM1 and EM2 increase DA release from the striatum and, though diprotin A does not affect the action of EM1, it inhibits the enzymatic degradation of EM2. The DA-stimulating action induced by EM1 seems to be mediated by MOR2, while that evoked by EM2 appears to be transmitted by MOR1.

  18. Stimulation of glutamate receptors in the ventral tegmental area is necessary for serotonin-2 receptor-induced increases in mesocortical dopamine release

    Science.gov (United States)

    Pehek, E.A.; Hernan, A.E.

    2017-01-01

    Modulation of dopamine (DA) released by serotonin-2 (5-HT2) receptors has been implicated in the mechanism of action of antipsychotic drugs. The mesocortical DA system has been implicated particularly in the cognitive deficits observed in schizophrenia. Agonism at 5-HT2A receptors in the prefrontal cortex is associated with increases in cortical DA release. Evidence indicates that 5-HT2A receptors in the cortex regulate mesocortical DA release through stimulation of a “long-loop” feedback system from the PFC to the VTA and back. However, a causal role for VTA glutamate in the 5-HT2-induced increases in PFC DA has not been established. The present study does so by measuring 5-HT2 agonist-induced DA release in the cortex after infusions of glutamate antagonists into the VTA. Infusions of a combination of a NMDA (AP-5: 2-amino-5-phosphopentanoic acid) and an AMPA/kainate (CNQX: 6-cyano-7-nitroquinoxaline-2,3-dione) receptor antagonist into the VTA blocked the increases in cortical DA produced by administration of the 5-HT2 agonist DOI [(±)-2,5-Dimethoxy-4-iodoamphetamine] (2.5 mg/kg s.c.). These results demonstrate that stimulation of glutamate receptors in the VTA is necessary for 5-HT2 agonist-induced increases in cortical DA. PMID:25637799

  19. Oral Administration of Methylphenidate (Ritalin) Affects Dopamine Release Differentially Between the Prefrontal Cortex and Striatum: A Microdialysis Study in the Monkey.

    Science.gov (United States)

    Kodama, Tohru; Kojima, Takashi; Honda, Yoshiko; Hosokawa, Takayuki; Tsutsui, Ken-Ichiro; Watanabe, Masataka

    2017-03-01

    Methylphenidate (MPH; trade name Ritalin) is a widely used drug for the treatment of attention deficit hyperactivity disorder (ADHD) and is often used as a cognitive enhancer. Because MPH increases dopamine (DA) release by blocking the DA transporter in the human striatum, MPH is supposed to work on attention and cognition through a DA increase in the striatum. However, ADHD patients show impaired prefrontal cortex (PFC) function and MPH administration is associated with increased neural activity in the PFC. Although MPH is indicated to increase DA release in the rat PFC, there has been no study to examine MPH-induced DA changes in the human PFC because of technical difficulties associated with the low level of PFC DA receptors. Using the microdialysis technique, we examined the effects of oral administration of MPH on DA release in both the PFC and striatum in the monkey. We also tested the effect of MPH on cognitive task performance. As in human studies, in the striatum, both high and low doses of MPH induced consistent increases in DA release ∼30 min after their administrations. In the PFC, a consistent increase in DA release was observed 1 h after a high dose, but not low doses, of MPH. Low doses of MPH improved cognitive task performance, but a high dose of MPH made the monkey drowsy. Therefore, low-dose MPH-induced cognitive enhancement is supported by striatum DA increase.SIGNIFICANCE STATEMENT Methylphenidate (MPH) is a widely used drug for the treatment of attention deficit hyperactivity disorder and is often used as a cognitive enhancer. Although human positron emission tomography studies suggest that MPH works on attention and cognition through dopamine (DA) changes in the striatum, there has been no study to examine MPH-induced DA changes in the human prefrontal cortex (PFC). Using the microdialysis technique in monkeys, we found, for the first time, that low doses of MPH consistently increased DA release in the striatum but did not in the PFC

  20. Acetylcholine release in the mesocorticolimbic dopamine system during cocaine seeking: conditioned and unconditioned contributions to reward and motivation.

    Science.gov (United States)

    You, Zhi-Bing; Wang, Bin; Zitzman, Dawnya; Wise, Roy A

    2008-09-03

    Microdialysis was used to assess the contribution to cocaine seeking of cholinergic input to the mesocorticolimbic dopamine system in ventral tegmental area (VTA). VTA acetylcholine (ACh) was elevated in animals lever pressing for intravenous cocaine and in cocaine-experienced and cocaine-naive animals passively receiving similar "yoked" injections. In cocaine-trained animals, the elevations comprised an initial (first hour) peak to approximately 160% of baseline and a subsequent plateau of 140% of baseline for the rest of the cocaine intake period. In cocaine-naive animals, yoked cocaine injections raised ACh levels to the 140% plateau but did not cause the initial 160% peak. In cocaine-trained animals that received unexpected saline (extinction conditions) rather than the expected cocaine, the initial peak was seen but the subsequent plateau was absent. VTA ACh levels played a causal role and were not just a correlate of cocaine seeking. Blocking muscarinic input to the VTA increased cocaine intake; the increase in intake offset the decrease in cholinergic input, resulting in the same VTA dopamine levels as were seen in the absence of the ACh antagonists. Increased VTA ACh levels (resulting from 10 microM VTA neostigmine infusion) increased VTA dopamine levels and reinstated cocaine seeking in cocaine-trained animals that had undergone extinction; these effects were strongly attenuated by local infusion of a muscarinic antagonist and weakly attenuated by a nicotinic antagonist. These findings identify two cholinergic responses to cocaine self-administration, an unconditioned response to cocaine itself and a conditioned response triggered by cocaine-predictive cues, and confirm that these cholinergic responses contribute to the control of cocaine seeking.

  1. Genetic disruption of dopamine production results in pituitary adenomas and severe prolactinemia

    Science.gov (United States)

    Dopamine release from tuberoinfundibular dopamine neurons into the median eminence activates dopamine-D2 receptors in the pituitary gland where it inhibits lactotroph function. We have previously described genetic dopamine-deficient mouse models which lack the ability to synthesize dopamine. Because...

  2. Pathological gamma oscillations, impaired dopamine release, synapse loss and reduced dynamic range of unitary glutamatergic synaptic transmission in the striatum of hypokinetic Q175 Huntington mice.

    Science.gov (United States)

    Rothe, T; Deliano, M; Wójtowicz, A M; Dvorzhak, A; Harnack, D; Paul, S; Vagner, T; Melnick, I; Stark, H; Grantyn, R

    2015-12-17

    Huntington's disease (HD) is a severe genetically inherited neurodegenerative disorder. Patients present with three principal phenotypes of motor symptoms: choreatic, hypokinetic-rigid and mixed. The Q175 mouse model of disease offers an opportunity to investigate the cellular basis of the hypokinetic-rigid form of HD. At the age of 1 year homozygote Q175 mice exhibited the following signs of hypokinesia: Reduced frequency of spontaneous movements on a precision balance at daytime (-55%), increased total time spent without movement in an open field (+42%), failures in the execution of unconditioned avoidance reactions (+32%), reduced ability for conditioned avoidance (-96%) and increased reaction times (+65%) in a shuttle box. Local field potential recordings revealed low-frequency gamma oscillations in the striatum as a characteristic feature of HD mice at rest. There was no significant loss of DARPP-32 immunolabeled striatal projection neurons (SPNs) although the level of DARPP-32 immunoreactivity was lower in HD. As a potential cause of hypokinesia, HD mice revealed a strong reduction in striatal KCl-induced dopamine release, accompanied by a decrease in the number of tyrosine hydroxylase-(TH)- and VMAT2-positive synaptic varicosities. The presynaptic TH fluorescence level was also reduced. Patch-clamp experiments were performed in slices from 1-year-old mice to record unitary EPSCs (uEPSCs) of presumed cortical origin in the absence of G-protein-mediated modulation. In HD mice, the maximal amplitudes of uEPSCs amounted to 69% of the WT level which matches the loss of VGluT1+/SYP+ synaptic terminals in immunostained sections. These results identify impairment of cortico-striatal synaptic transmission and dopamine release as a potential basis of hypokinesia in HD.

  3. Glucocorticoid receptor gene inactivation in dopamine-innervated areas selectively decreases behavioral responses to amphetamine

    Directory of Open Access Journals (Sweden)

    Sebastien eParnaudeau

    2014-02-01

    Full Text Available The meso-cortico-limbic system, via dopamine release, encodes the rewarding and reinforcing properties of natural rewards. It is also activated in response to abused substances and is believed to support drug-related behaviors. Dysfunctions of this system lead to several psychiatric conditions including feeding disorders and drug addiction. These disorders are also largely influenced by environmental factors and in particular stress exposure. Stressors activate the corticotrope axis ultimately leading to glucocorticoid hormone (GCs release. GCs bind the glucocorticoid receptor (GR a transcription factor ubiquitously expressed including within the meso-cortico-limbic tract. While the GR within dopamine-innervated areas drives cocaine’s behavioral responses, its implication in responses to other psychostimulants such as amphetamine has never been clearly established. Moreover, while extensive work has been made to uncover the role of this receptor in addicted behaviors, its contribution to the rewarding and reinforcing properties of food has yet to be investigated. Using mouse models carrying GR gene inactivation in either dopamine neurons or in dopamine-innervated areas, we found that GR in dopamine responsive neurones is essential to properly build amphetamine-induced conditioned place preference and locomotor sensitization. c-Fos quantification in the nucleus accumbens further confirmed defective neuronal activation following amphetamine injection. These diminished neuronal and behavioral responses to amphetamine may involve alterations in glutamate transmission as suggested by the decreased MK801-elicited hyperlocomotion and by the hyporeactivity to glutamate of a subpopulation of medium spiny neurons. In contrast, GR inactivation did not affect rewarding and reinforcing properties of food suggesting that responding for natural reward under basal conditions is preserved in these mice.

  4. Ventral tegmental area dopamine revisited: effects of acute and repeated stress

    OpenAIRE

    Holly, Elizabeth N.; Miczek, Klaus A.

    2015-01-01

    Aversive events rapidly and potently excite certain dopamine neurons in the ventral tegmental area (VTA), promoting phasic increases in the medial prefrontal cortex and nucleus accumbens. This is in apparent contradiction to a wealth of literature demonstrating that most VTA dopamine neurons are strongly activated by reward and reward-predictive cues while inhibited by aversive stimuli. How can these divergent processes both be mediated by VTA dopamine neurons? The answer may lie within the f...

  5. Imaging of Dopamine in PD and Implications for Motor and Neuropsychiatric Manifestations of PD

    OpenAIRE

    Raul ede la Fuente-Fernandez

    2013-01-01

    Parkinson’s disease (PD) is characterized by dopamine depletion in the putamen, which leads to motor dysfunction. As the disease progresses, a substantial degree of dopamine depletion also occurs in caudate and nucleus accumbens. This may explain a number of neuropsychiatric manifestations, including depression, apathy, and cognitive decline. Dopamine replacement therapy partially restores motor function but long-term treatment is often associated with motor complications (motor fluctuations ...

  6. N-methyl-d-aspartate-evoked release of [{sup 3}H]acetylcholine in striatal compartments of the rat: regulatory roles of dopamine and GABA

    Energy Technology Data Exchange (ETDEWEB)

    Glowinski, J.; Perez, S.; Desban, M.; Gauchy, C.; Kemel, M.L.; Blanchet, F. [Chaire de Neuropharmacologie, INSERM U114, College de France, 11 place Marcelin Berthelot, 75231 Paris (France)

    1997-08-26

    The N-methyl-d-aspartate-evoked release of [{sup 3}H]acetylcholine previously formed from [{sup 3}H]choline was estimated in striosome- (identified by [{sup 3}H]naloxone binding) or matrix-enriched areas of the rat striatum using an in vitro microsuperfusion procedure. Experiments were performed in either the absence or the presence of dopaminergic and/or GABAergic receptor antagonists. Although the cell bodies of the cholinergic interneurons were mainly found in the matrix, in the absence of magnesium, N-methyl-d-aspartate (50 {mu}M) stimulated the release of [{sup 3}H]acetylcholine in both striatal compartments. These responses were blocked by either magnesium, dizocilpine maleate, 7-chlorokynurenate or tetrodotoxin. N-Methyl-d-aspartate responses were concentration-dependent, but the 1 mM N-methyl-d-aspartate response was higher in striosomes than in the matrix. The co-application of d-serine (10 {mu}M) enhanced the 10 {mu}M N-methyl-d-aspartate response in both compartments, but reduced those induced by 1 mM N-methyl-d-aspartate, this reduction being higher in striosomes. The blockade of dopaminergic transmission with the D{sub 2} and D{sub 1} dopaminergic receptor antagonists, (-)-sulpiride (1 {mu}M) and SCH23390 (1 {mu}M), was without effect on the 50 {mu}M N-methyl-d-aspartate-evoked release of [{sup 3}H]acetylcholine, but markedly enhanced the 1 mM N-methyl-d-aspartate + d-serine-evoked response in striosomes and to a lesser extent in the matrix. Disinhibitory responses of similar amplitude were observed not only in striosomes but also in the matrix when (-)-sulpiride was used alone, while SCH23390 alone enhanced the 1 mM N-methyl-d-aspartate + d-serine response only in striosomes and to a lower extent than (-)-sulpiride. These results indicate that D{sub 2} receptors are mainly involved in the inhibitory effect of dopamine on the 1 mM N-methyl-d-aspartate + d-serine-evoked release of [{sup 3}H]acetylcholine. They also show that the stimulation of D{sub 1

  7. 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

  8. In vivo evidence for greater amphetamine-induced dopamine release in pathological gambling: a positron emission tomography study with [(11)C]-(+)-PHNO.

    Science.gov (United States)

    Boileau, I; Payer, D; Chugani, B; Lobo, D S S; Houle, S; Wilson, A A; Warsh, J; Kish, S J; Zack, M

    2014-12-01

    Drug addiction has been associated with deficits in mesostriatal dopamine (DA) function, but whether this state extends to behavioral addictions such as pathological gambling (PG) is unclear. Here we used positron emission tomography and the D3 receptor-preferring radioligand [(11)C]-(+)-PHNO during a dual-scan protocol to investigate DA release in response to oral amphetamine in pathological gamblers (n=12) and healthy controls (n=11). In contrast with human neuroimaging findings in drug addiction, we report the first evidence that PG is associated with greater DA release in dorsal striatum (54-63% greater [(11)C]-(+)-PHNO displacement) than controls. Importantly, dopaminergic response to amphetamine in gamblers was positively predicted by D3 receptor levels (measured in substantia nigra), and related to gambling severity, allowing for construction of a mechanistic model that could help explain DA contributions to PG. Our results are consistent with a hyperdopaminergic state in PG, and support the hypothesis that dopaminergic sensitization involving D3-related mechanisms might contribute to the pathophysiology of behavioral addictions.

  9. A comparison of two semi-mechanistic models for prolactin release and prediction of receptor occupancy following administration of dopamine D2 receptor antagonists in rats.

    Science.gov (United States)

    Taneja, Amit; Vermeulen, An; Huntjens, Dymphy R H; Danhof, Meindert; De Lange, Elizabeth C M; Proost, Johannes H

    2016-10-15

    We compared the model performance of two semi-mechanistic pharmacokinetic-pharmacodynamic models, the precursor pool model and the agonist-antagonist interaction model, to describe prolactin response following the administration of the dopamine D2 receptor antagonists risperidone, paliperidone or remoxipride in rats. The time course of pituitary dopamine D2 receptor occupancy was also predicted. Male Wistar rats received a single dose (risperidone, paliperidone, remoxipride) or two consecutive doses (remoxipride). Population modeling was applied to fit the pool and interaction models to the prolactin data. The pool model was modified to predict the time course of pituitary D2 receptor occupancy. Unbound plasma concentrations of the D2 receptor antagonists were considered the drivers of the prolactin response. Both models were used to predict prolactin release following multiple doses of paliperidone. Both models described the data well and model performance was comparable. Estimated unbound EC50 for risperidone and paliperidone was 35.1nM (relative standard error 51%) and for remoxipride it was 94.8nM (31%). KI values for these compounds were 11.1nM (21%) and 113nM (27%), respectively. Estimated pituitary D2 receptor occupancies for risperidone and remoxipride were comparable to literature findings. The interaction model better predicted prolactin profiles following multiple paliperidone doses, while the pool model predicted tolerance better. The performance of both models in describing the prolactin profiles was comparable. The pool model could additionally describe the time course of pituitary D2 receptor occupancy. Prolactin response following multiple paliperidone doses was better predicted by the interaction model.

  10. Hormonal induction of spawning in 4 species of frogs by coinjection with a gonadotropin-releasing hormone agonist and a dopamine antagonist

    Directory of Open Access Journals (Sweden)

    Wignall Jacqui

    2010-04-01

    Full Text Available Abstract Background It is well known that many anurans do not reproduce easily in captivity. Some methods are based on administration of mammalian hormones such as human chorionic gonadotropin, which are not effective in many frogs. There is a need for simple, cost-effective alternative techniques to induce spawning. Methods Our new method is based on the injection of a combination of a gonadotropin-releasing hormone (GnRH agonist and a dopamine antagonist. We have named this formulation AMPHIPLEX, which is derived from the combination of the words amphibian and amplexus. This name refers to the specific reproductive behavior of frogs when the male mounts and clasps the female to induce ovulation and to fertilize the eggs as they are laid. Results We describe the use of the method and demonstrate its applicability for captive breeding in 3 different anuran families. We tested several combinations of GnRH agonists with dopamine antagonists using Lithobates pipiens. The combination of des-Gly10, D-Ala6, Pro-LHRH (0.4 microrams/g body weight and metoclopramide (10 micrograms/g BWt. MET was most effective. It was used in-season, after short-term captivity and in frogs artificially hibernated under laboratory conditions. The AMPHIPLEX method was also effective in 3 Argentinian frogs, Ceratophrys ornata, Ceratophrys cranwelli and Odontophrynus americanus. Conclusion Our approach offers some advantages over other hormonally-based techniques. Both sexes are injected only once and at the same time, reducing handling stress. AMPHIPLEX is a new reproductive management tool for captive breeding in Anura.

  11. Dopamine Burden Triggers Neurodegeneration via Production and Release of TNF-α from Astrocytes in Minimal Hepatic Encephalopathy.

    Science.gov (United States)

    Ding, Saidan; Wang, Weikan; Wang, Xuebao; Liang, Yong; Liu, Leping; Ye, Yiru; Yang, Jianjing; Gao, Hongchang; Zhuge, Qichuan

    2016-10-01

    Dopamine (DA)-induced learning and memory impairment is well documented in minimal hepatic encephalopathy (MHE), but the contribution of DA to neurodegeneration and the involved underlying mechanisms are not fully understood. In this study, the effect of DA on neuronal apoptosis was initially detected. The results showed that MHE/DA (10 μg)-treated rats displayed neuronal apoptosis. However, we found that DA (10 μM) treatment did not induce evident apoptosis in primary cultured neurons (PCNs) but did produce TNF-α in primary cultured astrocytes (PCAs). Furthermore, co-cultures between PCAs and PCNs exposed to DA exhibited increased astrocytic TNF-α levels and neuronal apoptosis compared with co-cultures exposed to the vehicle, indicating the attribution of the neuronal apoptosis to astrocytic TNF-α. We also demonstrated that DA enhanced TNF-α production from astrocytes by activation of the TLR4/MyD88/NF-κB pathway, and secreted astrocytic TNF-α-potentiated neuronal apoptosis through inactivation of the PI3K/Akt/mTOR pathway. Overall, the findings from this study suggest that DA stimulates substantial production and secretion of astrocytic TNF-α, consequently and indirectly triggering progressive neurodegeneration, resulting in cognitive decline and memory loss in MHE.

  12. Characterization of Optically and Electrically Evoked Dopamine Release in Striatal Slices from Digenic Knock-in Mice with DAT-Driven Expression of Channelrhodopsin

    Science.gov (United States)

    2017-01-01

    Fast-scan cyclic voltammetry (FCV) is an established method to monitor increases in extracellular dopamine (DA) concentration ([DA]o) in the striatum, which is densely innervated by DA axons. Ex vivo brain slice preparations provide an opportunity to identify endogenous modulators of DA release. For these experiments, local electrical stimulation is often used to elicit release of DA, as well as other transmitters, in the striatal microcircuitry; changes in evoked increases in [DA]o after application of a pharmacological agent (e.g., a receptor antagonist) indicate a regulatory role for the transmitter system interrogated. Optogenetic methods that allow specific stimulation of DA axons provide a complementary, bottom-up approach for elucidating factors that regulate DA release. To this end, we have characterized DA release evoked by local electrical and optical stimulation in striatal slices from mice that genetically express a variant of channelrhodopsin-2 (ChR2). Evoked increases in [DA]o in the dorsal and ventral striatum (dStr and vStr) were examined in a cross of a Cre-dependent ChR2 line (“Ai32” mice) with a DAT::Cre mouse line. In dStr, repeated optical pulse-train stimulation at the same recording site resulted in rundown of evoked [DA]o using heterozygous mice, which contrasted with the stability seen with electrical stimulation. Similar rundown was seen in the presence of a nicotinic acetylcholine receptor (nAChR) antagonist, implicating the absence of concurrent nAChR activation in DA release instability in slices. Rundown with optical stimulation in dStr could be circumvented by recording from a population of sites, each stimulated only once. Same-site rundown was less pronounced with single-pulse stimulation, and a stable baseline could be attained. In vStr, stable optically evoked increases in [DA]o at single sites could be achieved using heterozygous mice, although with relatively low peak [DA]o. Low release could be overcome by using mice with a

  13. Temporal changes of striatal dopamine release during and after a video game with a monetary reward: a PET study with [{sup 11}C]raclopride continuous infusion

    Energy Technology Data Exchange (ETDEWEB)

    Kim, S. E. [Sungkyunkwon University School of Medicine, Suwon (Korea, Republic of); Cho, S. S.; Choe, Y. S.; Lee, S. Y.; Kang, E.; Kim, B. T. [Seoul National University hospital, Seoul (Korea, Republic of)

    2002-07-01

    In an attempt to understand the neurochemical changes associated with rewarded motor learning in human brain, we investigated the temporal changes of striatal dopamine (DA) release during and after a goal-directed psychomotor task (a video game) with a monetary incentive using [{sup 11}C]raclopride PET. Seven healthy, right-handed, nonsmokers were studied with PET for 120 min (50 min resting followed by 40 min video game and another 30 min resting) while receiving a bolus plus constant infusion of the DA D2 receptor radioligand [{sup 11}C]raclopride. During the video game (from 50 to 90 min postinjection), subjects played Tetris, which involved learning of joystick movement to fit falling jigsaw blocks, and periodically rewarded with unpredictable amount monetary incentives for improved performance. Striatal V3', calculated as striatal-cerebellar/cerebellar activity ratio, was measured under equilibrium condition, at baseline and during and after the video game. Striatal V3' was significantly reduced during the video game compared with baseline levels, indicating increased DA release in this region (caudate, -15{+-}6%; putamen, -30{+-}10%). During the 30 min after the game ended, striatal [{sup 11}C]raclopride binding was gradually increased and the V3' approached baseline levels. There was a significant correlation between the reduction in striatal V3' and the task performance during the video game. These results demonstrate DA release in the human striatum during a psychomotor task with a monetary reward and to our knowledge for the first time a gradual DA restoration to baseline levels following the offset of stimulation. They also illustrate that acute fluctuations of synaptic DA can be measured in vivo using [{sup 11}C]raclopride PET.

  14. Dopamine release via the vacuolar ATPase V0 sector c-subunit, confirmed in N18 neuroblastoma cells, results in behavioral recovery in hemiparkinsonian mice.

    Science.gov (United States)

    Jin, Duo; Muramatsu, Shin-Ichi; Shimizu, Nobuaki; Yokoyama, Shigeru; Hirai, Hirokazu; Yamada, Kiyofumi; Liu, Hong-Xiang; Higashida, Chiharu; Hashii, Minako; Higashida, Akihiko; Asano, Masahide; Ohkuma, Shoji; Higashida, Haruhiro

    2012-11-01

    A 16-kDa proteolipid, mediatophore, in Torpedo electric organs mediates Ca(2+)-dependent acetylcholine release. Mediatophore is identical to the pore-forming stalk c-subunit of the V0 sector of vacuolar proton ATPase (ATP6V0C). The function of ATP6V0C in the mammalian central nervous system is not clear. Here, we report transfection of adeno-associated viral vectors harboring rat ATP6V0C into the mouse substantia nigra, in which high potassium stimulation increased overflow of endogenous dopamine (DA) measured in the striatum by in vivo microdialysis. Next, in the striatum of 6-hydroxydopamine-lesioned mice, a model of Parkinson's disease (PD), human tyrosine hydroxylase, aromatic l-amino-acid decarboxylase and guanosine triphosphate cyclohydrolase 1, together with or without ATP6V0C, were expressed in the caudoputamen for rescue. Motor performance on the accelerating rotarod test and amphetamine-induced ipsilateral rotation were improved in the rescued mice coexpressing ATP6V0C. [(3)H]DA, taken up into cultured N18 neuronal tumor cells transformed to express ATP6V0C, was released by potassium stimulation. These results indicated that ATP6V0C mediates DA release from nerve terminals in the striatum of DA neurons of normal mice and from gene-transferred striatal cells of parkinsonian mice. The results suggested that ATP6V0C may be useful as a rescue molecule in addition to DA-synthetic enzymes in the gene therapy of PD.

  15. Selective expression of Parkinson's disease-related Leucine-rich repeat kinase 2 G2019S missense mutation in midbrain dopaminergic neurons impairs dopamine release and dopaminergic gene expression.

    Science.gov (United States)

    Liu, Guoxiang; Sgobio, Carmelo; Gu, Xinglong; Sun, Lixin; Lin, Xian; Yu, Jia; Parisiadou, Loukia; Xie, Chengsong; Sastry, Namratha; Ding, Jinhui; Lohr, Kelly M; Miller, Gary W; Mateo, Yolanda; Lovinger, David M; Cai, Huaibin

    2015-09-15

    Preferential dysfunction/degeneration of midbrain substantia nigra pars compacta (SNpc) dopaminergic (DA) neurons contributes to the main movement symptoms manifested in Parkinson's disease (PD). Although the Leucine-rich repeat kinase 2 (LRRK2) G2019S missense mutation (LRRK2 G2019S) is the most common causative genetic factor linked to PD, the effects of LRRK2 G2019S on the function and survival of SNpc DA neurons are poorly understood. Using a binary gene expression system, we generated transgenic mice expressing either wild-type human LRRK2 (WT mice) or the LRRK2 G2019S mutation (G2019S mice) selectively in the midbrain DA neurons. Here we show that overexpression of LRRK2 G2019S did not induce overt motor abnormalities or substantial SNpc DA neuron loss. However, the LRRK2 G2019S mutation impaired dopamine homeostasis and release in aged mice. This reduction in dopamine content/release coincided with the degeneration of DA axon terminals and decreased expression of DA neuron-enriched genes tyrosine hydroxylase (TH), vesicular monoamine transporter 2, dopamine transporter and aldehyde dehydrogenase 1. These factors are responsible for dopamine synthesis, transport and degradation, and their expression is regulated by transcription factor paired-like homeodomain 3 (PITX3). Levels of Pitx3 mRNA and protein were similarly decreased in the SNpc DA neurons of aged G2019S mice. Together, these findings suggest that PITX3-dependent transcription regulation could be one of the many potential mechanisms by which LRRK2 G2019S acts in SNpc DA neurons, resulting in downregulation of its downstream target genes critical for dopamine homeostasis and release.

  16. The glucagon-like peptide 1 analogue Exendin-4 attenuates the nicotine-induced locomotor stimulation, accumbal dopamine release, conditioned place preference as well as the expression of locomotor sensitization in mice.

    Directory of Open Access Journals (Sweden)

    Emil Egecioglu

    Full Text Available The gastrointestinal peptide glucagon-like peptide 1 (GLP-1 is known to regulate consummatory behavior and is released in response to nutrient ingestion. Analogues of this peptide recently emerged as novel pharmacotherapies for treatment of type II diabetes since they reduce gastric emptying, glucagon secretion as well as enhance glucose-dependent insulin secretion. The findings that GLP-1 targets reward related areas including mesolimbic dopamine areas indicate that the physiological role of GLP-1 extends beyond food intake and glucose homeostasis control to include reward regulation. The present series of experiments was therefore designed to investigate the effects of the GLP-1 receptor agonist, Exendin-4 (Ex4, on established nicotine-induced effects on the mesolimbic dopamine system in mice. Specifically, we show that treatment with Ex4, at a dose with no effect per se, attenuate nicotine-induced locomotor stimulation, accumbal dopamine release as well as the expression of conditioned place preference in mice. In accordance, Ex4 also blocks nicotine-induced expression of locomotor sensitization in mice. Given that development of nicotine addiction largely depends on the effects of nicotine on the mesolimbic dopamine system these findings indicate that the GLP-1 receptor may be a potential target for the development of novel treatment strategies for nicotine cessations in humans.

  17. Co-release of noradrenaline and dopamine in the cerebral cortex elicited by single train and repeated train stimulation of the locus coeruleus

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    Saba Pierluigi

    2005-05-01

    Full Text Available Abstract Background Previous studies by our group suggest that extracellular dopamine (DA and noradrenaline (NA may be co-released from noradrenergic nerve terminals in the cerebral cortex. We recently demonstrated that the concomitant release of DA and NA could be elicited in the cerebral cortex by electrical stimulation of the locus coeruleus (LC. This study analyses the effect of both single train and repeated electrical stimulation of LC on NA and DA release in the medial prefrontal cortex (mPFC, occipital cortex (Occ, and caudate nucleus. To rule out possible stressful effects of electrical stimulation, experiments were performed on chloral hydrate anaesthetised rats. Results Twenty min electrical stimulation of the LC, with burst type pattern of pulses, increased NA and DA both in the mPFC and in the Occ. NA in both cortices and DA in the mPFC returned to baseline within 20 min after the end of the stimulation period, while DA in the Occ reached a maximum increase during 20 min post-stimulation and remained higher than baseline values at 220 min post-stimulation. Local perfusion with tetrodotoxin (TTX, 10 μM markedly reduced baseline NA and DA in the mPFC and Occ and totally suppressed the effect of electrical stimulation in both areas. A sequence of five 20 min stimulations at 20 min intervals were delivered to the LC. Each stimulus increased NA to the same extent and duration as the first stimulus, whereas DA remained elevated at the time next stimulus was delivered, so that baseline DA progressively increased in the mPFC and Occ to reach about 130 and 200% the initial level, respectively. In the presence of the NA transport (NAT blocker desipramine (DMI, 100 μM, multiple LC stimulation still increased extracellular NA and DA levels. Electrical stimulation of the LC increased NA levels in the homolateral caudate nucleus, but failed to modify DA level. Conclusion The results confirm and extend that LC stimulation induces a concomitant

  18. r-bPiDI, an α6β2* Nicotinic Receptor Antagonist, Decreases Nicotine-Evoked Dopamine Release and Nicotine Reinforcement

    Science.gov (United States)

    Beckmann, Joshua S.; Meyer, Andrew C.; Pivavarchyk, M.; Horton, David B.; Zheng, Guangrong; Smith, Andrew M.; Wooters, Thomas E.; McIntosh, J. Michael; Crooks, Peter A.; Bardo, Michael T.

    2015-01-01

    α6β2* nicotinic acetylcholine receptors (nACh Rs) expressed by dopaminergic neurons mediate nicotine-evoked dopamine (DA) release and nicotine reinforcement. α6β2* antagonists inhibit these effects of nicotine, such that α6β2* receptors serve as therapeutic targets for nicotine addiction. The present research assessed the neuropharmacology of 1,10-bis(3-methyl-5,6-dihydropyridin-1(2H)-yl)decane (r-bPiDI), a novel small-molecule, tertiary amino analog of its parent compound, N,N-decane-1,10-diyl-bis-3-picolinium diiodide (bPiDI). bPiDI was previously shown to inhibit both nicotine-evoked DA release and the reinforcing effects of nicotine. In the current study, r-bPiDI inhibition of [3H]nicotine and [3H]methyllyca-conitine binding sites was evaluated to assess interaction with the recognition binding sites on α4β2* and α7* nAChRs, respectively. Further, r-bPiDI inhibition of nicotine-evoked DA release in vitro in the absence and presence of α-conotoxin MII and following chronic in vivo nicotine administration were determined. The ability of r-bPiDI to decrease nicotine self-administration and food-maintained responding was also assessed. Results show that r-bPiDI did not inhibit [3H]nicotine or [3H]methylly-caconitine binding, but potently (IC50 = 37.5 nM) inhibited nicotine-evoked DA release from superfused striatal slices obtained from either drug naïve rats or from those repeatedly treated with nicotine. r-bPiDI inhibition of nicotine-evoked DA release was not different in the absence or presence of α-conotoxin MII, indicating that r-bPiDI acts as a potent, selective α6β2* nAChR antagonist. Acute systemic administration of r-bPiDI specifically decreased nicotine self-administration by 75 %, and did not alter food-maintained responding, demonstrating greater specificity relative to bPiDI and bPiDDB, as well as the tertiary amino analog r-bPiDDB. The current work describes the discovery of r-bPiDI, a tertiary amino, α-conotoxin MII-like small molecule

  19. 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

  20. The effects of serotonin, dopamine, gonadotropin-releasing hormones, and corazonin, on the androgenic gland of the giant freshwater prawn, Macrobrachium rosenbergii.

    Science.gov (United States)

    Siangcham, Tanapan; Tinikul, Yotsawan; Poljaroen, Jaruwan; Sroyraya, Morakot; Changklungmoa, Narin; Phoungpetchara, Ittipon; Kankuan, Wilairat; Sumpownon, Chanudporn; Wanichanon, Chaitip; Hanna, Peter J; Sobhon, Prasert

    2013-11-01

    Neurotransmitters and neurohormones are agents that control gonad maturation in decapod crustaceans. Of these, serotonin (5-HT) and dopamine (DA) are neurotransmitters with known antagonist roles in female reproduction, whilst gonadotropin-releasing hormones (GnRHs) and corazonin (Crz) are neurohormones that exercise both positive and negative controls in some invertebrates. However, the effects of these agents on the androgenic gland (AG), which controls testicular maturation and male sex development in decapods, via insulin-like androgenic gland hormone (IAG), are unknown. Therefore, we set out to assay the effects of 5-HT, DA, l-GnRH-III, oct-GnRH and Crz, on the AG of small male Macrobrachium rosenbergii (Mr), using histological studies, a BrdU proliferative cell assay, immunofluorescence of Mr-IAG, and ELISA of Mr-IAG. The results showed stimulatory effects by 5-HT and l-GnRH-III through significant increases in AG size, proliferation of AG cells, and Mr-IAG production (Prosenbergii, as they induce increases in AG and testicular size, IAG production, and spermatogenesis. The mechanisms by which these occur are part of our on-going research.

  1. NMDA receptor antagonism potentiates the L-DOPA-induced extracellular dopamine release in the subthalamic nucleus of hemi-parkinson rats.

    Science.gov (United States)

    El Arfani, Anissa; Bentea, Eduard; Aourz, Najat; Ampe, Ben; De Deurwaerdère, Philippe; Van Eeckhaut, Ann; Massie, Ann; Sarre, Sophie; Smolders, Ilse; Michotte, Yvette

    2014-10-01

    Long term treatment with L-3,4-dihydroxyphenylalanine (L-DOPA) is associated with several motor complications. Clinical improvement of this treatment is therefore needed. Lesions or high frequency stimulation of the hyperactive subthalamic nucleus (STN) in Parkinson's disease (PD), alleviate the motor symptoms and reduce dyskinesia, either directly and/or by allowing the reduction of the L-DOPA dose. N-methyl-D-aspartate (NMDA) receptor antagonists might have similar actions. However it remains elusive how the neurochemistry changes in the STN after a separate or combined administration of L-DOPA and a NMDA receptor antagonist. By means of in vivo microdialysis, the effect of L-DOPA and/or MK 801, on the extracellular dopamine (DA) and glutamate (GLU) levels was investigated for the first time in the STN of sham and 6-hydroxydopamine-lesioned rats. The L-DOPA-induced DA increase in the STN was significantly higher in DA-depleted rats compared to shams. MK 801 did not influence the L-DOPA-induced DA release in shams. However, MK 801 enhanced the L-DOPA-induced DA release in hemi-parkinson rats. Interestingly, the extracellular STN GLU levels remained unchanged after nigral degeneration. Furthermore, administration of MK 801 alone or combined with L-DOPA did not alter the STN GLU levels in both sham and DA-depleted rats. The present study does not support the hypothesis that DA-ergic degeneration influences the STN GLU levels neither that MK 801 alters the GLU levels in lesioned and non-lesioned rats. However, NMDA receptor antagonists could be used as a beneficial adjuvant treatment for PD by enhancing the therapeutic efficacy of l-DOPA at least in part in the STN.

  2. 5-hydroxytryptamine- and dopamine-releasing effects of ring-substituted amphetamines on rat brain: a comparative study using in vivo microdialysis.

    Science.gov (United States)

    Matsumoto, T; Maeno, Y; Kato, H; Seko-Nakamura, Y; Monma-Ohtaki, J; Ishiba, A; Nagao, M; Aoki, Y

    2014-08-01

    Using in vivo microdialysis, a comparative study was conducted to examine the effects of amphetamine-related compounds (methamphetamine, MAP; 3,4-methylenedioxymethamphetamine, MDMA; p-methoxyamphetamine, PMA; p-methoxymethamphetamine, PMMA; 4-methylthioamphetamine, 4-MTA; 3,4,5-trimethoxyamphetamine, TMA; 2,5-dimethoxy-4-iodoamphetamine, DOI) on extracellular levels of serotonin (5-HT) and dopamine (DA). Dialysates were assayed using HPLC equipped with electrochemical detector following i.p. administration with each drug at a dose of 5 mg/kg. MAP was found to drastically and rapidly increase 5-HT and DA levels (870% and 1460%, respectively). PMA, PMMA, and 4-MTA slightly increased DA levels (150-290%) but remarkably increased 5-HT levels (540-900%). In contrast, TMA and DOI caused no detectable changes in levels of both monoamines. We observed that the potent DA-releasing action of MAP was remarkably decreased by introduction of methoxy or methylthio group at the para position (MAP vs. PMMA or 4-MTA), but introduction of two additional adjacent methoxy groups into PMA totally abolished its 5-HT-/DA-releasing action (PMA vs. TMA). In addition, para-mono-substituted compounds inhibited both monoamine oxidase (MAO) enzymes more strongly than other compounds; PMA and 4-MTA exhibited submicromolar IC50 values for MAO-A. On the other hand, TMA scarcely affected the activity of both MAO enzymes as well as extracellular levels of 5-HT and DA. In this comparative study, MDMA, PMA, and 4-MTA functioned similar to PMMA, a typical empathogen; these findings therefore could be helpful in clarifying the psychopharmacological properties of amphetamine-related, empathogenic designer drugs.

  3. CyPPA, a positive SK3/SK2 modulator, reduces activity of dopaminergic neurons, inhibits dopamine release, and counteracts hyperdopaminergic behaviors induced by methylphenidate

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    Kjartan F. Herrik

    2012-02-01

    Full Text Available Dopamine (DA containing midbrain neurons play critical roles in several psychiatric and neurological diseases, including schizophrenia and attention deficit hyperactivity disorder (ADHD, and the substantia nigra pars compacta neurons selectively degenerate in Parkinson’s disease. Pharmacological modulation of DA receptors and transporters are well established approaches for treatment of DA-related disorders. Direct modulation of the DA system by influencing the discharge pattern of these autonomously firing neurons has yet to be exploited as a potential therapeutic strategy. Small conductance Ca2+-activated K+ channels (SK channels, in particular the SK3 subtype, are important in the physiology of DA neurons, and agents modifying SK channel activity could potentially affect DA-signaling and DA-related behaviors. Here we show that CyPPA (cyclohexyl-[2-(3,5-dimethyl-pyrazol-1-yl-6-methyl-pyrimidin-4-yl]-amine, a subtype-selective positive modulator of SK channels (SK3 > SK2 >>> SK1, IK, decreased spontaneous firing rate, increased the duration of the apamin-sensitive, medium duration afterhyperpolarization (mAHP, and caused an activity-dependent inhibition of current-evoked action potentials in DA neurons from both mouse and rat midbrain slices. Using a immunohistochemically and pharmacologically validated DA release assay employing cultured DA neurons from rats, we show that CyPPA repressed DA release in a concentration-dependent manner with a maximal effect equal to the D2 receptor agonist quinpirole. In vivo studies revealed that systemic administration of CyPPA attenuated methylphenidate-induced hyperactivity and stereotypic behaviors in mice. Taken together, the data accentuate the important role played by SK3 channels in the physiology of DA neurons, and indicate that their facilitation by CyPPA profoundly influences physiological as well as pharmacologically induced hyperdopaminergic behavior.

  4. 5-HT modulation of dopamine release in basal ganglia in psilocybin-induced psychosis in man - A PET study with [C-11]raclopride

    NARCIS (Netherlands)

    Vollenweider, FX; Vontobel, P; Hell, D; Leenders, KL

    1999-01-01

    The modulating effects of serotonin on dopamine neurotransmission are not well understood, particularly in acute psychotic states. Positron emission tomography was used to examine the effect of psilocybin on the in vivo binding of [C-11]raclopride to D-2-dopamine receptors in the striatum in healthy

  5. The Novel Pyrrolidine Nor-Lobelane Analog UKCP-110 [cis-2,5-di-(2-phenethyl)-pyrrolidine hydrochloride] Inhibits VMAT2 Function, Methamphetamine-Evoked Dopamine Release, and Methamphetamine Self-Administration in RatsS⃞

    Science.gov (United States)

    Beckmann, Joshua S.; Siripurapu, Kiran B.; Nickell, Justin R.; Horton, David B.; Denehy, Emily D.; Vartak, Ashish; Crooks, Peter A.; Bardo, Michael T.

    2010-01-01

    Both lobeline and lobelane attenuate methamphetamine self-administration in rats by decreasing methamphetamine-induced dopamine release via interaction with vesicular monoamine transporter-2 (VMAT2). A novel derivative of nor-lobelane, cis-2,5-di-(2-phenethyl)-pyrrolidine hydrochloride (UKCP-110), and its trans-isomers, (2R,5R)-trans-di-(2-phenethyl)-pyrrolidine hydrochloride (UKCP-111) and (2S,5S)-trans-di-(2-phenethyl)-pyrrolidine hydrochloride (UKCP-112), were evaluated for inhibition of [3H]dihydrotetrabenazine binding and [3H]dopamine uptake by using a rat synaptic vesicle preparation to assess VMAT2 interaction. Compounds were evaluated for inhibition of [3H]nicotine and [3H]methyllycaconitine binding to assess interaction with the major nicotinic receptor subtypes. In addition, compounds were evaluated for inhibition of methamphetamine-evoked endogenous dopamine release by using striatal slices. The most promising compound, UKCP-110, was evaluated for its ability to decrease methamphetamine self-administration and methamphetamine discriminative stimulus cues and for its effect on food-maintained operant responding. UKCP-110, UKCP-111, and UKCP-112 inhibited [3H]dihydrotetrabenazine binding (Ki = 2.66 ± 0.37, 1.05 ± 0.10, and 3.80 ± 0.31 μM, respectively) and had high potency inhibiting [3H]dopamine uptake (Ki = 0.028 ± 0.001, 0.046 ± 0.008, 0.043 ± 0.004 μM, respectively), but lacked affinity at nicotinic receptors. Although the trans-isomers did not alter methamphetamine-evoked dopamine release, UKCP-110 inhibited (IC50 = 1.8 ± 0.2 μM; Imax = 67.18 ± 6.11 μM) methamphetamine-evoked dopamine release. At high concentrations, UKCP-110 also increased extracellular dihydroxyphenylacetic acid. It is noteworthy that UKCP-110 decreased the number of methamphetamine self-infusions, while having no effect on food-reinforced behavior or the methamphetamine stimulus cue. Thus, UKCP-110 represents a new lead in the development of novel pharmacotherapies for

  6. The novel pyrrolidine nor-lobelane analog UKCP-110 [cis-2,5-di-(2-phenethyl)-pyrrolidine hydrochloride] inhibits VMAT2 function, methamphetamine-evoked dopamine release, and methamphetamine self-administration in rats.

    Science.gov (United States)

    Beckmann, Joshua S; Siripurapu, Kiran B; Nickell, Justin R; Horton, David B; Denehy, Emily D; Vartak, Ashish; Crooks, Peter A; Dwoskin, Linda P; Bardo, Michael T

    2010-12-01

    Both lobeline and lobelane attenuate methamphetamine self-administration in rats by decreasing methamphetamine-induced dopamine release via interaction with vesicular monoamine transporter-2 (VMAT2). A novel derivative of nor-lobelane, cis-2,5-di-(2-phenethyl)-pyrrolidine hydrochloride (UKCP-110), and its trans-isomers, (2R,5R)-trans-di-(2-phenethyl)-pyrrolidine hydrochloride (UKCP-111) and (2S,5S)-trans-di-(2-phenethyl)-pyrrolidine hydrochloride (UKCP-112), were evaluated for inhibition of [(3)H]dihydrotetrabenazine binding and [(3)H]dopamine uptake by using a rat synaptic vesicle preparation to assess VMAT2 interaction. Compounds were evaluated for inhibition of [(3)H]nicotine and [(3)H]methyllycaconitine binding to assess interaction with the major nicotinic receptor subtypes. In addition, compounds were evaluated for inhibition of methamphetamine-evoked endogenous dopamine release by using striatal slices. The most promising compound, UKCP-110, was evaluated for its ability to decrease methamphetamine self-administration and methamphetamine discriminative stimulus cues and for its effect on food-maintained operant responding. UKCP-110, UKCP-111, and UKCP-112 inhibited [(3)H]dihydrotetrabenazine binding (K(i) = 2.66 ± 0.37, 1.05 ± 0.10, and 3.80 ± 0.31 μM, respectively) and had high potency inhibiting [(3)H]dopamine uptake (K(i) = 0.028 ± 0.001, 0.046 ± 0.008, 0.043 ± 0.004 μM, respectively), but lacked affinity at nicotinic receptors. Although the trans-isomers did not alter methamphetamine-evoked dopamine release, UKCP-110 inhibited (IC(50) = 1.8 ± 0.2 μM; I(max) = 67.18 ± 6.11 μM) methamphetamine-evoked dopamine release. At high concentrations, UKCP-110 also increased extracellular dihydroxyphenylacetic acid. It is noteworthy that UKCP-110 decreased the number of methamphetamine self-infusions, while having no effect on food-reinforced behavior or the methamphetamine stimulus cue. Thus, UKCP-110 represents a new lead in the development of novel

  7. Effects of metoclopramide and metoclopramide/dopamine on blood pressure and insulin release in normotensive, hypertensive, and type 2 diabetic subjects.

    Science.gov (United States)

    Contreras, Freddy; Fouillioux, Christian; Lares, Mary; Bolívar, Hector; Hernández, Rafael Hernández; Velasco, Manuel; Cano, Raquel; Chacin, Maricarmen; Bermúdez, Valmore

    2010-01-01

    The objective is to determine cardiovascular and insulin release effects under metoclopramide (MTC) and dopamine (DA) infusion by using an acute comparative design with the intravenous infusion of both drugs. We evaluated 15 normal (normotensive and normoglycemic) subjects, 13 hypertensive, and 15 type 2 diabetic subjects. Subjects were submitted to an experimental design in which we first gave them a 0.9% saline solution for 30 minutes, and then administered MTC at 7.5 microg kg min through an intravenous infusion during a period of 30 minutes. Although subjects were receiving MTC, we added an intravenous infusion of DA at 1-3 microg kg min during 30 minutes. Blood pressure, heart rate, serum lipid profile, and insulin levels were measured. Sympathetic reactivity by the cold pressor test was also measured. In normotensive subjects, there was a systolic blood pressure and heart rate increase during MTC plus DA infusion. In subjects with diabetes mellitus there was a heart rate increase without changes in blood pressure during the MTC plus DA infusion period. In hypertensive subjects, MTC induced a significant decrease of systolic and diastolic blood pressure. During MTC plus DA period there was an increase of heart rate but no significant changes in blood pressure. During cold pressor test in both diabetic and hypertensive subjects, there were significant increases of both blood pressure and heart rate. Insulin serum levels increased in normotensive and hypertensive subjects but were attenuated in subjects with diabetes mellitus. We conclude that there is a pharmacologic interaction between MTC and DA, that the pressor effects of DA are due to activation to beta and alpha adrenergic receptors, and that the cardiovascular effects of DA in type 2 diabetic subjects are attenuated by a probable defect in sympathetic system and to endothelial dysfunction.

  8. Unaltered striatal dopamine release levels in young Parkin knockout, Pink1 knockout, DJ-1 knockout and LRRK2 R1441G transgenic mice.

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    Gonzalo Sanchez

    Full Text Available Parkinson's disease (PD is one of the most prevalent neurodegenerative brain diseases; it is accompanied by extensive loss of dopamine (DA neurons of the substantia nigra that project to the putamen, leading to impaired motor functions. Several genes have been associated with hereditary forms of the disease and transgenic mice have been developed by a number of groups to produce animal models of PD and to explore the basic functions of these genes. Surprisingly, most of the various mouse lines generated such as Parkin KO, Pink1 KO, DJ-1 KO and LRRK2 transgenic have been reported to lack degeneration of nigral DA neuron, one of the hallmarks of PD. However, modest impairments of motor behavior have been reported, suggesting the possibility that the models recapitulate at least some of the early stages of PD, including early dysfunction of DA axon terminals. To further evaluate this possibility, here we provide for the first time a systematic comparison of DA release in four different mouse lines, examined at a young age range, prior to potential age-dependent compensations. Using fast scan cyclic voltammetry in striatal sections prepared from young, 6-8 weeks old mice, we examined sub-second DA overflow evoked by single pulses and action potential trains. Unexpectedly, none of the models displayed any dysfunction of DA overflow or reuptake. These results, compatible with the lack of DA neuron loss in these models, suggest that molecular dysfunctions caused by the absence or mutation of these individual genes are not sufficient to perturb the function and survival of mouse DA neurons.

  9. Salsolinol modulation of dopamine neurons

    OpenAIRE

    Xie, Guiqin; Krnjević, Krešimir; Ye, Jiang-Hong

    2013-01-01

    Salsolinol, a tetrahydroisoquinoline present in the human and rat brains, is the condensation product of dopamine and acetaldehyde, the first metabolite of ethanol. Previous evidence obtained in vivo links salsolinol with the mesolimbic dopaminergic (DA) system: salsolinol is self-administered into the posterior of the ventral tegmental area (pVTA) of rats; intra-VTA administration of salsolinol induces a strong conditional place preference and increases dopamine release in the nucleus accumb...

  10. Summary data of potency and parameter information from semi-mechanistic PKPD modeling of prolactin release following administration of the dopamine D2 receptor antagonists risperidone, paliperidone and remoxipride in rats

    Directory of Open Access Journals (Sweden)

    Amit Taneja

    2016-09-01

    Full Text Available We provide the reader with relevant data related to our recently published paper, comparing two mathematical models to describe prolactin turnover in rats following one or two doses of the dopamine D2 receptor antagonists risperidone, paliperidone and remoxipride, “A comparison of two semi-mechanistic models for prolactin release and prediction of receptor occupancy following administration of dopamine D2 receptor antagonists in rats” (Taneja et al., 2016 [1]. All information is tabulated. Summary level data on the in vitro potencies and the physicochemical properties is presented in Table 1. Model parameters required to explore the precursor pool model are presented in Table 2. In Table 3, estimated parameter comparisons for both models are presented, when separate potencies are estimated for risperidone and paliperidone, as compared to a common potency for both drugs. In Table 4, parameter estimates are compared when the drug effect is parameterized in terms of drug concentration or receptor occupancy.

  11. Dopamine in the Brain: Hypothesizing Surfeit or Deficit Links to Reward and Addiction

    Science.gov (United States)

    Blum, Kenneth; Thanos, Peter K.; Oscar-Berman, Marlene; Febo, Marcelo; Baron, David; Badgaiyan, Rajendra D.; Gardner, Eliot; Demetrovics, Zsolt; Fahlke, Claudia; Haberstick, Brett C.; Dushaj, Kristina; Gold, Mark S.

    2016-01-01

    Recently there has been debate concerning the role of brain dopamine in reward and addiction. David Nutt and associates eloquently proposed that dopamine (DA) may be central to psycho stimulant dependence and some what important for alcohol, but not important for opiates, nicotine or even cannabis. Others have also argued that surfeit theories can explain for example cocaine seeking behavior as well as non-substance-related addictive behaviors. It seems prudent to distinguish between what constitutes “surfeit” compared to” deficit” in terms of short-term (acute) and long-term (chronic) brain reward circuitry responsivity. In an attempt to resolve controversy regarding the contributions of mesolimbic DA systems to reward, we review the three main competing explanatory categories: “liking”, “learning”, and “wanting”. They are (a) the hedonic impact -liking reward, (b) the ability to predict rewarding effects-learning and (c) the incentive salience of reward-related stimuli -wanting. In terms of acute effects, most of the evidence seems to favor the “surfeit theory”. Due to preferential dopamine release at mesolimbic-VTA-caudate-accumbens loci most drugs of abuse and Reward Deficiency Syndrome (RDS) behaviors have been linked to heightened feelings of well-being and hyperdopaminergic states.The “dopamine hypotheses” originally thought to be simple, is now believed to be quite complex and involves encoding the set point of hedonic tone, encoding attention, reward expectancy, and incentive motivation. Importantly, Willuhn et al. shows that in a self-administration paradigm, (chronic) excessive use of cocaine is caused by decreased phasic dopamine signaling in the striatum. In terms of chronic addictions, others have shown a blunted responsivity at brain reward sites with food, nicotine, and even gambling behavior. Finally, we are cognizant of the differences in dopaminergic function as addiction progresses and argue that relapse may be tied

  12. The dopamine hypothesis of drug addiction and its potential therapeutic value.

    Directory of Open Access Journals (Sweden)

    Marco eDiana

    2011-11-01

    Full Text Available Dopamine (DA transmission is deeply affected by drugs of abuse, and alterations in DA function are involved in various phases of drug addiction and potentially exploitable therapeutically. In particular, basic studies have documented a reduction in the electrophysiological activity of DA neurons in alcohol, opiate, cannabinoid and other drug-dependent rats. Further, DA release in the Nacc is decreased in virtually all drug-dependent rodents. In parallel, these studies are supported by increments in intracranial self stimulation (ICSS thresholds during withdrawal from alcohol, nicotine, opiates, and other drugs of abuse, thereby suggesting a hypofunction of the neural substrate of ICSS. Accordingly, morphological evaluations fed into realistic computational analysis of the Medium Spiny Neuron (MSN of the Nucleus accumbens (Nacc, post-synaptic counterpart of DA terminals, show profound changes in structure and function of the entire mesolimbic system. In line with these findings, human imaging studies have shown a reduction of dopamine receptors accompanied by a lesser release of endogenous DA in the ventral striatum of cocaine, heroin and alcohol-dependent subjects, thereby offering visual proof of the ‘dopamine-impoverished’ addicted human brain.The reduction in physiological activity of the DA system leads to the idea that an increment in its activity, to restore pre-drug levels, may yield significant clinical improvements (reduction of craving, relapse and drug-seeking/taking. In theory, it may be achieved pharmacologically and/or with novel interventions such as Transcranial Magnetic Stimulation (TMS. Its anatomo-physiological rationale as a possible therapeutic aid in alcoholics and other addicts will be described and proposed as a theoretical framework to be subjected to experimental testing in human addicts.

  13. 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.

  14. High fat diet augments amphetamine sensitization in mice: Role of feeding pattern, obesity, and dopamine terminal changes.

    Science.gov (United States)

    Fordahl, Steve C; Locke, Jason L; Jones, Sara R

    2016-10-01

    High fat (HF) diet-induced obesity has been shown to augment behavioral responses to psychostimulants that target the dopamine system. The purpose of this study was to characterize dopamine terminal changes induced by a HF diet that correspond with enhanced locomotor sensitization to amphetamine. C57BL/6J mice had limited (2hr 3 d/week) or extended (24 h 7 d/week) access to a HF diet or standard chow for six weeks. Mice were then repeatedly exposed to amphetamine (AMPH), and their locomotor responses to an amphetamine challenge were measured. Fast scan cyclic voltammetry was used to identify changes in dopamine terminal function after AMPH exposure. Exposure to a HF diet reduced dopamine uptake and increased locomotor responses to acute, high-dose AMPH administration compared to chow fed mice. Microdialysis showed elevated extracellular dopamine in the nucleus accumbens (NAc) coincided with enhanced locomotion after acute AMPH in HF-fed mice. All mice exhibited locomotor sensitization to amphetamine, but both extended and limited access to a HF diet augmented this response. Neither HF-fed group showed the robust amphetamine sensitization-induced increases in dopamine release, reuptake, and amphetamine potency observed in chow fed animals. However, the potency of amphetamine as an uptake inhibitor was significantly elevated after sensitization in mice with extended (but not limited) access to HF. Conversely, after amphetamine sensitization, mice with limited (but not extended) access to HF displayed reduced autoreceptor sensitivity to the D2/D3 agonist quinpirole. Additionally, we observed reduced membrane dopamine transporter (DAT) levels after HF, and a shift in DAT localization to the cytosol was detected with limited access to HF. This study showed that different patterns of HF exposure produced distinct dopamine terminal adaptations to repeated AMPH, which differed from chow fed mice, and enhanced sensitization to AMPH. Locomotor sensitization in chow fed

  15. Grafted dopamine neurons: Morphology, neurochemistry, and electrophysiology.

    Science.gov (United States)

    Strömberg, Ingrid; Bickford, Paula; Gerhardt, Greg A

    2010-02-09

    Grafting of dopamine-rich tissue to counteract the symptoms in Parkinson's disease became a promising tool for future treatment. This article discusses how to improve the functional outcome with respect to graft outgrowth and functions of dopamine release and electrophysiological responses to graft implantation in the host brain striatal target. It has been documented that a subpopulation of the dopamine neurons innervates the host brain in a target-specific manner, while some of the grafted dopamine neurons never project to the host striatum. Neurochemical studies have demonstrated that the graft-induced outgrowth synthesize, store, metabolize and release dopamine and possibly other neurotransmitters such as 5-HT. Furthermore, the released dopamine affects the dopamine-depleted brain in areas that are larger than the graft-derived nerve fibers reach. While stem cells will most likely be the future source of cells to be used in grafting, it is important to find the guiding cues for how to reinnervate the dopamine-depleted striatum in a proper way with respect to the dopamine subpopulations of A9 and A10 to efficiently treat the motor abnormalities seen in Parkinson's disease.

  16. Effects of unilateral 6-OHDA lesions on [3H]-N-propylnorapomorphine binding in striatum ex vivo and vulnerability to amphetamine-evoked dopamine release in rat

    DEFF Research Database (Denmark)

    Palner, Mikael; Kjaerby, Celia; Knudsen, Gitte M

    2011-01-01

    ligands should likewise be fitter than antagonists for detecting responses to denervation in positron emission tomography studies of idiopathic Parkinson's disease. Agonist binding increases in vivo are likely to reflect the composite of a sensitization-like phenomenon, and relatively less competition...... to be more vulnerable to competition from endogenous dopamine than was the antagonist ligand [(11)C]raclopride, measured ex vivo in mouse striatum, and subsequently in multi-tracer PET studies of analogous design. Based on these results, we predicted that prolonged dopamine depletion would result...... in a preferential increase in agonist binding, and a lesser competition from residual dopamine to the agonist binding. To test this hypothesis we used autoradiography to measure [(3)H]NPA and [(3)H]raclopride binding sites in hemi-parkinsonian rats with unilateral 6-OHDA lesions, with and without amphetamine...

  17. Effects of unilateral 6-OHDA lesions on [3H]-N-propylnorapomorphine binding in striatum ex vivo and vulnerability to amphetamine-evoked dopamine release in rat

    DEFF Research Database (Denmark)

    Palner, Mikael; Kjaerby, Celia; Knudsen, Gitte M;

    2011-01-01

    ligands should likewise be fitter than antagonists for detecting responses to denervation in positron emission tomography studies of idiopathic Parkinson's disease. Agonist binding increases in vivo are likely to reflect the composite of a sensitization-like phenomenon, and relatively less competition...... from endogenous dopamine, as seen in the lesioned side of 6-OHDA induced hemi-parkinsonism....

  18. EFFECT OF PRECURSOR LOADING ON THE SYNTHESIS RATE AND RELEASE OF DOPAMINE AND SEROTONIN IN THE STRIATUM - A MICRODIALYSIS STUDY IN CONSCIOUS RATS

    NARCIS (Netherlands)

    WESTERINK, BHC; DEVRIES, JB

    1991-01-01

    The effects of systemic administration of tyrosine and phenylalanine on the extracellular levels of tyrosine and dopamine were determined by microdialysis in the striatum of awake rats. In addition, the effects of these precursors on in vivo 3,4-dihydroxyphenylalanine (DOPA) formation were determine

  19. Restoration of Dopamine Release Deficits during Object Recognition Memory Acquisition Attenuates Cognitive Impairment in a Triple Transgenic Mice Model of Alzheimer's Disease

    Science.gov (United States)

    Guzman-Ramos, Kioko; Moreno-Castilla, Perla; Castro-Cruz, Monica; McGaugh, James L.; Martinez-Coria, Hilda; LaFerla, Frank M.; Bermudez-Rattoni, Federico

    2012-01-01

    Previous findings indicate that the acquisition and consolidation of recognition memory involves dopaminergic activity. Although dopamine deregulation has been observed in Alzheimer's disease (AD) patients, the dysfunction of this neurotransmitter has not been investigated in animal models of AD. The aim of this study was to assess, by in vivo…

  20. 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.

  1. Ventral tegmental area dopamine revisited: effects of acute and repeated stress.

    Science.gov (United States)

    Holly, Elizabeth N; Miczek, Klaus A

    2016-01-01

    Aversive events rapidly and potently excite certain dopamine neurons in the ventral tegmental area (VTA), promoting phasic increases in the medial prefrontal cortex and nucleus accumbens. This is in apparent contradiction to a wealth of literature demonstrating that most VTA dopamine neurons are strongly activated by reward and reward-predictive cues while inhibited by aversive stimuli. How can these divergent processes both be mediated by VTA dopamine neurons? The answer may lie within the functional and anatomical heterogeneity of the VTA. We focus on VTA heterogeneity in anatomy, neurochemistry, electrophysiology, and afferent/efferent connectivity. Second, recent evidence for a critical role of VTA dopamine neurons in response to both acute and repeated stress will be discussed. Understanding which dopamine neurons are activated by stress, the neural mechanisms driving the activation, and where these neurons project will provide valuable insight into how stress can promote psychiatric disorders associated with the dopamine system, such as addiction and depression.

  2. Reduced insulin-receptor mediated modulation of striatal dopamine release by basal insulin as a possible contributing factor to hyperdopaminergia in schizophrenia.

    Science.gov (United States)

    Caravaggio, Fernando; Hahn, Margaret; Nakajima, Shinichiro; Gerretsen, Philip; Remington, Gary; Graff-Guerrero, Ariel

    2015-10-01

    Schizophrenia is a severe and chronic neuropsychiatric disorder which affects 1% of the world population. Using the brain imaging technique positron emission tomography (PET) it has been demonstrated that persons with schizophrenia have greater dopamine transmission in the striatum compared to healthy controls. However, little progress has been made as to elucidating other biological mechanisms which may account for this hyperdopaminergic state in this disease. Studies in animals have demonstrated that insulin receptors are expressed on midbrain dopamine neurons, and that insulin from the periphery acts on these receptors to modify dopamine transmission in the striatum. This is pertinent given that several lines of evidence suggest that insulin receptor functioning may be abnormal in the brains of persons with schizophrenia. Post-mortem studies have shown that persons with schizophrenia have less than half the number of cortical insulin receptors compared to healthy persons. Moreover, these post-mortem findings are unlikely due to the effects of antipsychotic treatment; studies in cell lines and animals suggest antipsychotics enhance insulin receptor functioning. Further, hyperinsulinemia - even prior to antipsychotic use - seems to be related to less psychotic symptoms in patients with schizophrenia. Collectively, these data suggest that midbrain insulin receptor functioning may be abnormal in persons with schizophrenia, resulting in reduced insulin-mediated regulation of dopamine transmission in the striatum. Such a deficit may account for the hyperdopaminergic state observed in these patients and would help guide the development of novel treatment strategies. We hypothesize that, (i) insulin receptor expression and/or function is reduced in midbrain dopamine neurons in persons with schizophrenia, (ii) basal insulin should reduce dopaminergic transmission in the striatum via these receptors, and (iii) this modulation of dopaminergic transmission by basal insulin

  3. Injection of Cocaine-Amphetamine Regulated Transcript (CART) peptide into the nucleus accumbens does not inhibit caffeine-induced locomotor activity: Implications for CART peptide mechanism.

    Science.gov (United States)

    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.

  4. 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.

  5. 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

  6. 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...

  7. 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

  8. Endomorphin-2 and endomorphin-1 promote the extracellular amount of accumbal dopamine via nonopioid and mu-opioid receptors, respectively.

    NARCIS (Netherlands)

    Okutsu, H.; Watanabe, S.; Takahashi, I.; Aono, Y.; Saigusa, T.; Koshikawa, N.; Cools, A.R.

    2006-01-01

    Activation of mu-opioid receptors in the nucleus accumbens (NAc) is known to increase accumbal dopamine efflux in rats. Endomorphin-2 (Tyr-Pro-Phe-Phe-NH(2); EM-2) and endomorphin-1 (Tyr-Pro-Trp-Phe-NH(2); EM-1) are suggested to be the endogenous ligands for the mu-opioid receptor. As the ability of

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

    Directory of Open Access Journals (Sweden)

    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.

  10. Dopamine synapse is a neuroligin-2-mediated contact between dopaminergic presynaptic and GABAergic postsynaptic structures.

    Science.gov (United States)

    Uchigashima, Motokazu; Ohtsuka, Toshihisa; Kobayashi, Kazuto; Watanabe, Masahiko

    2016-04-12

    Midbrain dopamine neurons project densely to the striatum and form so-called dopamine synapses on medium spiny neurons (MSNs), principal neurons in the striatum. Because dopamine receptors are widely expressed away from dopamine synapses, it remains unclear how dopamine synapses are involved in dopaminergic transmission. Here we demonstrate that dopamine synapses are contacts formed between dopaminergic presynaptic and GABAergic postsynaptic structures. The presynaptic structure expressed tyrosine hydroxylase, vesicular monoamine transporter-2, and plasmalemmal dopamine transporter, which are essential for dopamine synthesis, vesicular filling, and recycling, but was below the detection threshold for molecules involving GABA synthesis and vesicular filling or for GABA itself. In contrast, the postsynaptic structure of dopamine synapses expressed GABAergic molecules, including postsynaptic adhesion molecule neuroligin-2, postsynaptic scaffolding molecule gephyrin, and GABAA receptor α1, without any specific clustering of dopamine receptors. Of these, neuroligin-2 promoted presynaptic differentiation in axons of midbrain dopamine neurons and striatal GABAergic neurons in culture. After neuroligin-2 knockdown in the striatum, a significant decrease of dopamine synapses coupled with a reciprocal increase of GABAergic synapses was observed on MSN dendrites. This finding suggests that neuroligin-2 controls striatal synapse formation by giving competitive advantage to heterologous dopamine synapses over conventional GABAergic synapses. Considering that MSN dendrites are preferential targets of dopamine synapses and express high levels of dopamine receptors, dopamine synapse formation may serve to increase the specificity and potency of dopaminergic modulation of striatal outputs by anchoring dopamine release sites to dopamine-sensing targets.

  11. Dopamine in the medial amygdala network mediates human bonding

    Science.gov (United States)

    Touroutoglou, Alexandra; Rudy, Tali; Salcedo, Stephanie; Feldman, Ruth; Hooker, Jacob M.; Dickerson, Bradford C.; Catana, Ciprian; Barrett, Lisa Feldman

    2017-01-01

    Research in humans and nonhuman animals indicates that social affiliation, and particularly maternal bonding, depends on reward circuitry. Although numerous mechanistic studies in rodents demonstrated that maternal bonding depends on striatal dopamine transmission, the neurochemistry supporting maternal behavior in humans has not been described so far. In this study, we tested the role of central dopamine in human bonding. We applied a combined functional MRI-PET scanner to simultaneously probe mothers’ dopamine responses to their infants and the connectivity between the nucleus accumbens (NAcc), the amygdala, and the medial prefrontal cortex (mPFC), which form an intrinsic network (referred to as the “medial amygdala network”) that supports social functioning. We also measured the mothers’ behavioral synchrony with their infants and plasma oxytocin. The results of this study suggest that synchronous maternal behavior is associated with increased dopamine responses to the mother’s infant and stronger intrinsic connectivity within the medial amygdala network. Moreover, stronger network connectivity is associated with increased dopamine responses within the network and decreased plasma oxytocin. Together, these data indicate that dopamine is involved in human bonding. Compared with other mammals, humans have an unusually complex social life. The complexity of human bonding cannot be fully captured in nonhuman animal models, particularly in pathological bonding, such as that in autistic spectrum disorder or postpartum depression. Thus, investigations of the neurochemistry of social bonding in humans, for which this study provides initial evidence, are warranted. PMID:28193868

  12. Dopamine-induced apoptosis in human neuronal cells: inhibition by nucleic acides antisense to the dopamine transporter

    Energy Technology Data Exchange (ETDEWEB)

    Porat, S.; Gabbay, M.; Tauber, M.; Ratovitski, T.; Blinder, E.; Simantov, R. [Department of Molecular Genetics, Weizmann Institute of Science Rehovot 76100 (Israel)

    1996-09-01

    Human neuroblastoma NMB cells take up [{sup 3}H]dopamine in a selective manner indicating that dopamine transporters are responsible for this uptake. These cells were therefore used as a model to study dopamine neurotoxicity, and to elucidate the role of dopamine transporters in controlling cell death. Treatment with 0.05-0.4 mM dopamine changed cells' morphology within 4 h, accompanied by retraction of processes, shrinkage, apoptosis-like atrophy, accumulation of apoptotic particles, DNA fragmentation and cell death. Cycloheximide inhibited dopamine's effect, suggesting that induction of apoptosis by dopamine was dependent upon protein synthesis. Dopamine cytotoxicity, monitored morphologically by flow cytometric analysis, and by lactate dehydrogenase released, was blocked by cocaine but not by the noradrenaline and serotonin uptake blockers desimipramine and imipramine, respectively. Attempting to inhibit dopamine transport and toxicity in a drug-free and highly selective way, three 18-mer dopamine transporter antisense phosphorothioate oligonucleotides (numbers 1, 2 and 3) and a new plasmid vector expressing the entire rat dopamine transporter complementary DNA in the antisense orientation were prepared and tested. Antisense phosphorothioate oligonucleotide 3 inhibited [{sup 3}H]dopamine uptake in a time- and dose-dependent manner. Likewise, transient transfection of NMB cells with the plasmid expressing dopamine transporter complementary DNA in the antisense orientation partially blocked [{sup 3}H]dopamine uptake. Antisense phosphorothioate oligonucleotide 3 also decreased, dose-dependently, the toxic effect of dopamine and 6-hydroxydopamine. Western blot analysis with newly prepared anti-human dopamine transporter antibodies showed that antisense phosphorothioate oligonucleotide 3 decreased the transporter protein level. These studies contribute to better understand the mechanism of dopamine-induced apoptosis and neurotoxicity. (Copyright (c) 1996

  13. rTMS of the left dorsolateral prefrontal cortex modulates dopamine release in the ipsilateral anterior cingulate cortex and orbitofrontal cortex.

    Directory of Open Access Journals (Sweden)

    Sang Soo Cho

    Full Text Available BACKGROUND: Brain dopamine is implicated in the regulation of movement, attention, reward and learning and plays an important role in Parkinson's disease, schizophrenia and drug addiction. Animal experiments have demonstrated that brain stimulation is able to induce significant dopaminergic changes in extrastriatal areas. Given the up-growing interest of non-invasive brain stimulation as potential tool for treatment of neurological and psychiatric disorders, it would be critical to investigate dopaminergic functional interactions in the prefrontal cortex and more in particular the effect of dorsolateral prefrontal cortex (DLPFC (areas 9/46 stimulation on prefrontal dopamine (DA. METHODOLOGY/PRINCIPAL FINDINGS: Healthy volunteers were studied with a high-affinity DA D2-receptor radioligand, [(11C]FLB 457-PET following 10 Hz repetitive transcranial magnetic stimulation (rTMS of the left and right DLPFC. rTMS on the left DLPFC induced a significant reduction in [(11C]FLB 457 binding potential (BP in the ipsilateral subgenual anterior cingulate cortex (ACC (BA 25/12, pregenual ACC (BA 32 and medial orbitofrontal cortex (BA 11. There were no significant changes in [(11C]FLB 457 BP following right DLPFC rTMS. CONCLUSIONS/SIGNIFICANCE: To our knowledge, this is the first study to provide evidence of extrastriatal DA modulation following acute rTMS of DLPFC with its effect limited to the specific areas of medial prefrontal cortex. [(11C]FLB 457-PET combined with rTMS may allow to explore the neurochemical functions of specific cortical neural networks and help to identify the neurobiological effects of TMS for the treatment of different neurological and psychiatric diseases.

  14. 3,4-Methylenedioxyamphetamine (MDA) analogues exhibit differential effects on synaptosomal release of 3H-dopamine and 3H-5-hydroxytryptamine

    Energy Technology Data Exchange (ETDEWEB)

    McKenna, D.J.; Guan, X.M.; Shulgin, A.T. (Department of Neurology Neurological Sciences, Stanford University Medical Center, CA (USA))

    1991-03-01

    The effect of various analogues of the neurotoxic amphetamine derivative, MDA (3,4-methylenedioxyamphetamine) on carrier-mediated, calcium-independent release of 3H-5-HT and 3H-DA from rat brain synaptosomes was investigated. Both enantiomers of the neurotoxic analogues MDA and MDMA (3,4-methylenedioxymethamphetamine) induce synaptosomal release of 3H-5-HT and 3H-DA in vitro. The release of 3H-5-HT induced by MDMA is partially blocked by 10(-6) M fluoxetine. The (+) enantiomers of both MDA and MDMA are more potent than the (-) enantiomers as releasers of both 3H-5-HT and 3H-DA. Eleven analogues, differing from MDA with respect to the nature and number of ring and/or side chain substituents, also show some activity in the release experiments, and are more potent as releasers of 3H-5-HT than of 3H-DA. The amphetamine derivatives {plus minus}fenfluramine, {plus minus}norfenfluramine, {plus minus}MDE, {plus minus}PCA, and d-methamphetamine are all potent releasers of 3H-5-HT and show varying degrees of activity as 3H-DA releasers. The hallucinogen DOM does not cause significant release of either 3H-monoamine. Possible long-term serotonergic neurotoxicity was assessed by quantifying the density of 5-HT uptake sites in rats treated with multiple doses of selected analogues using 3H-paroxetine to label 5-HT uptake sites. In the neurotoxicity study of the compounds investigated, only (+)MDA caused a significant loss of 5-HT uptake sites in comparison to saline-treated controls. These results are discussed in terms of the apparent structure-activity properties affecting 3H-monoamine release and their possible relevance to neurotoxicity in this series of MDA congeners.

  15. 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.

  16. Computational systems analysis of dopamine metabolism.

    Directory of Open Access Journals (Sweden)

    Zhen Qi

    Full Text Available A prominent feature of Parkinson's disease (PD is the loss of dopamine in the striatum, and many therapeutic interventions for the disease are aimed at restoring dopamine signaling. Dopamine signaling includes the synthesis, storage, release, and recycling of dopamine in the presynaptic terminal and activation of pre- and post-synaptic receptors and various downstream signaling cascades. As an aid that might facilitate our understanding of dopamine dynamics in the pathogenesis and treatment in PD, we have begun to merge currently available information and expert knowledge regarding presynaptic dopamine homeostasis into a computational model, following the guidelines of biochemical systems theory. After subjecting our model to mathematical diagnosis and analysis, we made direct comparisons between model predictions and experimental observations and found that the model exhibited a high degree of predictive capacity with respect to genetic and pharmacological changes in gene expression or function. Our results suggest potential approaches to restoring the dopamine imbalance and the associated generation of oxidative stress. While the proposed model of dopamine metabolism is preliminary, future extensions and refinements may eventually serve as an in silico platform for prescreening potential therapeutics, identifying immediate side effects, screening for biomarkers, and assessing the impact of risk factors of the disease.

  17. Altered dopamine signaling in naturally occurring maternal neglect.

    Directory of Open Access Journals (Sweden)

    Stephen C Gammie

    Full Text Available BACKGROUND: Child neglect is the most common form of child maltreatment, yet the biological basis of maternal neglect is poorly understood and a rodent model is lacking. METHODOLOGY/PRINCIPAL FINDINGS: The current study characterizes a population of mice (MaD1 which naturally exhibit maternal neglect (little or no care of offspring at an average rate of 17% per generation. We identified a set of risk factors that can predict future neglect of offspring, including decreased self-grooming and elevated activity. At the time of neglect, neglectful mothers swam significantly more in a forced swim test relative to nurturing mothers. Cross-fostered offspring raised by neglectful mothers in turn exhibit increased expression of risk factors for maternal neglect and decreased maternal care as adults, suggestive of possible epigenetic contributions to neglect. Unexpectedly, offspring from neglectful mothers elicited maternal neglect from cross-fostered nurturing mothers, suggesting that factors regulating neglect are not solely within the mother. To identify a neurological pathway underlying maternal neglect, we examined brain activity in neglectful and nurturing mice. c-Fos expression was significantly elevated in neglectful relative to nurturing mothers in the CNS, particularly within dopamine associated areas, such as the zona incerta (ZI, ventral tegmental area (VTA, and nucleus accumbens. Phosphorylated tyrosine hydroxylase (a marker for dopamine production was significantly elevated in ZI and higher in VTA (although not significantly in neglectful mice. Tyrosine hydroxylase levels were unaltered, suggesting a dysregulation of dopamine activity rather than cell number. Phosphorylation of DARPP-32, a marker for dopamine D1-like receptor activation, was elevated within nucleus accumbens and caudate-putamen in neglectful versus nurturing dams. CONCLUSIONS/SIGNIFICANCE: These findings suggest that atypical dopamine activity within the maternal brain

  18. Addiction: Beyond dopamine reward circuitry

    Energy Technology Data Exchange (ETDEWEB)

    Volkow, N.D.; Wang, G.; Volkow, N.D.; Wang, G.-J.; Fowler, J.S.; Tomasi, D.; Telang, F.

    2011-09-13

    Dopamine (DA) is considered crucial for the rewarding effects of drugs of abuse, but its role in addiction is much less clear. This review focuses on studies that used PET to characterize the brain DA system in addicted subjects. These studies have corroborated in humans the relevance of drug-induced fast DA increases in striatum [including nucleus accumbens (NAc)] in their rewarding effects but have unexpectedly shown that in addicted subjects, drug-induced DA increases (as well as their subjective reinforcing effects) are markedly blunted compared with controls. In contrast, addicted subjects show significant DA increases in striatum in response to drug-conditioned cues that are associated with self-reports of drug craving and appear to be of a greater magnitude than the DA responses to the drug. We postulate that the discrepancy between the expectation for the drug effects (conditioned responses) and the blunted pharmacological effects maintains drug taking in an attempt to achieve the expected reward. Also, whether tested during early or protracted withdrawal, addicted subjects show lower levels of D2 receptors in striatum (including NAc), which are associated with decreases in baseline activity in frontal brain regions implicated in salience attribution (orbitofrontal cortex) and inhibitory control (anterior cingulate gyrus), whose disruption results in compulsivity and impulsivity. These results point to an imbalance between dopaminergic circuits that underlie reward and conditioning and those that underlie executive function (emotional control and decision making), which we postulate contributes to the compulsive drug use and loss of control in addiction.

  19. Effects of Repeated Electroacupuncture on Gene Expression of Cannabinoid Receptor-1 and Dopamine 1 Receptor in Nucleus Accumbens-Caudate Nucleus Region in Inflammatory-pain Rats%反复电针对佐剂性关节炎大鼠伏隔核-尾状核区大麻素CB1受体与多巴胺Dl受体基因表达的影响

    Institute of Scientific and Technical Information of China (English)

    寿鉴; 赵颖倩; 徐鸣曙; 葛林宝

    2011-01-01

    Objective To observe the effect of repeated electroacupuncture (EA) on the expression of cannabinoid receptor-1 (CB 1 ) mRNA and dopamine 1 receptor (D 1 ) mRNA in Nucleus Accumbens (NAC)-Caudate Nucleus (CN) region in inflammatory-pain rats, so as to study its underlying mechanism in analgesia. Methods A total of 30 SD rats were randomized into normal control, model, EA, EA + AM 251 and WIN 552 12-2 groups, with 6 cases in each group. EA (2 Hz/100 Hz, 1 - 3 mA)was applied to "Zusanli"(ST 36) and "Kunlun"(BL 60) for 30 min, once every other day, and 4 sessions all together. Arthritis model was established by injection of Freund's complete adjuvant 0.05 mL in the rat's left ankle. Thermal pain threshold (paw withdrawal latency, PWL) was detected before and after modeling and after repeated EA and/or intraperitoneal injection of AM 251 (an inverse antagonist at the CB 1 cannabinoid receptor, 0. 1 mg/1 00 g) and WIN 55212-2 (a potent cannabinoid receptor agonist, 0.2 mg/100 g). The expression of CB 1 receptor mRNA and D 1 receptor mRNA in the NAC-CN region was measured by real time fluorescence quantitative-polymerase chain reaction. Results Compared with the control group, the pain threshold values of the model group was decreased significantly (P<0.01). In comparison with the model group, the pain threshold values of the EA group and WIN 55212-2 group were increased considerably on day 10 (P<0.01). No significant differences were found between the EA+AM 251 and model groups and between the EA and WIN 55212-2 groups in PWL after the treatment (P>0.05).Compared with the control group, both CB 1 R mRNA and D 1 R mRNA expression levels in the model group were increased slightly, while in comparison with the model group and EA+ AM 251 group, CB 1 R mRNA and D 1 R mRNA expression levels in the EAgroup and WIN 55212-2 group were upregulated obviously. No significant differences were found between the EA+ AM 251 and model groups and between the EA and WIN 55212

  20. 4-Methylthioamphetamine increases dopamine in the rat striatum and has rewarding effects in vivo.

    Science.gov (United States)

    Sotomayor-Zárate, Ramón; Quiroz, Gabriel; Araya, Katherine A; Abarca, Jorge; Ibáñez, María R; Montecinos, Alejandro; Guajardo, Carlos; Núñez, Gabriel; Fierro, Angélica; Moya, Pablo R; Iturriaga-Vásquez, Patricio; Gómez-Molina, Cristóbal; Gysling, Katia; Reyes-Parada, Miguel

    2012-12-01

    4-Methylthioamphetamine (MTA) is a phenylisopropylamine derivative whose use has been associated with severe intoxications. MTA is usually regarded as a selective serotonin-releasing agent. Nevertheless, previous data have suggested that its mechanism of action probably involves a catecholaminergic component. As little is known about dopaminergic effects of this drug, in this work the actions of MTA upon the dopamine (DA) transporter (DAT) were studied in vitro, in vivo and in silico. Also, the possible abuse liability of MTA was behaviourally assessed. MTA exhibited an in vitro affinity for the rat DAT in the low micromolar range (6.01 μM) and induced a significant, dose-dependent increase in striatal DA. MTA significantly increased c-Fos-positive cells in striatum and nucleus accumbens, induced conditioned place preference and increased locomotor activity. Docking experiments were performed in a homology model of the DAT. In conclusion, our results show that MTA is able to increase extracellular striatal DA levels and that its administration has rewarding properties. These effects were observed at concentrations or doses that can be relevant to its use in human beings.

  1. Motivation deficit in ADHD is associated with dysfunction of the dopamine reward pathway

    Energy Technology Data Exchange (ETDEWEB)

    Volkow, N.D.; Wang, G.; Volkow, N.D.; Wang, G.-J.; Newcorn, J.H.; Kollins, S.H.; Wigal, T.L.; Telang, F.; Folwer, J.S.; Goldstein, R.Z.; Klein, N.; Logan, J.; Wong, C.; Swanson, J.M.

    2010-08-17

    Attention-deficit hyperactivity disorder (ADHD) is typically characterized as a disorder of inattention and hyperactivity/impulsivity but there is increasing evidence of deficits in motivation. Using positron emission tomography (PET), we showed decreased function in the brain dopamine reward pathway in adults with ADHD, which, we hypothesized, could underlie the motivation deficits in this disorder. To evaluate this hypothesis, we performed secondary analyses to assess the correlation between the PET measures of dopamine D2/D3 receptor and dopamine transporter availability (obtained with [{sup 11}C]raclopride and [{sup 11}C]cocaine, respectively) in the dopamine reward pathway (midbrain and nucleus accumbens) and a surrogate measure of trait motivation (assessed using the Achievement scale on the Multidimensional Personality Questionnaire or MPQ) in 45 ADHD participants and 41 controls. The Achievement scale was lower in ADHD participants than in controls (11 {+-} 5 vs 14 {+-} 3, P < 0.001) and was significantly correlated with D2/D3 receptors (accumbens: r = 0.39, P < 0.008; midbrain: r = 0.41, P < 0.005) and transporters (accumbens: r = 0.35, P < 0.02) in ADHD participants, but not in controls. ADHD participants also had lower values in the Constraint factor and higher values in the Negative Emotionality factor of the MPQ but did not differ in the Positive Emotionality factor - and none of these were correlated with the dopamine measures. In ADHD participants, scores in the Achievement scale were also negatively correlated with symptoms of inattention (CAARS A, E and SWAN I). These findings provide evidence that disruption of the dopamine reward pathway is associated with motivation deficits in ADHD adults, which may contribute to attention deficits and supports the use of therapeutic interventions to enhance motivation in ADHD.

  2. Hypothesizing that, A Pro-Dopamine Regulator (KB220Z) Should Optimize, but Not Hyper-Activate the Activity of Trace Amine-Associated Receptor 1 (TAAR-1) and Induce Anti-Craving of Psychostimulants in the Long-Term

    Science.gov (United States)

    Blum, Kenneth; Badgaiyan, Rajendra D.; Braverman, Eric R.; Dushaj, Kristina; Li, Mona; Thanos, Peter K.; Demetrovics, Zsolt; Febo, Marcelo

    2017-01-01

    Unlike other drugs of abuse such as alcohol, nicotine, opiates/opioids, the FDA has not approved any agent to treat psychostimulant dependence. Certainly, it is widely acceptable that dopaminergic signaling is a key factor in both the initiation and continued motivation to abuse this class of stimulant substances. It is also well accepted that psychostimulants such as cocaine affect not only the release of neuronal dopamine at the nucleus accumbens (NAc), but also has powerful inhibitory actions on the dopamine transporter system. Understandably, certain individuals are at high risk and very vulnerable to abuse this class of substances. Trace-amine-associated receptor 1 (TAAR1) is a G -protein coupled receptor activated by trace amines. The encoded protein responds little or not at all to dopamine, serotonin, epinephrine, or histamine, but responds well to beta-phenylethylamine, p-tyramine, octopamine, and tryptamine. This gene is thought to be intronless. TAAR1 agonists reduce the neurochemical effects of cocaine and amphetamines as well as attenuate addiction and abuse associated with these two psychostimulants. The mechanism involves blocking the firing rate of dopamine in the limbic system thereby decreasing a hyperdopaminergic trait/state, whereby the opposite is true for TAAR1 antagonists. Based on many studies, it is accepted that in Reward Deficiency Syndrome (RDS), there is weakened tonic and improved phasic dopamine discharge leading to a hypodopaminergic/glutamatergic trait. The dopamine pro-complex mixture KB220, following many clinical trials including neuroimaging studies, has been shown to enhance resting state functional connectivity in humans (abstinent heroin addicts), naïve rodent models, and regulates extensive theta action in the cingulate gyrus of abstinent psychostimulant abusers. In this article, we are hypothesizing that KB220 may induce its action on resting state functional connectivity, for example, by actually balancing (optimizing

  3. Voxelwise lp-ntPET for detecting localized, transient dopamine release of unknown timing: sensitivity analysis and application to cigarette smoking in the PET scanner.

    Science.gov (United States)

    Kim, Su Jin; Sullivan, Jenna M; Wang, Shuo; Cosgrove, Kelly P; Morris, Evan D

    2014-09-01

    The "linear parametric neurotransmitter PET" (lp-ntPET) model estimates time variation in endogenous neurotransmitter levels from dynamic PET data. The pattern of dopamine (DA) change over time may be an important element of the brain's response to addictive substances such as cigarettes or alcohol. We have extended the lp-ntPET model from the original region of interest (ROI) - based implementation to be able to apply the model at the voxel level. The resulting endpoint is a dynamic image, or movie, of transient neurotransmitter changes. Simulations were performed to select threshold values to reduce the false positive rate when applied to real (11)C-raclopride PET data. We tested the new voxelwise method on simulated data, and finally, we applied it to (11)C-raclopride PET data of subjects smoking cigarettes in the PET scanner. In simulation, the temporal precision of neurotransmitter response was shown to be similar to that of ROI-based lp-ntPET (standard deviation ∼ 3 min). False positive rates for the voxelwise method were well controlled by combining a statistical threshold (the F-test) with a new spatial (cluster-size) thresholding operation. Sensitivity of detection for the new algorithm was greater than 80% for the case of short-lived DA changes that occur in subregions of the striatum as might be the case with cigarette smoking. Finally, in (11)C-raclopride PET data, DA movies reveal for the first time that different temporal patterns of the DA response to smoking may exist in different subregions of the striatum. These spatiotemporal patterns of neurotransmitter change created by voxelwise lp-ntPET may serve as novel biomarkers for addiction and/or treatment efficacy.

  4. Early increase in dopamine release in the ipsilateral striatum after unilateral intranigral administration of lactacystin produces spontaneous contralateral rotations in rats.

    Science.gov (United States)

    Konieczny, J; Lenda, T; Czarnecka, A

    2016-06-02

    Since the discovery of the role of the ubiquitin-proteasome system (UPS) in the pathogenesis of Parkinson's disease, UPS inhibitors, such as lactacystin have been used to investigate the relationship between UPS impairment and degeneration of dopamine (DA) neurons. However, mostly long-term neurotoxic effects of lactacystin have been studied in animal models. Therefore, the aim of our study was to investigate behavioral and biochemical changes related to the DA system during the first week following unilateral intranigral injection of lactacystin to rats. We found that lactacystin produced early spontaneous contralateral rotations which were inhibited by combined administration of DA D1 and D2 receptor antagonists. Simultaneously, an increase in the extracellular level of DA and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanilic acid (HVA) was found in the ipsilateral striatum. In contrast, one week after lesion, when turning behavior was no longer visible, a decrease in the extracellular level of DA, DOPAC and HVA was demonstrated. It was accompanied by a substantial reduction in the tissue levels of DA and its metabolites in the lesioned substantia nigra and striatum. We concluded that unilateral intranigral administration of lactacystin produces an early increase in DA neurotransmission which precedes a decrease in the striatal and nigral tissue DA content. It is manifested by the appearance of spontaneous contralateral rotations and an elevation of the extracellular DA level in the ipsilateral striatum. Since similar behavior was previously observed after intranigral administration of rotenone and MPP(+) but not 6-hydroxydopamine (6-OHDA), it may indicate a common mechanism of action shared by these neurotoxins.

  5. 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

  6. Minireview: new roles for peripheral dopamine on metabolic control and tumor growth: let's seek the balance.

    Science.gov (United States)

    Rubí, Blanca; Maechler, Pierre

    2010-12-01

    In peripheral tissues, dopamine is released from neuronal cells and is synthesized within specific parenchyma. Dopamine released from sympathetic nerves predominantly contributes to plasma dopamine levels. Despite growing evidence for peripheral source and action of dopamine and the widespread expression of dopamine receptors in peripheral tissues, most studies have focused on functions of dopamine in the central nervous system. Symptoms of several brain disorders, including schizophrenia, Parkinson's disease, attention-deficit hyperactivity disorder, and depression, are alleviated by pharmacological modulation of dopamine transmission. Regarding systemic disorders, the role of dopamine is still poorly understood. Here we describe the pioneering and recent evidence for functional roles of peripheral dopamine. Peripheral and central dopamine systems are sensitive to environmental stress, such as a high-fat diet, suggesting a basis of covariance of peripheral and central actions of dopaminergic agents. Given the extended use of such medications, it is crucial to better understand the integrated effects of dopamine in the whole organism. Delineation of peripheral and central dopaminergic mechanisms would facilitate targeted and safer use of drugs modulating dopamine action. We discuss the increasing evidence for a link between peripheral dopamine and obesity. This review also describes the recently uncovered protective actions of dopamine on energy metabolism and proliferation in tumoral cells.

  7. Agonist signalling properties of radiotracers used for imaging of dopamine D-2/3 receptors

    NARCIS (Netherlands)

    van Wieringen, Jan-Peter; Michel, Martin C.; Janssen, Henk M.; Janssen, Anton G.; Elsinga, Philip H.; Booij, Jan

    2014-01-01

    Background: Dopamine D-2/3 receptor (D2/3R) agonist radiopharmaceuticals are considered superior to antagonists to detect dopamine release, e.g. induced by amphetamines. Agonists bind preferentially to the high-affinity state of the dopamine D2R, which has been proposed as the reason why agonists ar

  8. Recognition unit-free and self-cleaning photoelectrochemical sensing platform on TiO2 nanotube photonic crystals for sensitive and selective detection of dopamine release from mouse brain.

    Science.gov (United States)

    Xin, Yanmei; Li, Zhenzhen; Wu, Wenlong; Fu, Baihe; Wu, Hongjun; Zhang, Zhonghai

    2017-01-15

    For implementing sensitive and selective detection of biological molecules, the biosensors are been designed more and more complicated. The exploration of detection platform in a simple way without loss their sensitivity and selectivity is always a big challenge. Herein, a prototype of recognition biomolecule unit-free photoelectrochemical (PEC) sensing platform with self-cleaning activity is proposed with TiO2 nanotube photonic crystal (TiO2 NTPCs) materials as photoelectrode, and dopamine (DA) molecule as both sensitizer and target analyte. The unique adsorption between DA and TiO2 NTPCs induces the formation of charge transfer complex, which not only expends the optical absorption of TiO2 into visible light region, thus significantly boosts the PEC performance under illumination of visible light, but also implements the selective detection of DA on TiO2 photoelectrode. This simple but efficient PEC analysis platform presents a low detection limit of 0.15nm for detection of DA, which allows to realize the sensitive and selective determination of DA release from the mouse brain for its practical application after coupled with a microdialysis probe. The DA functionalized TiO2 NTPCs PEC sensing platform opens up a new PEC detection model, without using extra-biomolecule auxiliary, just with target molecule naturally adsorbed on the electrode for sensitive and selective detection, and paves a new avenue for biosensors design with minimalism idea.

  9. Reinforcement signalling in Drosophila; dopamine does it all after all.

    Science.gov (United States)

    Waddell, Scott

    2013-06-01

    Reinforcement systems are believed to drive synaptic plasticity within neural circuits that store memories. Recent evidence from the fruit fly suggests that anatomically distinct dopaminergic neurons ultimately provide the key instructive signals for both appetitive and aversive learning. This dual role for dopamine overturns the previous model that octopamine signalled reward and dopamine punishment. More importantly, this anatomically segregated double role for dopamine in reward and aversion mirrors that emerging in mammals. Therefore, an antagonistic organization of distinct reinforcing dopaminegic neurons is a conserved feature of brains. It now seems crucial to understand how the dopaminergic neurons are controlled and what the released dopamine does to the underlying circuits to convey opposite valence.

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

    Science.gov (United States)

    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.

  11. Dopamine receptor and hypertension.

    Science.gov (United States)

    Zeng, Chunyu; Eisner, Gilbert M; Felder, Robin A; Jose, Pedro A

    2005-01-01

    Dopamine plays an important role in the pathogenesis of hypertension by regulating epithelial sodium transport and reactive oxygen and by interacting with vasopressin, renin-angiotensin, and the sympathetic nervous system. Decreased renal dopamine production and/or impaired dopamine receptor function have been reported in hypertension. Disruption of any of the dopamine receptors (D(1), D(2), D(3), D(4), and D(5)) results in hypertension. In this paper, we review the mechanisms by which hypertension develops when dopamine receptor function is perturbed.

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

    Directory of Open Access Journals (Sweden)

    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.

  13. Reward-based hypertension control by a synthetic brain–dopamine interface

    OpenAIRE

    Rossger, K.; Charpin-El Hamri, G.; Fussenegger, M

    2013-01-01

    Essential activities such as feeding and reproduction as well as social, emotional, and mental behavior are reinforced by the brain’s reward system. Pleasure status directly correlates with dopamine levels released in the brain. Because dopamine leaks into the bloodstream via the sympathetic nervous system, brain and blood dopamine levels are interrelated. We designed a synthetic dopamine sensor-effector device that enables engineered human cells, insulated by immunoprotective microcontainers...

  14. Dopamine encoding of Pavlovian incentive stimuli diminishes with extended training.

    Science.gov (United States)

    Clark, Jeremy J; Collins, Anne L; Sanford, Christina Akers; Phillips, Paul E M

    2013-02-20

    Dopamine is highly implicated both as a teaching signal in reinforcement learning and in motivating actions to obtain rewards. However, theoretical disconnects remain between the temporal encoding properties of dopamine neurons and the behavioral consequences of its release. Here, we demonstrate in rats that dopamine evoked by Pavlovian cues increases during acquisition, but dissociates from stable conditioned appetitive behavior as this signal returns to preconditioning levels with extended training. Experimental manipulation of the statistical parameters of the behavioral paradigm revealed that this attenuation of cue-evoked dopamine release during the postasymptotic period was attributable to acquired knowledge of the temporal structure of the task. In parallel, conditioned behavior became less dopamine dependent after extended training. Thus, the current work demonstrates that as the presentation of reward-predictive stimuli becomes anticipated through the acquisition of task information, there is a shift in the neurobiological substrates that mediate the motivational properties of these incentive stimuli.

  15. Dopamine receptors and hypertension.

    Science.gov (United States)

    Banday, Anees Ahmad; Lokhandwala, Mustafa F

    2008-08-01

    Dopamine plays an important role in regulating renal function and blood pressure. Dopamine synthesis and dopamine receptor subtypes have been shown in the kidney. Dopamine acts via cell surface receptors coupled to G proteins; the receptors are classified via pharmacologic and molecular cloning studies into two families, D1-like and D2-like. Two D1-like receptors cloned in mammals, the D1 and D5 receptors (D1A and D1B in rodents), are linked to adenylyl cyclase stimulation. Three D2-like receptors (D2, D3, and D4) have been cloned and are linked mainly to adenylyl cyclase inhibition. Activation of D1-like receptors on the proximal tubules inhibits tubular sodium reabsorption by inhibiting Na/H-exchanger and Na/K-adenosine triphosphatase activity. Reports exist of defective renal dopamine production and/or dopamine receptor function in human primary hypertension and in genetic models of animal hypertension. In humans with essential hypertension, renal dopamine production in response to sodium loading is often impaired and may contribute to hypertension. A primary defect in D1-like receptors and an altered signaling system in proximal tubules may reduce dopamine-mediated effects on renal sodium excretion. The molecular basis for dopamine receptor dysfunction in hypertension is being investigated, and may involve an abnormal posttranslational modification of the dopamine receptor.

  16. Unexpected global impact of VTA dopamine neuron activation as measured by opto-fMRI

    Science.gov (United States)

    Lohani, Sweyta; Poplawsky, Alexander John; Kim, Seong-Gi; Moghaddam, Bita

    2016-01-01

    Dopamine neurons in the ventral tegmental area (VTA) are strongly implicated in cognitive and affective processing as well as in psychiatric disorders including schizophrenia, ADHD and substance abuse disorders. In human studies, dopamine-related functions are routinely assessed using functional magnetic resonance imaging (fMRI) measures of blood oxygenation-level dependent (BOLD) signals during the performance of dopamine-dependent tasks. There is, however, a critical void in our knowledge about if and how activation of VTA dopamine neurons specifically influences regional or global fMRI signals. Here we used optogenetics in Th::Cre rats to selectively stimulate VTA dopamine neurons while simultaneously measuring global hemodynamic changes using BOLD and cerebral blood volume-weighted (CBVw) fMRI. Phasic activation of VTA dopamine neurons increased BOLD and CBVw fMRI signals in VTA-innervated limbic regions, including the ventral striatum (nucleus accumbens). Surprisingly, basal ganglia regions that receive sparse or no VTA dopaminergic innervation, including the dorsal striatum and the globus pallidus, were also activated. In fact, the most prominent fMRI signal increase in the forebrain was observed in the dorsal striatum that is not traditionally associated with VTA dopamine neurotransmission. These data establish causation between phasic activation of VTA dopamine neurons and global fMRI signals. They further suggest that mesolimbic and non-limbic basal ganglia dopamine circuits are functionally connected and, thus, provide a potential novel framework for understanding dopamine-dependent functions and interpreting data obtained from human fMRI studies. PMID:27457809

  17. The dopamine theory of addiction: 40 years of highs and lows.

    Science.gov (United States)

    Nutt, David J; Lingford-Hughes, Anne; Erritzoe, David; Stokes, Paul R A

    2015-05-01

    For several decades, addiction has come to be viewed as a disorder of the dopamine neurotransmitter system; however, this view has not led to new treatments. In this Opinion article, we review the origins of the dopamine theory of addiction and discuss the ability of addictive drugs to elicit the release of dopamine in the human striatum. There is robust evidence that stimulants increase striatal dopamine levels and some evidence that alcohol may have such an effect, but little evidence, if any, that cannabis and opiates increase dopamine levels. Moreover, there is good evidence that striatal dopamine receptor availability and dopamine release are diminished in individuals with stimulant or alcohol dependence but not in individuals with opiate, nicotine or cannabis dependence. These observations have implications for understanding reward and treatment responses in various addictions.

  18. Dopamine Dynamics during Continuous Intracranial Self-Stimulation: Effect of Waveform on Fast-Scan Cyclic Voltammetry Data.

    Science.gov (United States)

    Rodeberg, Nathan T; Johnson, Justin A; Bucher, Elizabeth S; Wightman, R Mark

    2016-11-16

    The neurotransmitter dopamine is heavily implicated in intracranial self-stimulation (ICSS). Many drugs of abuse that affect ICSS behavior target the dopaminergic system, and optogenetic activation of dopamine neurons is sufficient to support self-stimulation. However, the patterns of phasic dopamine release during ICSS remain unclear. Early ICSS studies using fast-scan cyclic voltammetry (FSCV) rarely observed phasic dopamine release, which led to the surprising conclusion that it is dissociated from ICSS. However, several advances in the sensitivity (i.e., the use of waveforms with extended anodic limits) and analysis (i.e., principal component regression) of FSCV measurements have made it possible to detect smaller, yet physiologically relevant, dopamine release events. Therefore, this study revisits phasic dopamine release during ICSS using these tools. It was found that the anodic limit of the voltammetric waveform has a substantial effect on the patterns of dopamine release observed during continuous ICSS. While data collected with low anodic limits (i.e., +1.0 V) support the disappearance of phasic dopamine release observed in previous investigation, the use of high anodic limits (+1.3 V, +1.4 V) allows for continual detection of dopamine release throughout ICSS. However, the +1.4 V waveform lacks the ability to resolve narrowly spaced events, with the best balance of temporal resolution and sensitivity provided by the +1.3 V waveform. Ultimately, it is revealed that the amplitude of phasic dopamine release decays but does not fully disappear during continuous ICSS.

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

    Directory of Open Access Journals (Sweden)

    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.

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  7. Ultrastructural characterization of the mesostriatal dopamine innervation in mice, including two mouse lines of conditional VGLUT2 knockout in dopamine neurons.

    Science.gov (United States)

    Bérubé-Carrière, Noémie; Guay, Ginette; Fortin, Guillaume M; Kullander, Klas; Olson, Lars; Wallén-Mackenzie, Åsa; Trudeau, Louis-Eric; Descarries, Laurent

    2012-02-01

    Despite the increasing use of genetically modified mice to investigate the dopamine (DA) system, little is known about the ultrastructural features of the striatal DA innervation in the mouse. This issue is particularly relevant in view of recent evidence for expression of the vesicular glutamate transporter 2 (VGLUT2) by a subset of mesencephalic DA neurons in mouse as well as rat. We used immuno-electron microscopy to characterize tyrosine hydroxylase (TH)-labeled terminals in the core and shell of nucleus accumbens and the neostriatum of two mouse lines in which the Vglut2 gene was selectively disrupted in DA neurons (cKO), their control littermates, and C57BL/6/J wild-type mice, aged P15 or adult. The three regions were also examined in cKO mice and their controls of both ages after dual TH-VGLUT2 immunolabeling. Irrespective of the region, age and genotype, the TH-immunoreactive varicosities appeared similar in size, vesicular content, percentage with mitochondria, and exceedingly low frequency of synaptic membrane specialization. No dually labeled axon terminals were found at either age in control or in cKO mice. Unless TH and VGLUT2 are segregated in different axon terminals of the same neurons, these results favor the view that the glutamatergic cophenotype of mesencephalic DA neurons is more important during the early development of these neurons than for the establishment of their scarce synaptic connectivity. They also suggest that, in mouse even more than rat, the mesostriatal DA system operates mainly through non-targeted release of DA, diffuse transmission and the maintenance of an ambient DA level.

  8. Prenatal inflammation-induced hypoferremia alters dopamine function in the adult offspring in rat: relevance for schizophrenia.

    Directory of Open Access Journals (Sweden)

    Argel Aguilar-Valles

    Full Text Available Maternal infection during pregnancy has been associated with increased incidence of schizophrenia in the adult offspring. Mechanistically, this has been partially attributed to neurodevelopmental disruption of the dopamine neurons, as a consequence of exacerbated maternal immunity. In the present study we sought to target hypoferremia, a cytokine-induced reduction of serum non-heme iron, which is common to all types of infections. Adequate iron supply to the fetus is fundamental for the development of the mesencephalic dopamine neurons and disruption of this following maternal infection can affect the offspring's dopamine function. Using a rat model of localized injury induced by turpentine, which triggers the innate immune response and inflammation, we investigated the effects of maternal iron supplementation on the offspring's dopamine function by assessing behavioral responses to acute and repeated administration of the dopamine indirect agonist, amphetamine. In addition we measured protein levels of tyrosine hydroxylase, and tissue levels of dopamine and its metabolites, in ventral tegmental area, susbtantia nigra, nucleus accumbens, dorsal striatum and medial prefrontal cortex. Offspring of turpentine-treated mothers exhibited greater responses to a single amphetamine injection and enhanced behavioral sensitization following repeated exposure to this drug, when compared to control offspring. These behavioral changes were accompanied by increased baseline levels of tyrosine hydroxylase, dopamine and its metabolites, selectively in the nucleus accumbens. Both, the behavioral and neurochemical changes were prevented by maternal iron supplementation. Localized prenatal inflammation induced a deregulation in iron homeostasis, which resulted in fundamental alterations in dopamine function and behavioral alterations in the adult offspring. These changes are characteristic of schizophrenia symptoms in humans.

  9. Application of fast-scan cyclic voltammetry for the in vivo characterization of optically evoked dopamine in the olfactory tubercle of the rat brain.

    Science.gov (United States)

    Wakabayashi, Ken T; Bruno, Michael J; Bass, Caroline E; Park, Jinwoo

    2016-06-21

    The olfactory tubercle (OT), as a component of the ventral striatum, serves as an important multisensory integration center for reward-related processes in the brain. Recent studies show that dense dopaminergic innervation from the ventral tegmental area (VTA) into the OT may play an outsized role in disorders such as psychostimulant addiction and disorders of motivation, increasing recent scientific interest in this brain region. However, due to its anatomical inaccessibility, relative small size, and proximity to other dopamine-rich structures, neurochemical assessments using conventional methods cannot be readily employed. Here, we investigated dopamine (DA) regulation in the OT of urethane-anesthetized rats using in vivo fast-scan voltammetry (FSCV) coupled with carbon-fiber microelectrodes, following optogenetic stimulation of the VTA. The results were compared with DA regulation in the nucleus accumbens (NAc), a structure located adjacent to the OT and which also receives dense DA innervation from the VTA. FSCV coupled with optically evoked release allowed us to investigate the spatial distribution of DA in the OT and characterize OT DA dynamics (release and clearance) with subsecond temporal and micrometer spatial resolution for the first time. In this study, we demonstrated that DA transporters play an important role in regulating DA in the OT. However, the control of extracellular DA by uptake in the OT was less than in the NAc. The difference in DA transmission in the terminal fields of the OT and NAc may be involved in region-specific responses to drugs of abuse and contrasting roles in mediating reward-related behavior.

  10. Label-free dopamine imaging in live rat brain slices.

    Science.gov (United States)

    Sarkar, Bidyut; Banerjee, Arkarup; Das, Anand Kant; Nag, Suman; Kaushalya, Sanjeev Kumar; Tripathy, Umakanta; Shameem, Mohammad; Shukla, Shubha; Maiti, Sudipta

    2014-05-21

    Dopaminergic neurotransmission has been investigated extensively, yet direct optical probing of dopamine has not been possible in live cells. Here we image intracellular dopamine with sub-micrometer three-dimensional resolution by harnessing its intrinsic mid-ultraviolet (UV) autofluorescence. Two-photon excitation with visible light (540 nm) in conjunction with a non-epifluorescent detection scheme is used to circumvent the UV toxicity and the UV transmission problems. The method is established by imaging dopamine in a dopaminergic cell line and in control cells (glia), and is validated by mass spectrometry. We further show that individual dopamine vesicles/vesicular clusters can be imaged in cultured rat brain slices, thereby providing a direct visualization of the intracellular events preceding dopamine release induced by depolarization or amphetamine exposure. Our technique opens up a previously inaccessible mid-ultraviolet spectral regime (excitation ~270 nm, emission free imaging of native molecules in live tissue.

  11. 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.

  12. Role of dopamine in distal retina.

    Science.gov (United States)

    Popova, E

    2014-05-01

    Dopamine is the most abundant catecholamine in the vertebrate retina. Despite the description of retinal dopaminergic cells three decades ago, many aspects of their function in the retina remain unclear. There is no consensus among the authors about the stimulus conditions for dopamine release (darkness, steady or flickering light) as well as about its action upon the various types of retinal cells. Many contradictory results exist concerning the dopamine effect on the gross electrical activity of the retina [reflected in electroretinogram (ERG)] and the receptors involved in its action. This review summarized current knowledge about the types of the dopaminergic neurons and receptors in the retina as well as the effects of dopamine receptor agonists and antagonists on the light responses of photoreceptors, horizontal and bipolar cells in both nonmammalian and mammalian retina. Special focus of interest concerns their effects upon the diffuse ERG as a useful tool for assessment of the overall function of the distal retina. An attempt is made to reveal some differences between the dopamine actions upon the activity of the ON versus OFF channel in the distal retina. The author has included her own results demonstrating such differences.

  13. Dopamine neurons modulate neural encoding and expression of depression-related behaviour.

    Science.gov (United States)

    Tye, Kay M; Mirzabekov, Julie J; Warden, Melissa R; Ferenczi, Emily A; Tsai, Hsing-Chen; Finkelstein, Joel; Kim, Sung-Yon; Adhikari, Avishek; Thompson, Kimberly R; Andalman, Aaron S; Gunaydin, Lisa A; Witten, Ilana B; Deisseroth, Karl

    2013-01-24

    Major depression is characterized by diverse debilitating symptoms that include hopelessness and anhedonia. Dopamine neurons involved in reward and motivation are among many neural populations that have been hypothesized to be relevant, and certain antidepressant treatments, including medications and brain stimulation therapies, can influence the complex dopamine system. Until now it has not been possible to test this hypothesis directly, even in animal models, as existing therapeutic interventions are unable to specifically target dopamine neurons. Here we investigated directly the causal contributions of defined dopamine neurons to multidimensional depression-like phenotypes induced by chronic mild stress, by integrating behavioural, pharmacological, optogenetic and electrophysiological methods in freely moving rodents. We found that bidirectional control (inhibition or excitation) of specified midbrain dopamine neurons immediately and bidirectionally modulates (induces or relieves) multiple independent depression symptoms caused by chronic stress. By probing the circuit implementation of these effects, we observed that optogenetic recruitment of these dopamine neurons potently alters the neural encoding of depression-related behaviours in the downstream nucleus accumbens of freely moving rodents, suggesting that processes affecting depression symptoms may involve alterations in the neural encoding of action in limbic circuitry.

  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. 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

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

    Science.gov (United States)

    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.

  17. Dopamine and T cells: dopamine receptors and potent effects on T cells, dopamine production in T cells, and abnormalities in the dopaminergic system in T cells in autoimmune, neurological and psychiatric diseases.

    Science.gov (United States)

    Levite, M

    2016-01-01

    Dopamine, a principal neurotransmitter, deserves upgrading to 'NeuroImmunotransmitter' thanks to its multiple, direct and powerful effects on most/all immune cells. Dopamine by itself is a potent activator of resting effector T cells (Teffs), via two independent ways: direct Teffs activation, and indirect Teffs activation by suppression of regulatory T cells (Tregs). The review covers the following findings: (i) T cells express functional dopamine receptors (DRs) D1R-D5R, but their level and function are dynamic and context-sensitive, (ii) DR membranal protein levels do not necessarily correlate with DR mRNA levels, (iii) different T cell types/subtypes have different DR levels and composition and different responses to dopamine, (iv) autoimmune and pro-inflammatory T cells and T cell leukaemia/lymphoma also express functional DRs, (v) dopamine (~10(-8) M) activates resting/naive Teffs (CD8(+) >CD4(+) ), (vi) dopamine affects Th1/Th2/Th17 differentiation, (vii) dopamine inhibits already activated Teffs (i.e. T cells that have been already activated by either antigen, mitogen, anti-CD3 antibodies cytokines or other molecules), (viii) dopamine inhibits activated Tregs in an autocrine/paracrine manner. Thus, dopamine 'suppresses the suppressors' and releases the inhibition they exert on Teffs, (ix) dopamine affects intracellular signalling molecules and cascades in T cells (e.g. ERK, Lck, Fyn, NF-κB, KLF2), (x) T cells produce dopamine (Tregs>Teffs), can release dopamine, mainly after activation (by antigen, mitogen, anti-CD3 antibodies, PKC activators or other), uptake extracellular dopamine, and most probably need dopamine, (xi) dopamine is important for antigen-specific interactions between T cells and dendritic cells, (xii) in few autoimmune diseases (e.g. multiple sclerosis/SLE/rheumatoid arthritis), and neurological/psychiatric diseases (e.g. Parkinson disease, Alzheimer's disease, Schizophrenia and Tourette), patient's T cells seem to have abnormal DRs

  18. 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.

  19. Comparison of dopamine kinetics in the larval Drosophila ventral nerve cord and protocerebrum with improved optogenetic stimulation.

    Science.gov (United States)

    Privman, Eve; Venton, B Jill

    2015-11-01

    Dopamine release and uptake have been studied in the Drosophila larval ventral nerve cord (VNC) using optogenetics to stimulate endogenous release. However, other areas of the central nervous system remain uncharacterized. Here, we compare dopamine release in the VNC and protocerebrum of larval Drosophila. Stimulations were performed with CsChrimson, a new, improved, red light-activated channelrhodopsin. In both regions, dopamine release was observed after only a single, 4 ms duration light pulse. Michaelis-Menten modeling was used to understand release and uptake parameters for dopamine. The amount of dopamine released ([DA]p ) on the first stimulation pulse is higher than the average [DA]p released from subsequent pulses. The initial and average amount of dopamine released per stimulation pulse is smaller in the protocerebrum than in the VNC. The average Vmax of 0.08 μM/s in the protocerebrum was significantly higher than the Vmax of 0.05 μM/s in the VNC. The average Km of 0.11 μM in the protocerebrum was not significantly different from the Km of 0.10 μM in the VNC. When the competitive dopamine transporter (DAT) inhibitor nisoxetine was applied, the Km increased significantly in both regions while Vmax stayed the same. This work demonstrates regional differences in dopamine release and uptake kinetics, indicating important variation in the amount of dopamine available for neurotransmission and neuromodulation. We use a new optogenetic tool, red light activated CsChrimson, to stimulate the release of dopamine in the ventral nerve cord and medial protocerebrum of the larval Drosophila central nervous system. We monitored extracellular dopamine by fast scan cyclic voltammetry and used Michaelis-Menten modeling to probe the regulation of extracellular dopamine, discovering important similarities and differences in these two regions.

  20. The neurotropic parasite Toxoplasma gondii increases dopamine metabolism.

    Directory of Open Access Journals (Sweden)

    Emese Prandovszky

    Full Text Available The highly prevalent parasite Toxoplasma gondii manipulates its host's behavior. In infected rodents, the behavioral changes increase the likelihood that the parasite will be transmitted back to its definitive cat host, an essential step in completion of the parasite's life cycle. The mechanism(s responsible for behavioral changes in the host is unknown but two lines of published evidence suggest that the parasite alters neurotransmitter signal transduction: the disruption of the parasite-induced behavioral changes with medications used to treat psychiatric disease (specifically dopamine antagonists and identification of a tyrosine hydroxylase encoded in the parasite genome. In this study, infection of mammalian dopaminergic cells with T. gondii enhanced the levels of K+-induced release of dopamine several-fold, with a direct correlation between the number of infected cells and the quantity of dopamine released. Immunostaining brain sections of infected mice with dopamine antibody showed intense staining of encysted parasites. Based on these analyses, T. gondii orchestrates a significant increase in dopamine metabolism in neural cells. Tyrosine hydroxylase, the rate-limiting enzyme for dopamine synthesis, was also found in intracellular tissue cysts in brain tissue with antibodies specific for the parasite-encoded tyrosine hydroxylase. These observations provide a mechanism for parasite-induced behavioral changes. The observed effects on dopamine metabolism could also be relevant in interpreting reports of psychobehavioral changes in toxoplasmosis-infected humans.

  1. 促性腺激素释放激素及多巴胺对斜带石斑鱼生长激素分泌及其mRNA表达的调控%Stimulatory effects of gonadotropin-releasing hormone and dopamine on growth hormone release and growth hormone mRNA expression in Epinephelus coioides

    Institute of Scientific and Technical Information of China (English)

    冉雪琴; 李文笙; 林浩然

    2004-01-01

    研究斜带石斑鱼生长激素分泌及其mRNA表达的调控规律对于性别分化的控制、临床药物的选择,以及石斑鱼的增养殖等均具有重要的理论意义和实践意义.本文应用静态孵育系统,采用放射免疫测定法和化学发光液相杂交实验,研究GnRH和DA对斜带石斑鱼GH分泌、GH mRNA合成的调控作用.100 nmol/L sGnRH作用斜带石斑鱼脑垂体碎片1~24 h,明显促进GH的释放和GH mRNA的合成,并具有时间依存性;10 nmol/L~1μmol/L sGnRH作用1 h能明显促进斜带石斑鱼脑垂体释放GH,促进GH mRNA的合成,表现出明显的剂量效应.100 nmol/L、1μmol/L mGnRH作用1 h以一定的剂量依存方式促进GH的释放、促进GH mRNA的合成,但mGnRH的效应比相应剂量的sGnRH的作用弱.APO为DA受体的非选择性激动剂,不同剂量APO对斜带石斑鱼脑垂体碎片的作用结果显示,10 nmol/L~lμmol/L APO以剂量依存方式促进斜带石斑鱼脑垂体碎片释放GH、促进GH mRNA的合成;1μmol/L APO作用12 h以上明显促进GH的释放和GH mRNA的合成,并随时间的延长而增加.与sGnRH对斜带石斑鱼GH释放、GH mRNA合成的作用相比,APO的作用较弱.本文研究结果证实GnRH和DA能促进斜带石斑鱼脑垂体GH释放和GH mRNA合成.%Gonadotropin-releasing hormone (GnRH) and dopamine (DA) can stimulate growth hormone (GH) release, but their effects on GH mRNA synthesis are controversial and deficient in fish. Orange-spotted grouper (Epinephelus coioides) is a hermaphroditic marine fish with sex reversal. Few data are available concerning the regulation of GH in grouper. In the present study, the effects of GnRH and DA on GH release and GH mRNA expression were determined using pituitary fragments of orange-spotted grouper under static culture conditions. After incubation from 1 h to 24 h, salmon GnRH (sGnRH, 100 nmol/L) stimulated the release of GH and increased the level of GH mRNA time-dependently. The minimum duration of s

  2. Direct affinity of dopamine to lipid membranes investigated by Nuclear Magnetic Resonance spectroscopy.

    Science.gov (United States)

    Matam, Yashasvi; Ray, Bruce D; Petrache, Horia I

    2016-04-08

    Dopamine, a naturally occurring neurotransmitter, plays an important role in the brain's reward system and acts on sensory receptors in the brain. Neurotransmitters are contained in lipid membraned vesicles and are released by exocytosis. All neurotransmitters interact with transport and receptor proteins in glial cells, on neuronal dendrites, and at the axonal button, and also must interact with membrane lipids. However, the extent of direct interaction between lipid membranes in the absence of receptors and transport proteins has not been extensively investigated. In this report, we use UV and NMR spectroscopy to determine the affinity and the orientation of dopamine interacting with lipid vesicles made of either phosphatidylcholine (PC) or phosphatidylserine (PS) lipids which are primary lipid components of synaptic vesicles. We quantify the interaction of dopamine's aromatic ring with lipid membranes using our newly developed method that involves reference spectra in hydrophobic environments. Our measurements show that dopamine interacts with lipid membranes primarily through the aromatic side opposite to the hydroxyl groups, with this aromatic side penetrating deeper into the hydrophobic region of the membrane. Since dopamine's activity involves its release into extracellular space, we have used our method to also investigate dopamine's release from lipid vesicles. We find that dopamine trapped inside PC and PS vesicles is released into the external solution despite its affinity to membranes. This result suggests that dopamine's interaction with lipid membranes is complex and involves both binding as well as permeation through lipid bilayers, a combination that could be an effective trigger for apoptosis of dopamine-generating cells.

  3. De novo mutation in the dopamine transporter gene associates dopamine dysfunction with autism spectrum disorder

    DEFF Research Database (Denmark)

    Hamilton, P J; Campbell, N G; Sharma, S

    2013-01-01

    De novo genetic variation is an important class of risk factors for autism spectrum disorder (ASD). Recently, whole-exome sequencing of ASD families has identified a novel de novo missense mutation in the human dopamine (DA) transporter (hDAT) gene, which results in a Thr to Met substitution...... at site 356 (hDAT T356M). The dopamine transporter (DAT) is a presynaptic membrane protein that regulates dopaminergic tone in the central nervous system by mediating the high-affinity reuptake of synaptically released DA, making it a crucial regulator of DA homeostasis. Here, we report the first...

  4. 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.

  5. Dopamins renale virkninger

    DEFF Research Database (Denmark)

    Olsen, Niels Vidiendal

    1990-01-01

    Dopamine is an endogenic catecholamine which, in addition to being the direct precursor of noradrenaline, has also an effect on peripheral dopaminergic receptors. These are localized mainly in the heart, splanchnic nerves and the kidneys. Dopamine is produced in the kidneys and the renal metaboli...... dialysis unnecessary in a number of patients on account of increased diuresis and natriuresis. The effect of GFR and the significance for the prognosis are not known....

  6. Behavioral expression of opiate withdrawal is altered after prefrontocortical dopamine depletion in rats: monoaminergic correlates.

    Science.gov (United States)

    Espejo, E F; Serrano, M I; Caillé, S; Stinus, L

    2001-08-01

    The objective of this study was to establish the effects of prefrontocortical dopamine depletion on opiate withdrawal and prefrontocortical neurochemical changes elicited by morphine dependence and withdrawal. The dopaminergic content was also measured in the nucleus accumbens during withdrawal, in order to detect reactive changes induced by prefrontocortical lesion. Withdrawal was induced by naloxone in morphine-dependent rats. Monoamine levels were analyzed post-mortem by high performance liquid cromatography. The results showed that chronic morphine dependence did not modify basal levels of monoamines in sham rats, revealing neuroadaptation of prefrontocortical dopamine, noradrenaline and serotonin systems to chronic morphine. The neuroadaptive phenomenon remained after prefrontocortical lesion (> 79% dopamine depletion). On the other hand, a strong increase of dopamine, noradrenaline, and serotonin contents in the medial prefrontal cortex of sham rats was detected during opiate withdrawal. However, in lesioned rats, the increase of prefrontocortical dopamine and serotonin content, but not that of noradrenaline, was much lower. In the nucleus accumbens, prefrontocortical lesion reactively enhanced the dopaminergic tone and, although opiate withdrawal reduced dopaminergic activity in both sham and lesioned rats, this reduction was less intense in the latter group. At a behavioral level, some symptoms of physical opiate withdrawal were exacerbated in lesioned rats (writhing, mastication, teeth-chattering, global score) and exploration was reduced. The findings hence indicate that: (i) prefrontocortical monoaminergic changes play a role in the behavioral expression of opiate withdrawal; (ii) the severity of some withdrawal signs are related to the dopaminergic and serotonergic tone of the medial prefrontal cortex rather than to the noradrenergic one, and (iii) an inverse relationship between mesocortical and mesolimbic dopaminergic systems exists.

  7. Effects of the histamine H₁ receptor antagonist and benztropine analog diphenylpyraline on dopamine uptake, locomotion and reward.

    Science.gov (United States)

    Oleson, Erik B; Ferris, Mark J; España, Rodrigo A; Harp, Jill; Jones, Sara R

    2012-05-15

    Diphenylpyraline hydrochloride (DPP) is an internationally available antihistamine that produces therapeutic antiallergic effects by binding to histamine H₁ receptors. The complete neuropharmacological and behavioral profile of DPP, however, remains uncharacterized. Here we describe studies that suggest DPP may fit the profile of a potential agonist replacement medication for cocaine addiction. Aside from producing the desired histamine reducing effects, many antihistamines can also elicit psychomotor activation and reward, both of which are associated with increased dopamine concentrations in the nucleus accumbens (NAc). The primary aim of this study was to investigate the potential ability of DPP to inhibit the dopamine transporter, thereby leading to elevated dopamine concentrations in the NAc in a manner similar to cocaine and other psychostimulants. The psychomotor activating and rewarding effects of DPP were also investigated. For comparative purposes cocaine, a known dopamine transporter inhibitor, psychostimulant and drug of abuse, was used as a positive control. As predicted, both cocaine (15 mg/kg) and an equimolar dose of DPP (14 mg/kg) significantly inhibited dopamine uptake in the NAc in vivo and produced locomotor activation, although the time-course of pharmacological effects of the two drugs was different. In comparison to cocaine, DPP showed a prolonged effect on dopamine uptake and locomotion. Furthermore, cocaine, but not DPP, produced significant conditioned place preference, a measure of drug reward. The finding that DPP functions as a potent dopamine uptake inhibitor without producing significant rewarding effects suggests that DPP merits further study as a potential candidate as an agonist pharmacotherapy for cocaine addiction.

  8. Evaluating Dopamine Reward Pathway in ADHD; clinical implications

    Energy Technology Data Exchange (ETDEWEB)

    Volkow, N.D.; Wang, G.; Volkow, N.D.; Wang, G.-J.; Kollins, S.H., Wigal, t.L.; Newcorn, J.H.; Telang, F.; Fowler, J.S.; Zhu, W.; Logan, J.; Ma, Y.; Pradhan, K.; Wong, C.T.; Swanson, J.M.

    2009-09-09

    Attention-deficit/hyperactivity disorder (ADHD) - characterized by symptoms of inattention and hyperactivity-impulsivity - is the most prevalent childhood psychiatric disorder that frequently persists into adulthood, and there is increasing evidence of reward-motivation deficits in this disorder. To evaluate biological bases that might underlie a reward/motivation deficit by imaging key components of the brain dopamine reward pathway (mesoaccumbens). We used positron emission tomography to measure dopamine synaptic markers (transporters and D{sub 2}/D{sub 3} receptors) in 53 nonmedicated adults with ADHD and 44 healthy controls between 2001-2009 at Brookhaven National Laboratory. We measured specific binding of positron emission tomographic radioligands for dopamine transporters (DAT) using [{sup 11}C]cocaine and for D{sub 2}/D{sub 3} receptors using [{sup 11}C]raclopride, quantified as binding potential (distribution volume ratio -1). For both ligands, statistical parametric mapping showed that specific binding was lower in ADHD than in controls (threshold for significance set at P < .005) in regions of the dopamine reward pathway in the left side of the brain. Region-of-interest analyses corroborated these findings. The mean (95% confidence interval [CI] of mean difference) for DAT in the nucleus accumbens for controls was 0.71 vs 0.63 for those with ADHD (95% CI, 0.03-0.13, P = .004) and in the midbrain for controls was 0.16 vs 0.09 for those with ADHD (95% CI, 0.03-0.12; P {le} .001); for D{sub 2}/D{sub 3} receptors, the mean accumbens for controls was 2.85 vs 2.68 for those with ADHD (95% CI, 0.06-0.30, P = .004); and in the midbrain, it was for controls 0.28 vs 0.18 for those with ADHD (95% CI, 0.02-0.17, P = .01). The analysis also corroborated differences in the left caudate: the mean DAT for controls was 0.66 vs 0.53 for those with ADHD (95% CI, 0.04-0.22; P = .003) and the mean D{sub 2}/D{sub 3} for controls was 2.80 vs 2.47 for those with ADHD (95% CI, 0

  9. Repeated stressful experiences differently affect brain dopamine receptor subtypes

    Energy Technology Data Exchange (ETDEWEB)

    Puglisi-Allegra, S.; Cabib, S. (Istituto di Psicobiologia e Psicofarmacologia (CNR), Roma (Italy)); Kempf, E.; Schleef, C. (Centre de Neurochimi, Strasbourg (Italy))

    1991-01-01

    The binding of tritiated spiperone (D2 antagonist) and tritiated SCH 23390 (D1 antagonist), in vivo, was investigated in the caudatus putamen (CP) and nucleus accumbens septi (NAS) of mice submitted to ten daily restraint stress sessions. Mice sacrificed 24 hr after the last stressful experience presented a 64% decrease of D2 receptor density (Bmax) but no changes in D1 receptor density in the NAS. In the CP a much smaller (11%) reduction of D2 receptor density was accompanied by a 10% increase of D1 receptors. These results show that the two types of dopamine (DA) receptors adapt in different or even opposite ways to environmental pressure, leading to imbalance between them.

  10. 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 ...

  11. Striatal dopamine D1 and D2 receptors: widespread influences on methamphetamine-induced dopamine and serotonin neurotoxicity.

    Science.gov (United States)

    Gross, Noah B; Duncker, Patrick C; Marshall, John F

    2011-11-01

    Methamphetamine (mAMPH) is an addictive psychostimulant drug that releases monoamines through nonexocytotic mechanisms. In animals, binge mAMPH dosing regimens deplete markers for monoamine nerve terminals, for example, dopamine and serotonin transporters (DAT and SERT), in striatum and cerebral cortex. Although the precise mechanism of mAMPH-induced damage to monoaminergic nerve terminals is uncertain, both dopamine D1 and D2 receptors are known to be important. Systemic administration of dopamine D1 or D2 receptor antagonists to rodents prevents mAMPH-induced damage to striatal dopamine nerve terminals. Because these studies employed systemic antagonist administration, the specific brain regions involved remain to be elucidated. The present study examined the contribution of dopamine D1 and D2 receptors in striatum to mAMPH-induced DAT and SERT neurotoxicities. In this experiment, either the dopamine D1 antagonist, SCH23390, or the dopamine D2 receptor antagonist, sulpiride, was intrastriatally infused during a binge mAMPH regimen. Striatal DAT and cortical, hippocampal, and amygdalar SERT were assessed as markers of mAMPH-induced neurotoxicity 1 week following binge mAMPH administration. Blockade of striatal dopamine D1 or D2 receptors during an otherwise neurotoxic binge mAMPH regimen produced widespread protection against mAMPH-induced striatal DAT loss and cortical, hippocampal, and amygdalar SERT loss. This study demonstrates that (1) dopamine D1 and D2 receptors in striatum, like nigral D1 receptors, are needed for mAMPH-induced striatal DAT reductions, (2) these same receptors are needed for mAMPH-induced SERT loss, and (3) these widespread influences of striatal dopamine receptor antagonists are likely attributable to circuits connecting basal ganglia to thalamus and cortex.

  12. Projection-Target-Defined Effects of Orexin and Dynorphin on VTA Dopamine Neurons

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    Corey Baimel

    2017-02-01

    Full Text Available Circuit-specific signaling of ventral tegmental area (VTA dopamine neurons drives different aspects of motivated behavior, but the neuromodulatory control of these circuits is unclear. We tested the actions of co-expressed lateral hypothalamic peptides, orexin A (oxA and dynorphin (dyn, on projection-target-defined dopamine neurons in mice. We determined that VTA dopamine neurons that project to the nucleus accumbens lateral shell (lAcbSh, medial shell (mAcbSh, and basolateral amygdala (BLA are largely non-overlapping cell populations with different electrophysiological properties. Moreover, the neuromodulatory effects of oxA and dyn on these three projections differed. OxA selectively increased firing in lAcbSh- and mAcbSh-projecting dopamine neurons. Dyn decreased firing in the majority of mAcbSh- and BLA-projecting dopamine neurons but reduced firing only in a small fraction of those that project to the lAcbSh. In conclusion, the oxA-dyn input to the VTA may drive reward-seeking behavior by tuning dopaminergic output in a projection-target-dependent manner.

  13. A Physical Interaction between the Dopamine Transporter and DJ-1 Facilitates Increased Dopamine Reuptake.

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    Beryl Luk

    Full Text Available The regulation of the dopamine transporter (DAT impacts extracellular dopamine levels after release from dopaminergic neurons. Furthermore, a variety of protein partners have been identified that can interact with and modulate DAT function. In this study we show that DJ-1 can potentially modulate DAT function. Co-expression of DAT and DJ-1 in HEK-293T cells leads to an increase in [3H] dopamine uptake that does not appear to be mediated by increased total DAT expression but rather through an increase in DAT cell surface localization. In addition, through a series of GST affinity purifications and co-immunoprecipitations, we provide evidence that the DAT can be found in a complex with DJ-1, which involve distinct regions within both DAT and DJ-1. Using in vitro binding experiments we also show that this complex can be formed in part by a direct interaction between DAT and DJ-1. Co-expression of a mini-gene that can disrupt the DAT/DJ-1 complex appears to block the increase in [3H] dopamine uptake by DJ-1. Mutations in DJ-1 have been linked to familial forms of Parkinson's disease, yet the normal physiological function of DJ-1 remains unclear. Our study suggests that DJ-1 may also play a role in regulating dopamine levels by modifying DAT activity.

  14. Drug seeking under a second-order schedule of reinforcement depends on dopamine D3 receptors in the basolateral amygdala.

    Science.gov (United States)

    Di Ciano, Patricia

    2008-02-01

    Drug seeking under the control of drug-associated stimuli and its reinstatement after extinction can be decreased by systemic administration of dopamine D3 receptor antagonists. It is demonstrated that responding by rats on the active lever for cocaine under a 2nd-order schedule of reinforcement, under which responding is maintained by response-contingent cocaine-paired conditioned reinforcers, is markedly attenuated by infusion of the dopamine D3 receptor antagonist SB-277011-A into the amygdala (2 and 4 microg/0.3 microl). By contrast, infusions of SB-277011-A into the shell subregion of the nucleus accumbens and also into the dorsal striatum were without effect. These results show that the control over drug seeking by conditioned reinforcers depends on D3 receptor-dependent dopamine transmission in the amygdala.

  15. Dopamine, hypertension and obesity.

    Science.gov (United States)

    Contreras, F; Fouillioux, C; Bolívar, A; Simonovis, N; Hernández-Hernández, R; Armas-Hernandez, M J; Velasco, M

    2002-03-01

    Dopamine, a neurotransmitter, precursor of noradrenaline, is responsible for cardiovascular and renal actions, such as increase in myocardial contractility and cardiac output, without changes in heart rate, producing passive and active vasodilatation, diuresis and natriuresis. These cardiovascular and renal actions take place through the interaction with dopamine receptors, D(1), D(2), D(3), D(4), and D(5). Recent findings point to the possibility of D(6) and D(7)receptors. Dopamine is known to influence the control of arterial pressure by influencing the central and peripheral nervous system and target organs such as kidneys and adrenal glands, in some types of hypertension. Although dopamine and its derivatives have been shown to have antihypertensive effects, these are still being studied; therefore it is important to explain some physiological and pharmacological aspects of dopamine, its receptors, and the clinical uses it could have in the treatment of arterial hypertension and more recently in obesity, based on evidence proving a clear association between obesity and the decrease in the expression of D(2) receptors in the brain of obese persons.

  16. Postendocytic sorting of constitutively internalized dopamine transporter in cell lines and dopaminergic neurons

    DEFF Research Database (Denmark)

    Eriksen, Jacob; Bjørn-Yoshimoto, Walden Emil; Jørgensen, Trine Nygaard;

    2010-01-01

    The dopamine transporter (DAT) mediates reuptake of released dopamine and is the target for psychostimulants, such as cocaine and amphetamine. DAT undergoes marked constitutive endocytosis, but little is known about the fate and sorting of the endocytosed transporter. To study DAT sorting in cell...

  17. Intrinsic vascular dopamine - a key modulator of hypoxia-induced vasodilatation in splanchnic vessels.

    Science.gov (United States)

    Pfeil, Uwe; Kuncova, Jitka; Brüggmann, Doerthe; Paddenberg, Renate; Rafiq, Amir; Henrich, Michael; Weigand, Markus A; Schlüter, Klaus-Dieter; Mewe, Marco; Middendorff, Ralf; Slavikova, Jana; Kummer, Wolfgang

    2014-04-15

    Dopamine not only is a precursor of the catecholamines noradrenaline and adrenaline but also serves as an independent neurotransmitter and paracrine hormone. It plays an important role in the pathogenesis of hypertension and is a potent vasodilator in many mammalian systemic arteries, strongly suggesting an endogenous source of dopamine in the vascular wall. Here we demonstrated dopamine, noradrenaline and adrenaline in rat aorta and superior mesenteric arteries (SMA) by radioimmunoassay. Chemical sympathectomy with 6-hydroxydopamine showed a significant reduction of noradrenaline and adrenaline, while dopamine levels remained unaffected. Isolated endothelial cells were able to synthesize and release dopamine upon cAMP stimulation. Consistent with these data, mRNAs coding for catecholamine synthesizing enzymes, i.e. tyrosine hydroxylase (TH), aromatic l-amino acid decarboxylase, and dopamine-β-hydroxylase were detected by RT-PCR in cultured endothelial cells from SMA. TH protein was detected by immunohistochemisty and Western blot. Exposure of endothelial cells to hypoxia (1% O2) increased TH mRNA. Vascular smooth muscle cells partially expressed catecholaminergic traits. A physiological role of endogenous vascular dopamine was shown in SMA, where D1 dopamine receptor blockade abrogated hypoxic vasodilatation. Experiments on SMA with endothelial denudation revealed a significant contribution of the endothelium, although subendothelial dopamine release dominated. From these results we conclude that endothelial cells and cells of the underlying vascular wall synthesize and release dopamine in an oxygen-regulated manner. In the splanchnic vasculature, this intrinsic non-neuronal dopamine is the dominating vasodilator released upon lowering of oxygen tension.

  18. Testosterone induces molecular changes in dopamine signaling pathway molecules in the adolescent male rat nigrostriatal pathway.

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    Tertia D Purves-Tyson

    Full Text Available Adolescent males have an increased risk of developing schizophrenia, implicating testosterone in the precipitation of dopamine-related psychopathology. Evidence from adult rodent brain indicates that testosterone can modulate nigrostriatal dopamine. However, studies are required to understand the role testosterone plays in maturation of dopamine pathways during adolescence and to elucidate the molecular mechanism(s by which testosterone exerts its effects. We hypothesized that molecular indices of dopamine neurotransmission [synthesis (tyrosine hydroxylase, breakdown (catechol-O-methyl transferase; monoamine oxygenase, transport [vesicular monoamine transporter (VMAT, dopamine transporter (DAT] and receptors (DRD1-D5] would be changed by testosterone or its metabolites, dihydrotestosterone and 17β-estradiol, in the nigrostriatal pathway of adolescent male rats. We found that testosterone and dihydrotestosterone increased DAT and VMAT mRNAs in the substantia nigra and that testosterone increased DAT protein at the region of the cell bodies, but not in target regions in the striatum. Dopamine receptor D2 mRNA was increased and D3 mRNA was decreased in substantia nigra and/or striatum by androgens. These data suggest that increased testosterone at adolescence may change dopamine responsivity of the nigrostriatal pathway by modulating, at a molecular level, the capacity of neurons to transport and respond to dopamine. Further, dopamine turnover was increased in the dorsal striatum following gonadectomy and this was prevented by testosterone replacement. Gene expression changes in the dopaminergic cell body region may serve to modulate both dendritic dopamine feedback inhibition and reuptake in the dopaminergic somatodendritic field as well as dopamine release and re-uptake dynamics at the presynaptic terminals in the striatum. These testosterone-induced changes of molecular indices of dopamine neurotransmission in males are primarily androgen

  19. Increased dopamine tone during meditation-induced change of consciousness

    DEFF Research Database (Denmark)

    Kjaer, Troels W; Bertelsen, Camilla; Piccini, Paola

    2002-01-01

    This is the first in vivo demonstration of an association between endogenous neurotransmitter release and conscious experience. Using 11C-raclopride PET we demonstrated increased endogenous dopamine release in the ventral striatum during Yoga Nidra meditation. Yoga Nidra is characterized by a dep......This is the first in vivo demonstration of an association between endogenous neurotransmitter release and conscious experience. Using 11C-raclopride PET we demonstrated increased endogenous dopamine release in the ventral striatum during Yoga Nidra meditation. Yoga Nidra is characterized...... by a depressed level of desire for action, associated with decreased blood flow in prefrontal, cerebellar and subcortical regions, structures thought to be organized in open loops subserving executive control. In the striatum, dopamine modulates excitatory glutamatergic synapses of the projections from...... the frontal cortex to striatal neurons, which in turn project back to the frontal cortex via the pallidum and ventral thalamus. The present study was designed to investigate whether endogenous dopamine release increases during loss of executive control in meditation. Participants underwent two 11C...

  20. 埃他卡林通过上调Kir6.1和Kir6.2 mRNA表达抑制可卡因激发诱导的大鼠纹状体和伏隔核多巴胺水平的增加%Iptkalim inhibits cocaine challenge-induced enhancement of dopamine levels in nucleus accumbens and striatum of rats by up-regulating Kir6.1 and Kir6.2 mRNA expression

    Institute of Scientific and Technical Information of China (English)

    刘昀; 何海蓉; 丁建花; 顾兵; 汪海; 胡刚

    2003-01-01

    AIM: To investigate the effect and mechanism of novel ATP-sensitive potassium channel opener (KCO) iptkalim(IPT) on acute and cocaine challenge-induced alterations in the levels of dopamine (DA) and glutamate (Glu) fromnucleus accumbens (NAc), striatum, and prefrontal cortex (PFC) in rats. METHODS: The levels of DA and Gluwere assayed using high performance liquid chromatography (HPLC) combined with amperometric and fluores-cent detection, respectively. The mRNA levels of Kir6.1, Kir6.2, SUR1, and SUR2 were measured by semiquantitativereverse transcription polymerase chain reaction (RT-PCR). RESULTS: IPT did not affect acute cocaine (30 mg/kg, ip)-induced elevations in either DA levels from NAc and striatum or Glu levels from NAc and PFC. An acutecocaine challenge (30 mg/kg, ip) on d 21 after withdrawal caused an elevation in DA levels in NAc and striatum.Moreover, the same treatment also increased Glu levels in PFC and NAc of cocaine-pretreated rats. Repeated IPTinjections reversed cocaine challenge-induced DA increase in NAc and striatum. Cocaine challenge increasedKir6.1 and Kir6.2 mRNA expression in striatum and NAc and only elevate Kir6.2 expression in PFC in both cocaine-pretreated rats and rats pretreated with IPT plus cocaine. Moreover, expression of Kir6.1 and Kir6.2 mRNA wasaugmented in rats pretreated with IPT plus cocaine compared to rats pretreated with cocaine alone. No significantchange was found in the SUR1 and SUR2 expression of all four groups. CONCLUSION: IPT inhibited cocainechallenge-induced enhancement of DA levels in NAc and striatum by up-regulating Kir6.1 and Kir6.2 mRNAexpression.%目的:研究钾通道开放剂埃他卡林对急慢性可卡因应用引起的伏隔核、纹状体和额叶皮层的多巴胺和谷氨酸水平变化的影响及其机制.方法:采用高效液相色谱与电化学检测、荧光检测联用的方法测定各脑区谷氨酸和多巴胺的含量;采用半定量逆转录聚合酶链反应(RT-PCR)研究ATP

  1. 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.

  2. Characterization of actions of dopamine in the pituitary of the goldfish, Carassius auratus

    Energy Technology Data Exchange (ETDEWEB)

    Omeljaniuk, R.J.

    1988-01-01

    The dopamine receptor in the goldfish (Carassius auratus) pituitary and its involvement with inhibition of gonadotropin (GtH) and {alpha}-melanocyte stimulating hormone ({alpha}-MSH) release was studied. In vitro dopamine, in a dose-related manner, inhibited spontaneous GtH and {alpha}-MSH release from superfused fragments of pars distalis (PD) and neurointermediate lob (NIL), respectively; dopamine also inhibited sGnRH-A stimulation of GtH release. Thyrotropin releasing-hormone (TRH), in a dose-related manner, stimulated {alpha}-MSH release from NIL fragments; dopamine inhibited TRH action. The stereoisomers of apomorphine were equivalent in inhibiting GtH and {alpha}-MSH release from fragments treated with releasing factors. Domperidone, in a dose-related manner, antagonized dopamine action. ({sup 3}H)-Spiperone was used to radiolabel the goldfish pituitary dopamine receptor in vitro. The binding of ({sup 3}H)-spiperone had the characteristics of a receptor: tissue specificity, dependence on tissue quantity, reversibility, saturability, displaceability, specificity of binding with various drugs and a correlation of binding with biological effects were demonstrated. This is a low-affinity, high-capacity receptor which does not show binding stereoselectivity for apomorphine; domperidone binds avidly to this receptor. The NIL contains significantly greater numbers of this receptor compared to the PD.

  3. Autoradiography of dopamine receptors and dopamine uptake sites in the spontaneously hypertensive rat

    Energy Technology Data Exchange (ETDEWEB)

    Kujirai, K.; Przedborski, S.; Kostic, V.; Jackson-Lewis, V.; Fahn, S.; Cadet, J.L. (Columbia Univ., New York, NY (USA))

    1990-11-01

    We examined the status of dopamine (DA) D1 and D2 receptors by using (3H)SCH 23390 and (3H)spiperone binding, respectively, and DA uptake sites by using (3H)mazindol binding in spontaneously hypertensive rats (SHR) and Sprague-Dawley (SD) rats. SHR showed significantly higher (3H)SCH 23390 and (3H)spiperone binding in the caudate-putamen (CPu), the nucleus accumbens (NAc) and the olfactory tubercle (OT) in comparison to the SD rats. There were no significant differences in (3H)mazindol-labeled DA uptake sites between the two strains. Unilateral 6-hydroxydopamine (6-OHDA) injection into the striatum resulted in more than 90% depletion of DA uptake sites in the CPu in both strains. 6-OHDA-induced DA depletion was associated with significant increases in striatal (3H)spiperone binding which were of similar magnitude in the SD rats (+64.1%) and SHR (+51.3%). There were only small decreases (-5.4%) in D1 receptor binding in the dorsolateral aspect of the CPu in the SHR, whereas there were no changes in striatal D1 receptors in the SD rats. These results indicate that, although the SHR have higher concentrations of both D1 and D2 receptors in the basal ganglia, these receptors are regulated in a fashion similar to DA receptors in SD rats after 6-OHDA-induced striatal DA depletion.

  4. Dopamine and anorexia nervosa.

    Science.gov (United States)

    Södersten, P; Bergh, C; Leon, M; Zandian, M

    2016-01-01

    We have suggested that reduced food intake increases the risk for anorexia nervosa by engaging mesolimbic dopamine neurons, thereby initially rewarding dieting. Recent fMRI studies have confirmed that dopamine neurons are activated in anorexia nervosa, but it is not clear whether this response is due to the disorder or to its resulting nutritional deficit. When the body senses the shortage of nutrients, it rapidly shifts behavior toward foraging for food as a normal physiological response and the mesolimbic dopamine neurons may be involved in that process. On the other hand, the altered dopamine status of anorexics has been suggested to result from a brain abnormality that underlies their complex emotional disorder. We suggest that the outcomes of the treatments that emerge from that perspective remain poor because they target the mental symptoms that are actually the consequences of the food deprivation that accompanies anorexia. On the other hand, a method that normalizes the disordered eating behavior of anorexics results in much better physiological, behavioral, and emotional outcomes.

  5. Dopamine receptor gene expression by enkephalin neurons in rat forebrain

    Energy Technology Data Exchange (ETDEWEB)

    Le Moine, C.; Normand, E.; Guitteny, A.F.; Fouque, B.; Teoule, R.; Bloch, B. (Universite de Bordeaux II (France))

    1990-01-01

    In situ hybridization experiments were performed with brain sections from normal, control and haloperidol-treated rats to identify and map the cells expressing the D2 dopamine receptor gene. D2 receptor mRNA was detected with radioactive or biotinylated oligonucleotide probes. D2 receptor mRNA was present in glandular cells of the pituitary intermediate lobe and in neurons of the substantia nigra, ventral tegmental area, and forebrain, especially in caudate putamen, nucleus accumbens, olfactory tubercle, and piriform cortex. Hybridization with D2 and preproenkephalin A probes in adjacent sections, as well as combined hybridization with the two probes in the same sections, demonstrated that all detectable enkephalin neurons in the striatum contained the D2 receptor mRNA. Large neurons in caudate putamen, which were unlabeled with the preproenkephalin A probe and which may have been cholinergic, also expressed the D2 receptor gene. Haloperidol treatment (14 or 21 days) provoked an increase in mRNA content for D2 receptor and preproenkephalin A in the striatum. This suggests that the increase in D2 receptor number observed after haloperidol treatment is due to increased activity of the D2 gene. These results indicate that in the striatum, the enkephalin neurons are direct targets for dopamine liberated from mesostriatal neurons.

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

    Science.gov (United States)

    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.

  7. Effects of dopamine on adenylyl cyclase activity and amylase secretion in rat parotid tissue.

    Science.gov (United States)

    Hatta, S; Amemiya, N; Takemura, H; Ohshika, H

    1995-06-01

    Several previous studies have shown that dopamine causes amylase secretion from rat parotid tissue. However, the mechanism of this dopamine action is still unclear. The present study was designed to characterize dopamine action in rat parotid gland tissue by examining the effects of dopamine on cyclic AMP accumulation, adenylyl cyclase activity, and amylase release. Dopamine significantly enhanced accumulation of cyclic AMP in parotid slices and stimulated adenylyl cyclase activity in parotid membrane preparations. It also significantly stimulated amylase release from parotid slices. The stimulatory effects of dopamine on cyclic AMP accumulation, adenylyl cyclase activity, and amylase release were effectively blocked with propranolol, a beta-adrenergic antagonist, but not by either SCH 23390, a preferential D1 antagonist, or butaclamol, a preferential D2 antagonist. No substantial specific binding sites for D1 receptors were detectable by [3H]SCH 23390 binding in parotid membranes. These results suggest that the stimulatory effect of dopamine on amylase secretion in rat parotid tissue is not mediated through specific D1 dopamine receptors but rather through beta-adrenergic receptors.

  8. Terminal effects of optogenetic stimulation on dopamine dynamics in rat striatum.

    Science.gov (United States)

    Bass, Caroline E; Grinevich, Valentina P; Kulikova, Alexandra D; Bonin, Keith D; Budygin, Evgeny A

    2013-04-15

    In this study, the first in-depth analysis of optically induced dopamine release using fast-scan cyclic voltammetry on striatal slices from rat brain was performed. An adeno-associated virus that expresses Channelrhodopsin-2 was injected in the substantia nigra. Tissue was collected and sectioned into 400μm-thick coronal slices 4 weeks later. Blue laser light (473nm) was delivered through a fiber optic inserted into slice tissue. Experiments revealed some difference between maximal amplitudes measured from optically and electrically evoked dopamine effluxes. Specifically, there was an increase in the amplitude of dopamine release induced by electrical stimulation in comparison with light stimulations. However, we found that dopamine release is more sensitive to changes in the pulse width in the case of optical stimulation. Light-stimulated dopamine was increased as the stimulation pulse widened. There was no difference with repeated stimulations at five minute intervals between stimulation sources and dopamine signal was stable during recording sessions, while one minute intervals resulted in a decline in the amplitude from both sources. Optical stimulation can also produce an artifact that is distinguishable from dopamine by the cyclic voltammogram. These results confirm that optical stimulation of dopamine is a sound approach for future pharmacological studies in slices.

  9. 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.

  10. Dopamine D3 Receptor Mediates Preadolescent Stress-Induced Adult Psychiatric Disorders.

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    Joon H Seo

    Full Text Available Several studies have shown that repeated stressful experiences during childhood increases the likelihood of developing depression- and anxiety-related disorders in adulthood; however, the underlying mechanisms are not well understood. We subjected drd3-EGFP and drd3-null mice to daily, two hour restraint stress episodes over a five day period during preadolescence (postnatal day 35 to 39, followed by social isolation. When these mice reached adulthood (post-natal day > 90, we assessed locomotor behavior in a novel environment, and assessed depression-related behavior in the Porsolt Forced Swim test. We also measured the expression and function of dopamine D3 receptor in limbic brain areas such as hippocampus, nucleus accumbens and amygdala in control and stressed drd3-EGFP mice in adulthood. Adult male mice subjected to restraint stress during preadolescence exhibited both anxiety- and depression-related behaviors; however, adult female mice subjected to preadolescent restraint stress exhibited only depression-related behaviors. The development of preadolescent stress-derived psychiatric disorders was blocked by D3 receptor selective antagonist, SB 277011-A, and absent in D3 receptor null mice. Adult male mice that experienced stress during preadolescence exhibited a loss of D3 receptor expression and function in the amygdala but not in hippocampus or nucleus accumbens. In contrast, adult female mice that experienced preadolescent stress exhibited increased D3 receptor expression in the nucleus accumbens but not in amygdala or hippocampus. Our results suggest that the dopamine D3 receptor is centrally involved in the etiology of adult anxiety- and depression-related behaviors that arise from repeated stressful experiences during childhood.

  11. Dopamine D3 Receptor Mediates Preadolescent Stress-Induced Adult Psychiatric Disorders.

    Science.gov (United States)

    Seo, Joon H; Kuzhikandathil, Eldo V

    2015-01-01

    Several studies have shown that repeated stressful experiences during childhood increases the likelihood of developing depression- and anxiety-related disorders in adulthood; however, the underlying mechanisms are not well understood. We subjected drd3-EGFP and drd3-null mice to daily, two hour restraint stress episodes over a five day period during preadolescence (postnatal day 35 to 39), followed by social isolation. When these mice reached adulthood (post-natal day > 90), we assessed locomotor behavior in a novel environment, and assessed depression-related behavior in the Porsolt Forced Swim test. We also measured the expression and function of dopamine D3 receptor in limbic brain areas such as hippocampus, nucleus accumbens and amygdala in control and stressed drd3-EGFP mice in adulthood. Adult male mice subjected to restraint stress during preadolescence exhibited both anxiety- and depression-related behaviors; however, adult female mice subjected to preadolescent restraint stress exhibited only depression-related behaviors. The development of preadolescent stress-derived psychiatric disorders was blocked by D3 receptor selective antagonist, SB 277011-A, and absent in D3 receptor null mice. Adult male mice that experienced stress during preadolescence exhibited a loss of D3 receptor expression and function in the amygdala but not in hippocampus or nucleus accumbens. In contrast, adult female mice that experienced preadolescent stress exhibited increased D3 receptor expression in the nucleus accumbens but not in amygdala or hippocampus. Our results suggest that the dopamine D3 receptor is centrally involved in the etiology of adult anxiety- and depression-related behaviors that arise from repeated stressful experiences during childhood.

  12. Levodopa therapy: consequences of the nonphysiologic replacement of dopamine.

    Science.gov (United States)

    Chase, T N

    1998-05-01

    Normal motor function is dependent on the highly regulated synthesis and release of the transmitter dopamine by neurons projecting from the substantia nigra to the corpus striatum. Parkinson's disease involves the progressive degeneration of these neurons. Its core symptoms are a direct consequence of a striatal insufficiency of intrasynaptic dopamine. Levodopa, the standard of care for the treatment of PD, acts after its conversion to dopamine by restoring striatal dopaminergic transmission. However, there are significant differences between the normally functioning dopamine system and the restoration of function provided by standard levodopa treatment. Increasing clinical and preclinical evidence suggests that the intermittent stimulation of dopamine receptors resulting from current therapeutic regimens contributes to the response complications that ultimately affect most parkinsonian patients. It now appears that chronic nonphysiologic stimulation of dopaminergic receptors on striatal GABAergic neurons activates characteristic signaling pathways, leading to a potentiation of the synaptic efficacy of adjacent glutamatergic receptors of the N-methyl-D-aspartate (NMDA) subtype. As a result, function of these GABAergic efferent neurons changes in ways that favor the appearance of motor complications. Conceivably, use of dopaminomimetic replacement strategies that provide more continuous dopamine receptor stimulation will act to prevent or alleviate these disabling complications. A number of promising approaches to achieving this goal are now under development.

  13. Differential effects of dopamine-directed treatments on cognition

    Directory of Open Access Journals (Sweden)

    Ashby FG

    2015-07-01

    Full Text Available F Gregory Ashby, Vivian V Valentin, Stella S von Meer Department of Psychological and Brain Sciences, University of California, Santa Barbara, CA, USA Abstract: Dopamine, a prominent neuromodulator, is implicated in many neuropsychiatric disorders. It has wide-ranging effects on both cortical and subcortical brain regions and on many types of cognitive tasks that rely on a variety of different learning and memory systems. As neuroscience and behavioral evidence for the existence of multiple memory systems and their corresponding neural networks accumulated, so did the notion that dopamine’s role is markedly different depending on which memory system is engaged. As a result, dopamine-directed treatments will have different effects on different types of cognitive behaviors. To predict what these effects will be, it is critical to understand: which memory system is mediating the behavior; the neural basis of the mediating memory system; the nature of the dopamine projections into that system; and the time course of dopamine after its release into the relevant brain regions. Consideration of these questions leads to different predictions for how changes in brain dopamine levels will affect automatic behaviors and behaviors mediated by declarative, procedural, and perceptual representation memory systems. Keywords: dopamine, cognition, memory systems, learning

  14. NEW DOPAMINE AGONISTS IN CARDIOVASCULAR THERAPY

    NARCIS (Netherlands)

    GIRBES, ARJ; VANVELDHUISEN, DJ; SMIT, AJ

    1992-01-01

    Dopamine, a naturally occurring catecholamine, has been extensively used in intensive care for many years. Dopamine stimulates different types of adrenergic receptors: alpha-1 and -2, beta-1 and -2, and dopamine-1 and -2. The renal effects of dopamine are the result of dopamine-1 receptor (DA1) stim

  15. Regulation of dopamine transporter trafficking by intracellular amphetamine

    DEFF Research Database (Denmark)

    Kahlig, Kristopher M; Lute, Brandon J; Wei, Yuqiang

    2006-01-01

    The dopamine (DA) transporter (DAT) mediates the removal of released DA. DAT is the major molecular target responsible for the rewarding properties and abuse potential of the psychostimulant amphetamine (AMPH). AMPH has been shown to reduce the number of DATs at the cell surface, and this AMPH...

  16. Renal dopamine receptors and hypertension.

    Science.gov (United States)

    Hussain, Tahir; Lokhandwala, Mustafa F

    2003-02-01

    Dopamine has been recognized as an important modulator of central as well as peripheral physiologic functions in both humans and animals. Dopamine receptors have been identified in a number of organs and tissues, which include several regions within the central nervous system, sympathetic ganglia and postganglionic nerve terminals, various vascular beds, the heart, the gastrointestinal tract, and the kidney. The peripheral dopamine receptors influence cardiovascular and renal function by decreasing afterload and vascular resistance and promoting sodium excretion. Within the kidney, dopamine receptors are present along the nephron, with highest density on proximal tubule epithelial cells. It has been reported that there is a defective dopamine receptor, especially D(1) receptor function, in the proximal tubule of various animal models of hypertension as well as in humans with essential hypertension. Recent reports have revealed the site of and the molecular mechanisms responsible for the defect in D(1) receptors in hypertension. Moreover, recent studies have also demonstrated that the disruption of various dopamine receptor subtypes and their function produces hypertension in rodents. In this review, we present evidence that dopamine and dopamine receptors play an important role in regulating renal sodium excretion and that defective renal dopamine production and/or dopamine receptor function may contribute to the development of various forms of hypertension.

  17. 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

  18. Dopamine, kidney, and hypertension: studies in dopamine receptor knockout mice

    OpenAIRE

    Wang, Xiaoyan; Villar, Van Anthony M.; Armando, Ines; Eisner, Gilbert M.; Felder, Robin A.; Pedro A. Jose

    2008-01-01

    Dopamine is important in the pathogenesis of hypertension because of abnormalities in receptor-mediated regulation of renal sodium transport. Dopamine receptors are classified into D1-like (D1, D5) and D2-like (D2, D3, D4) subtypes, all of which are expressed in the kidney. Mice deficient in specific dopamine receptors have been generated to provide holistic assessment on the varying physiological roles of each receptor subtype. This review examines recent studies on these mutant mouse models...

  19. 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.

  20. Dopamine and glucose, obesity and Reward Deficiency Syndrome

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    Kenneth eBlum

    2014-09-01

    Full Text Available Obesity and many well described eating disorders are accurately considered a global epidemic. The consequences of Reward Deficiency Syndrome, a genetic and epigenetic phenomena that involves the interactions of powerful neurotransmitters, are impairments of brain reward circuitry, hypodopaminergic function and abnormal craving behavior. Numerous sound neurochemical and genetic studies provide strong evidence that food addiction is similar to psychoactive drug addiction. Important facts which could translate to potential therapeutic targets espoused in this review include: 1 brain dopamine (DA production and use is stimulated by consumption of alcohol in large quantities or carbohydrates bingeing; 2 in the mesolimbic system the enkephalinergic neurons are in close proximity, to glucose receptors; 3 highly concentrated glucose activates the calcium channel to stimulate dopamine release from P12 cells; 4 blood glucose and cerebrospinal fluid concentrations of homovanillic acid, the dopamine metabolite, are significantly correlated and 5 2-deoxyglucose the glucose analogue, in pharmacological doses associates with enhanced dopamine turnover and causes acute glucoprivation. Evidence from animal studies and human fMRI support the hypothesis that multiple, but similar brain circuits are disrupted in obesity and drug dependence and DA-modulated reward circuits are involved in pathologic eating behaviors. Treatment for addiction to glucose and drugs alike, based on a consensus of neuroscience research, should incorporate dopamine agonist therapy, in contrast to current theories and practices that use dopamine antagonists. Until now, powerful dopamine-D2 agonists have failed clinically, due to chronic down regulation of D2 receptors instead, consideration of novel less powerful D2 agonists that up-regulate D2 receptors seems prudent. We encourage new strategies targeted at improving DA function in the treatment and prevention of obesity a subtype of

  1. Dopamine, kidney, and hypertension: studies in dopamine receptor knockout mice.

    Science.gov (United States)

    Wang, Xiaoyan; Villar, Van Anthony M; Armando, Ines; Eisner, Gilbert M; Felder, Robin A; Jose, Pedro A

    2008-12-01

    Dopamine is important in the pathogenesis of hypertension because of abnormalities in receptor-mediated regulation of renal sodium transport. Dopamine receptors are classified into D(1)-like (D(1), D(5)) and D(2)-like (D(2), D(3), D(4)) subtypes, all of which are expressed in the kidney. Mice deficient in specific dopamine receptors have been generated to provide holistic assessment on the varying physiological roles of each receptor subtype. This review examines recent studies on these mutant mouse models and evaluates the impact of individual dopamine receptor subtypes on blood pressure regulation.

  2. Growth of dopamine crystals

    Science.gov (United States)

    Patil, Vidya; Patki, Mugdha

    2016-05-01

    Many nonlinear optical (NLO) crystals have been identified as potential candidates in optical and electro-optical devices. Use of NLO organic crystals is expected in photonic applications. Hence organic nonlinear optical materials have been intensely investigated due to their potentially high nonlinearities, and rapid response in electro-optic effect compared to inorganic NLO materials. There are many methods to grow organic crystals such as vapor growth method, melt growth method and solution growth method. Out of these methods, solution growth method is useful in providing constraint free crystal. Single crystals of Dopamine have been grown by evaporating the solvents from aqueous solution. Crystals obtained were of the size of orders of mm. The crystal structure of dopamine was determined using XRD technique. Images of crystals were obtained using FEG SEM Quanta Series under high vacuum and low KV.

  3. Optogenetic inhibition of D1R containing nucleus accumbens neurons alters cocaine- mediated regulation of Tiam1

    Directory of Open Access Journals (Sweden)

    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.

  4. 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.

  5. Breathing is affected by dopamine D2-like receptors in the basolateral amygdala.

    Science.gov (United States)

    Sugita, Toshihisa; Kanamaru, Mitsuko; Iizuka, Makito; Sato, Kanako; Tsukada, Setsuro; Kawamura, Mitsuru; Homma, Ikuo; Izumizaki, Masahiko

    2015-04-01

    The precise mechanisms underlying how emotions change breathing patterns remain unclear, but dopamine is a candidate neurotransmitter in the process of emotion-associated breathing. We investigated whether basal dopamine release occurs in the basolateral amygdala (BLA), where sensory-related inputs are received and lead to fear or anxiety responses, and whether D1- and D2-like receptor antagonists affect breathing patterns and dopamine release in the BLA. Adult male mice (C57BL/6N) were perfused with artificial cerebrospinal fluid, a D1-like receptor antagonist (SCH 23390), or a D2-like receptor antagonist ((S)-(-)-sulpiride) through a microdialysis probe in the BLA. Respiratory variables were measured using a double-chamber plethysmograph. Dopamine release was measured by an HPLC. Perfusion of (S)-(-)-sulpiride in the BLA, not SCH 23390, specifically decreased respiratory rate without changes in local release of dopamine. These results suggest that basal dopamine release in the BLA, at least partially, increases respiratory rates only through post-synaptic D2-like receptors, not autoreceptors, which might be associated with emotional responses.

  6. The Iowa Gambling Task and the Three Fallacies of Dopamine in Gambling Disorder.

    Directory of Open Access Journals (Sweden)

    Jakob eLinnet

    2013-10-01

    Full Text Available Gambling disorder sufferers prefer immediately larger rewards despite long term losses on the Iowa Gambling Task (IGT, and these impairments are associated with dopamine dysfunctions. Dopamine is a neurotransmitter linked with temporal and structural dysfunctions in substance use disorder, which has supported the idea of impaired decision-making and dopamine dysfunctions in gambling disorder. However, evidence from substance use disorders cannot be directly transferred to gambling disorder. This article focuses on three hypotheses of dopamine dysfunctions in gambling disorder, which appear to be fallacies, i.e., have not been supported in a series of positron emission tomography (PET studies. The first fallacy suggests that gambling disorder suffers, similar to substance use disorders, have lower dopamine receptor availability. No evidence supported this hypothesis. The second fallacy suggests that maladaptive decision-making in gambling disorder is associated with higher dopamine release during gambling. No evidence supported the hypothesis, and the literature on substance use disorders offers limited support for this hypothesis. The third fallacy suggests that maladaptive decision-making in gambling disorder is associated with higher dopamine release during winning. The evidence did not support this hypothesis either. Instead, dopaminergic coding of reward prediction and uncertainty might better account for dopamine dysfunctions in gambling disorder. Studies of reward prediction and reward uncertainty shows a sustained dopamine response towards stimuli with maximum uncertainty, which may explain the continued dopamine release and gambling despite losses in gambling disorder. The findings from the studies presented here are consistent with the notion of dopaminergic dysfunctions of reward prediction and reward uncertainty signals in gambling disorder.

  7. Occupancy of pramipexole (Sifrol) at cerebral dopamine D2/3 receptors in Parkinson's disease patients.

    Science.gov (United States)

    Deutschländer, Angela; la Fougère, Christian; Boetzel, Kai; Albert, Nathalie L; Gildehaus, Franz-Josef; Bartenstein, Peter; Xiong, Guoming; Cumming, Paul

    2016-01-01

    Whereas positron emission tomography (PET) with the antagonist ligand [(18)F]fallypride reveals the composite of dopamine D2 and D3 receptors in brain, treatment of Parkinson's disease (PD) patients with the D3-prefering agonist pramipexole should result in preferential occupancy in the nucleus accumbens, where the D3-subtype is most abundant. To test this prediction we obtained pairs of [(18)F]fallypride PET recordings in a group of nine PD patients, first in a condition of treatment as usual with pramipexole (ON-Sifrol; 3 × 0.7 mg p.d.), and again at a later date, after withholding pramipexole 48-72 h (OFF-Sifrol); in that condition the serum pramipexole concentration had declined by 90% and prolactin levels had increased four-fold, in conjunction with a small but significant worsening of PD motor symptoms. Exploratory comparison with historical control material showed 14% higher dopamine D2/3 availability in the more-affected putamen of patients OFF medication. On-Sifrol there was significant (p ˂ 0.01) occupancy at [(18)F]fallypride binding sites in globus pallidus (8%) thalamus (9%) and substantia nigra (19%), as well as marginally significant occupancy in frontal and temporal cortex of patients. Contrary to expectation, comparison of ON- and OFF-Sifrol results did not reveal any discernible occupancy in nucleus accumbens, or elsewhere in the extended striatum; present methods should be sensitive to a 10% change in dopamine D2/3 receptor availability in striatum; the significant findings elsewhere in the basal ganglia and in cerebral cortex are consistent with a predominance of D3 receptors in those structures, especially in substantia nigra, and imply that therapeutic effects of pramipexole may be obtained at sites outside the extended striatum.

  8. Occupancy of pramipexole (Sifrol at cerebral dopamine D2/3 receptors in Parkinson's disease patients

    Directory of Open Access Journals (Sweden)

    Angela Deutschländer

    2016-01-01

    Full Text Available Whereas positron emission tomography (PET with the antagonist ligand [18F]fallypride reveals the composite of dopamine D2 and D3 receptors in brain, treatment of Parkinson's disease (PD patients with the D3-prefering agonist pramipexole should result in preferential occupancy in the nucleus accumbens, where the D3-subtype is most abundant. To test this prediction we obtained pairs of [18F]fallypride PET recordings in a group of nine PD patients, first in a condition of treatment as usual with pramipexole (ON-Sifrol; 3 × 0.7 mg p.d., and again at a later date, after withholding pramipexole 48–72 h (OFF-Sifrol; in that condition the serum pramipexole concentration had declined by 90% and prolactin levels had increased four-fold, in conjunction with a small but significant worsening of PD motor symptoms. Exploratory comparison with historical control material showed 14% higher dopamine D2/3 availability in the more-affected putamen of patients OFF medication. On-Sifrol there was significant (p ˂ 0.01 occupancy at [18F]fallypride binding sites in globus pallidus (8% thalamus (9% and substantia nigra (19%, as well as marginally significant occupancy in frontal and temporal cortex of patients. Contrary to expectation, comparison of ON- and OFF-Sifrol results did not reveal any discernible occupancy in nucleus accumbens, or elsewhere in the extended striatum; present methods should be sensitive to a 10% change in dopamine D2/3 receptor availability in striatum; the significant findings elsewhere in the basal ganglia and in cerebral cortex are consistent with a predominance of D3 receptors in those structures, especially in substantia nigra, and imply that therapeutic effects of pramipexole may be obtained at sites outside the extended striatum.

  9. Methamphetamine Increases Locomotion and Dopamine Transporter Activity in Dopamine D5 Receptor-Deficient Mice

    OpenAIRE

    Seiji Hayashizaki; Shinobu Hirai; Yumi Ito; Yoshiko Honda; Yosefu Arime; Ichiro Sora; Haruo Okado; Tohru Kodama; Masahiko Takada

    2013-01-01

    Dopamine regulates the psychomotor stimulant activities of amphetamine-like substances in the brain. The effects of dopamine are mediated through five known dopamine receptor subtypes in mammals. The functional relevance of D5 dopamine receptors in the central nervous system is not well understood. To determine the functional relevance of D5 dopamine receptors, we created D5 dopamine receptor-deficient mice and then used these mice to assess the roles of D5 dopamine receptors in the behaviora...

  10. 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.

  11. Orexin receptors within the nucleus accumbens shell mediate the stress but not drug priming-induced reinstatement of morphine conditioned place preference

    Directory of Open Access Journals (Sweden)

    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. Dopamine and renal function and blood pressure regulation.

    Science.gov (United States)

    Armando, Ines; Villar, Van Anthony M; Jose, Pedro A

    2011-07-01

    Dopamine is an important regulator of systemic blood pressure via multiple mechanisms. It affects fluid and electrolyte balance by its actions on renal hemodynamics and epithelial ion and water transport and by regulation of hormones and humoral agents. The kidney synthesizes dopamine from circulating or filtered L-DOPA independently from innervation. The major determinants of the renal tubular synthesis/release of dopamine are probably sodium intake and intracellular sodium. Dopamine exerts its actions via two families of cell surface receptors, D1-like receptors comprising D1R and D5R, and D2-like receptors comprising D2R, D3R, and D4R, and by interactions with other G protein-coupled receptors. D1-like receptors are linked to vasodilation, while the effect of D2-like receptors on the vasculature is variable and probably dependent upon the state of nerve activity. Dopamine secreted into the tubular lumen acts mainly via D1-like receptors in an autocrine/paracrine manner to regulate ion transport in the proximal and distal nephron. These effects are mediated mainly by tubular mechanisms and augmented by hemodynamic mechanisms. The natriuretic effect of D1-like receptors is caused by inhibition of ion transport in the apical and basolateral membranes. D2-like receptors participate in the inhibition of ion transport during conditions of euvolemia and moderate volume expansion. Dopamine also controls ion transport and blood pressure by regulating the production of reactive oxygen species and the inflammatory response. Essential hypertension is associated with abnormalities in dopamine production, receptor number, and/or posttranslational modification.

  13. (TH)205-501, a non-catechol dopaminergic agonist, labels selectively and with high affinity dopamine D2 receptors

    Energy Technology Data Exchange (ETDEWEB)

    Closse, A.; Frick, W.; Markstein, R.; Maurer, R.; Nordmann, R.

    1985-01-01

    (TH)205-501, a non dopaminergic agonist, is presented as a ligand with high affinity (Ksub(D) approx= 1 nM) and high selectivity for dopamine receptors. pKsubi values of dopaminergic agonists derived from competition isotherms in the (TH)205-501 binding assay correlate very well with their potency in the acetylcholine release assay, which is controlled by dopamine D2 receptors. There is however no correlation with their potency stimulating aldenylate cyclase, a process controlled by dopamine D1 receptors. Thus (TH)205-501 is the first agonist ligand selective for dopamine D2 receptors. (Author).

  14. Cocaine and amphetamine elicit differential effects in rats with a unilateral injection of dopamine transporter antisense oligodeoxynucleotides.

    Science.gov (United States)

    Silvia, C P; Jaber, M; King, G R; Ellinwood, E H; Caron, M G

    1997-02-01

    We have developed an antisense oligodeoxynucleotide to the dopamine transporter and used it to discriminate the behavioral properties of amphetamine and cocaine. In SK-N-MC cells permanently transfected with the dopamine transporter complementary DNA, treatment with 5 mM antisense oligodeoxynucleotide reduced dopamine uptake by 25% when compared to sense control. Unilateral intranigral administration of dopamine transporter antisense (50 microM) twice daily in freely moving rats for 2.5 days was sufficient to reduce dopamine transporter messenger RNA by 70% as measured by in situ hybridization, but not protein levels as measured by [3H]mazindol binding. However, intranigral treatment via implanted osmotic minipump over a period of seven days produced reductions in both dopamine transporter messenger RNA and protein levels (32%) at a dose of 500 pmol/day. These results indicate a longer half-life for the dopamine transporter than expected. Potassium chloride depolarization of ipsilateral striatal slices showed a greater than 200% increase in dopamine overflow on the antisense-treated side compared to the control side. Since imbalance of dopamine tone is known to induce rotational activity, we tested this behavioral paradigm in rats treated with various oligodeoxynucleotides at different doses and time-points. We have found that antisense-treated animals did not rotate spontaneously under any experimental conditions. Using various psychostimulants that target the dopamine transporter and increase dopamine levels, we found that the antisense-treated animals consistently rotated contralaterally in response to amphetamine (2 mg/kg), but not to cocaine (10 mg/kg) or nomifensine (10 mg/kg). These results bring in vivo evidence for a different mode of action of amphetamine and cocaine on the dopamine transporter and lend direct support to the view that amphetamine acts as a dopamine releaser, whereas cocaine acts by blocking dopamine transport.

  15. Characterization of [(3) H]LS-3-134, a novel arylamide phenylpiperazine D3 dopamine receptor selective radioligand.

    Science.gov (United States)

    Rangel-Barajas, Claudia; Malik, Maninder; Taylor, Michelle; Neve, Kim A; Mach, Robert H; Luedtke, Robert R

    2014-11-01

    LS-3-134 is a substituted N-phenylpiperazine derivative that has been reported to exhibit: (i) high-affinity binding (Ki value 0.2 nM) at human D3 dopamine receptors, (ii) > 100-fold D3 versus D2 dopamine receptor subtype binding selectivity, and (iii) low-affinity binding (Ki  > 5000 nM) at sigma 1 and sigma 2 receptors. Based upon a forskolin-dependent activation of the adenylyl cyclase inhibition assay, LS-3-134 is a weak partial agonist at both D2 and D3 dopamine receptor subtypes (29% and 35% of full agonist activity, respectively). In this study, [(3) H]-labeled LS-3-134 was prepared and evaluated to further characterize its use as a D3 dopamine receptor selective radioligand. Kinetic and equilibrium radioligand binding studies were performed. This radioligand rapidly reaches equilibrium (10-15 min at 37°C) and binds with high affinity to both human (Kd  = 0.06 ± 0.01 nM) and rat (Kd  = 0.2 ± 0.02 nM) D3 receptors expressed in HEK293 cells. Direct and competitive radioligand binding studies using rat caudate and nucleus accumbens tissue indicate that [(3) H]LS-3-134 selectively binds a homogeneous population of binding sites with a dopamine D3 receptor pharmacological profile. Based upon these studies, we propose that [(3) H]LS-3-134 represents a novel D3 dopamine receptor selective radioligand that can be used for studying the expression and regulation of the D3 dopamine receptor subtype.

  16. Dopamine Oxidation and Autophagy

    Directory of Open Access Journals (Sweden)

    Patricia Muñoz

    2012-01-01

    Full Text Available The molecular mechanisms involved in the neurodegenerative process of Parkinson's disease remain unclear. Currently, there is a general agreement that mitochondrial dysfunction, α-synuclein aggregation, oxidative stress, neuroinflammation, and impaired protein degradation are involved in the neurodegeneration of dopaminergic neurons containing neuromelanin in Parkinson's disease. Aminochrome has been proposed to play an essential role in the degeneration of dopaminergic neurons containing neuromelanin by inducing mitochondrial dysfunction, oxidative stress, the formation of neurotoxic α-synuclein protofibrils, and impaired protein degradation. Here, we discuss the relationship between the oxidation of dopamine to aminochrome, the precursor of neuromelanin, autophagy dysfunction in dopaminergic neurons containing neuromelanin, and the role of dopamine oxidation to aminochrome in autophagy dysfunction in dopaminergic neurons. Aminochrome induces the following: (i the formation of α-synuclein protofibrils that inactivate chaperone-mediated autophagy; (ii the formation of adducts with α- and β-tubulin, which induce the aggregation of the microtubules required for the fusion of autophagy vacuoles and lysosomes.

  17. 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...

  18. Dopamine D(2) receptor function is compromised in the brain of the methionine sulfoxide reductase A knockout mouse.

    Science.gov (United States)

    Oien, Derek B; Ortiz, Andrea N; Rittel, Alexander G; Dobrowsky, Rick T; Johnson, Michael A; Levant, Beth; Fowler, Stephen C; Moskovitz, Jackob

    2010-07-01

    Previous research suggests that brain oxidative stress and altered rodent locomotor behavior are linked. We observed bio-behavioral changes in methionine sulfoxide reductase A knockout mice associated with abnormal dopamine signaling. Compromised ability of these knockout mice to reduce methionine sulfoxide enhances accumulation of sulfoxides in proteins. We examined the dopamine D(2)-receptor function and expression, which has an atypical arrangement and quantity of methionine residues. Indeed, protein expression levels of dopamine D(2)-receptor were higher in knockout mice compared with wild-type. However, the binding of dopamine D(2)-receptor agonist was compromised in the same fractions of knockout mice. Coupling efficiency of dopamine D(2)-receptors to G-proteins was also significantly reduced in knockout mice, supporting the compromised agonist binding. Furthermore, pre-synaptic dopamine release in knockout striatal sections was less responsive than control sections to dopamine D(2)-receptor ligands. Behaviorally, the locomotor activity of knockout mice was less responsive to the inhibitory effect of quinpirole than wild-type mice. Involvement of specific methionine residue oxidation in the dopamine D(2)-receptor third intracellular loop is suggested by in vitro studies. We conclude that ablation of methionine sulfoxide reductase can affect dopamine signaling through altering dopamine D(2)-receptor physiology and may be related to symptoms associated with neurological disorders and diseases.

  19. Dopamine D2 receptor function is compromised in the brain of the methionine sulfoxide reductase A knockout mouse

    Science.gov (United States)

    Oien, Derek B.; Ortiz, Andrea N.; Rittel, Alexander G.; Dobrowsky, Rick T.; Johnson, Michael A.; Levant, Beth; Fowler, Stephen C.; Moskovitz, Jackob

    2010-01-01

    Previous research suggests that brain oxidative stress and altered rodent locomotor behavior are linked. We observed bio-behavioral changes in methionine sulfoxide reductase A knockout mice associated with abnormal dopamine signaling. Compromised ability of these knockout mice to reduce methionine sulfoxide enhances accumulation of sulfoxides in proteins. We examined the dopamine D2-receptor function and expression, which has an atypical arrangement and quantity of methionine residues. Indeed, protein expression levels of dopamine D2-receptor were higher in knockout mice compared with wild-type. However, the binding of dopamine D2-receptor agonist was compromised in the same fractions of knockout mice. Coupling efficiency of dopamine D2-receptors to G-proteins was also significantly reduced in knockout mice, supporting the compromised agonist binding. Furthermore, pre-synaptic dopamine release in knockout striatal sections was less responsive than control sections to dopamine D2-receptor ligands. Behaviorally, the locomotor activity of knockout mice was less responsive to the inhibitory effect of quinpirole than wild-type mice. Involvement of specific methionine residue oxidation in the dopamine D2-receptor third intracellular loop is suggested by in vitro studies. We conclude that ablation of methionine sulfoxide reductase can affect dopamine signaling through altering dopamine D2-receptor physiology and may be related to symptoms associated with neurological disorders and diseases. PMID:20374422

  20. Phasic-like stimulation of the medial forebrain bundle augments striatal gene expression despite methamphetamine-induced partial dopamine denervation.

    Science.gov (United States)

    Howard, Christopher D; Pastuzyn, Elissa D; Barker-Haliski, Melissa L; Garris, Paul A; Keefe, Kristen A

    2013-05-01

    Methamphetamine-induced partial dopamine depletions are associated with impaired basal ganglia function, including decreased preprotachykinin mRNA expression and impaired transcriptional activation of activity-regulated, cytoskeleton-associated (Arc) gene in striatum. Recent work implicates deficits in phasic dopamine signaling as a potential mechanism linking methamphetamine-induced dopamine loss to impaired basal ganglia function. This study thus sought to establish a causal link between phasic dopamine transmission and altered basal ganglia function by determining whether the deficits in striatal neuron gene expression could be restored by increasing phasic dopamine release. Three weeks after pretreatment with saline or a neurotoxic regimen of methamphetamine, rats underwent phasic- or tonic-like stimulation of ascending dopamine neurons. Striatal gene expression was examined using in situ hybridization histochemistry. Phasic-like, but not tonic-like, stimulation induced immediate-early genes Arc and zif268 in both groups, despite the partial striatal dopamine denervation in methamphetamine-pretreated rats, with the Arc expression occurring in presumed striatonigral efferent neurons. Phasic-like stimulation also restored preprotachykinin mRNA expression. These results suggest that disruption of phasic dopamine signaling likely underlies methamphetamine-induced impairments in basal ganglia function, and that restoring phasic dopamine signaling may be a viable approach to manage long-term consequences of methamphetamine-induced dopamine loss on basal ganglia functions.

  1. Disruption of dopamine neuron activity pattern regulation through selective expression of a human KCNN3 mutation.

    Science.gov (United States)

    Soden, Marta E; Jones, Graham L; Sanford, Christina A; Chung, Amanda S; Güler, Ali D; Chavkin, Charles; Luján, Rafael; Zweifel, Larry S

    2013-11-20

    The calcium-activated small conductance potassium channel SK3 plays an essential role in the regulation of dopamine neuron activity patterns. Here we demonstrate that expression of a human disease-related SK3 mutation (hSK3Δ) in dopamine neurons of mice disrupts the balance between tonic and phasic dopamine neuron activity. Expression of hSK3Δ suppressed endogenous SK currents, reducing coupling between SK channels and NMDA receptors (NMDARs) and increasing permissiveness for burst firing. Consistent with enhanced excitability of dopamine neurons, hSK3Δ increased evoked calcium signals in dopamine neurons in vivo and potentiated evoked dopamine release. Specific expression of hSK3Δ led to deficits in attention and sensory gating and heightened sensitivity to a psychomimetic drug. Sensory-motor alterations and psychomimetic sensitivity were recapitulated in a mouse model of transient, reversible dopamine neuron activation. These results demonstrate the cell-autonomous effects of a human ion channel mutation on dopamine neuron physiology and the impact of activity pattern disruption on behavior.

  2. Mescaline: its effects on learning rate and dopamine metabolism in goldfish (Carassius auratus).

    Science.gov (United States)

    Zeller, E A; Couper, G S; Huprikar, S V; Mellow, A M; Moody, R R

    1976-11-15

    The pharmacological action of mescaline on goldfish was studied with the Bitterman-Agranoff shock-avoidance test. In short term experiments with high mescaline doses an increase in learning rates was observed. Similar results were obtained with apomorphine and L-dopa. However, when the fish were exposed to smaller mescaline doses (or to fluphenazine) for 3 days, their ability to avoid electric shock was reduced. Apparently, mescaline induced a release of dopamine which stimulated central dopaminergic systems. Subsequently, MAO destroys the liberated dopamine. Thus, the ensuing dopamine deficit appears to be responsible for the marked changes in behavior in the chronic experiment.

  3. Effects of Gonadotropin-releasing Hormone (GnRH) and Dopamine on Gonadotropin(GTH) Secretion from in vitro Pituitary Cells of Rainbow Trout%促性腺激素释放激素和多巴胺对虹鳟( Oncorhynchus mykiss )离体脑垂体细胞分泌促性腺激素的影响

    Institute of Scientific and Technical Information of China (English)

    侯亚义

    2001-01-01

    本文研究了不同性腺发育时期淡水饲养的雌雄虹鳟(Oncorhynchus mykiss)血浆促性腺激素(GTH)浓度的变化规律;以及在离体条件下,探讨了促性腺激素释放激素(GnRH)、GnRH拮抗物和多巴胺对虹鳟脑垂体细胞分泌促性腺激素(GTH-Ⅱ)的影响。结果表明:(1)在雄性,血浆中GTH-Ⅱ的水平随性腺发育而逐渐增高;在雌性,仅排卵期血浆中GTH-Ⅱ的水平明显增高。(2)未成熟期和成熟期的雌性虹鳟脑垂体细胞对sGnRH和cGnRH刺激的敏感性表现不尽相同。成熟期和排卵后的脑垂体细胞对GnRH的刺激较为敏感,GTH-Ⅱ的分泌量较多。(3)在没有sGnRH的存在下,GnRH拮抗物对GTH-Ⅱ的分泌不发生作用,而在sGnRH的存在下,GnRH拮抗物对GTH-Ⅱ的分泌表现出浓度依赖的抑制作用。(4)在没有sGnRH的存在下,多巴胺对GTH-Ⅱ的分泌不发生作用,而当多巴胺的浓度一定时,随着sGnRH浓度的增加,GTH-Ⅱ分泌的量增大。另外,不论sGnRH还是cGnRH都不影响不同时期的脑垂体细胞GTH-I的分泌这些结果可为虹鳟的人工催产提供一些理论依据。%Plasma gonadotropin (GTH) levels during immature, mature and ovulated periods and effects of gonadotropin-releasing hormone (GnRH) and dopamine on GTH secretion of in vitro pituitary cells of rainbow trout were investigated. Plasma GTH levels increased with gonadal development. The different effects of sGnRH and cGnRH on GTH- Ⅱ secretions of pituitary cells in vitro from immature, mature and ovulated periods of rainbow trout were observed. GnRH antagonist did not change GTH - Ⅱ contents under the absence of sGnRH while GnRH antagonist suppressed dose-dependently GTH- Ⅱ secretions of pituitary cells in combination with sGnRH.Dopamine also did not affect GTH- Ⅱ levels under the absence of sGnRH, while GTH- Ⅱ secretions of pituitary cells were enhanced when the dosage of sGnRH was increased with the presence of

  4. Serotonin2C receptor stimulation inhibits cocaine-induced Fos expression and DARPP-32 phosphorylation in the rat striatum independently of dopamine outflow.

    Science.gov (United States)

    Devroye, Céline; Cathala, Adeline; Maitre, Marlène; Piazza, Pier Vincenzo; Abrous, Djoher Nora; Revest, Jean-Michel; Spampinato, Umberto

    2015-02-01

    The serotonin(2C) receptor (5-HT(2C)R) is known to control dopamine (DA) neuron function by modulating DA neuronal firing and DA exocytosis at terminals. Recent studies assessing the influence of 5-HT(2C)Rs on cocaine-induced neurochemical and behavioral responses have shown that 5-HT2CRs can also modulate mesoaccumbens DA pathway activity at post-synaptic level, by controlling DA transmission in the nucleus accumbens (NAc), independently of DA release itself. A similar mechanism has been proposed to occur at the level of the nigrostriatal DA system. Here, using in vivo microdialysis in freely moving rats and molecular approaches, we assessed this hypothesis by studying the influence of the 5-HT(2C)R agonist Ro 60-0175 on cocaine-induced responses in the striatum. The intraperitoneal (i.p.) administration of 1 mg/kg Ro 60-0175 had no effect on the increase in striatal DA outflow induced by cocaine (15 mg/kg, i.p.). Conversely, Ro 60-0175 inhibited cocaine-induced Fos immunoreactivity and phosphorylation of the DA and c-AMP regulated phosphoprotein of Mr 32 kDa (DARPP-32) at threonine 75 residue in the striatum. Finally, the suppressant effect of Ro 60-0175 on cocaine-induced DARPP-32 phosphorylation was reversed by the selective 5-HT(2C)R antagonist SB 242084 (0.5 mg/kg, i.p.). In keeping with the key role of DARPP-32 in DA neurotransmission, our results demonstrate that 5-HT(2C)Rs are capable of modulating nigrostriatal DA pathway activity at post-synaptic level, by specifically controlling DA signaling in the striatum.

  5. Dopamine, the kidney, and hypertension.

    Science.gov (United States)

    Harris, Raymond C; Zhang, Ming-Zhi

    2012-04-01

    There is increasing evidence that the intrarenal dopaminergic system plays an important role in the regulation of blood pressure, and defects in dopamine signaling appear to be involved in the development of hypertension. Recent experimental models have definitively demonstrated that abnormalities in intrarenal dopamine production or receptor signaling can predispose to salt-sensitive hypertension and a dysregulated renin-angiotensin system. In addition, studies in both experimental animal models and in humans with salt-sensitive hypertension implicate abnormalities in dopamine receptor regulation due to receptor desensitization resulting from increased G-protein receptor kinase 4 (GRK4) activity. Functional polymorphisms that predispose to increased basal GRK4 activity both decrease dopamine receptor activity and increase angiotensin II type 1 (AT1) receptor activity and are associated with essential hypertension in a number of different human cohorts.

  6. Dopamine D1 and D2 Receptors in the Nucleus Accumbens Core and Shell Mediate Pavlovian-Instrumental Transfer

    Science.gov (United States)

    Lex, Anja; Hauber, Wolfgang

    2008-01-01

    Pavlovian stimuli previously paired with food can markedly elevate the rate of food-reinforced instrumental responding. This effect, termed Pavlovian-instrumental transfer (PIT), depends both on general activating and specific cueing properties of Pavlovian stimuli. Recent evidence suggests that the general activating properties of Pavlovian…

  7. 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.

  8. 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

  9. Dopamine, the Kidney, and Hypertension

    OpenAIRE

    Raymond C. Harris; Zhang, Ming-Zhi

    2012-01-01

    There is increasing evidence that the intrarenal dopaminergic system plays an important role in the regulation of blood pressure, and defects in dopamine signaling appear to be involved in the development of hypertension. Recent experimental models have definitively demonstrated that abnormalities in intrarenal dopamine production or receptor signaling can predispose to salt-sensitive hypertension and a dysregulated renin-angiotensin system. In addition, studies in both experimental animal mo...

  10. Interval timing, dopamine, and motivation

    OpenAIRE

    Balcı, Fuat

    2014-01-01

    The dopamine clock hypothesis suggests that the dopamine level determines the speed of the hypothetical internal clock. However, dopaminergic function has also been implicated for motivation and thus the effect of dopaminergic manipulations on timing behavior might also be independently mediated by altered motivational state. Studies that investigated the effect of motivational manipulations on peak responding are reviewed in this paper. The majority of these studies show that a higher reward...

  11. Dopamine in Socioecological and Evolutionary Perspectives: Implications for Psychiatric Disorders

    Directory of Open Access Journals (Sweden)

    Yoshie eYamaguchi

    2015-06-01

    Full Text Available Dopamine (DA transmission in brain areas such as the prefrontal cortex (PFC and nucleus accumbens (NAcc plays important roles in cognitive and affective function. As such, DA deficits have been implicated in a number of psychiatric disorders such as schizophrenia and attention deficit/hyperactivity disorder (ADHD. Accumulating evidence suggests that DA is also involved in social behavior of animals and humans. Although most animals organize and live in social groups, how the DA system functions in such social groups of animals, and its dysfunction causes compromises in the groups has remained less understood. Here we propose that alterations of DA signaling and associated genetic variants and behavioral phenotypes, which have been normally considered as deficits in investigation at an individual level, may not necessarily yield disadvantages, and even work advantageously, depending on social contexts in subjects with such DA alterations living in social groups. This hypothesis could provide a novel insight into our understanding of the biological mechanisms of psychiatric disorders, and a potential explanation that disadvantageous phenotypes associated with DA deficits in psychiatric disorders have remained in humans through evolution.

  12. 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.

  13. Dopamine, affordance and active inference.

    Directory of Open Access Journals (Sweden)

    Karl J Friston

    2012-01-01

    Full Text Available The role of dopamine in behaviour and decision-making is often cast in terms of reinforcement learning and optimal decision theory. Here, we present an alternative view that frames the physiology of dopamine in terms of Bayes-optimal behaviour. In this account, dopamine controls the precision or salience of (external or internal cues that engender action. In other words, dopamine balances bottom-up sensory information and top-down prior beliefs when making hierarchical inferences (predictions about cues that have affordance. In this paper, we focus on the consequences of changing tonic levels of dopamine firing using simulations of cued sequential movements. Crucially, the predictions driving movements are based upon a hierarchical generative model that infers the context in which movements are made. This means that we can confuse agents by changing the context (order in which cues are presented. These simulations provide a (Bayes-optimal model of contextual uncertainty and set switching that can be quantified in terms of behavioural and electrophysiological responses. Furthermore, one can simulate dopaminergic lesions (by changing the precision of prediction errors to produce pathological behaviours that are reminiscent of those seen in neurological disorders such as Parkinson's disease. We use these simulations to demonstrate how a single functional role for dopamine at the synaptic level can manifest in different ways at the behavioural level.

  14. Circuit Architecture of VTA Dopamine Neurons Revealed by Systematic Input-Output Mapping.

    Science.gov (United States)

    Beier, Kevin T; Steinberg, Elizabeth E; DeLoach, Katherine E; Xie, Stanley; Miyamichi, Kazunari; Schwarz, Lindsay; Gao, Xiaojing J; Kremer, Eric J; Malenka, Robert C; Luo, Liqun

    2015-07-30

    Dopamine (DA) neurons in the midbrain ventral tegmental area (VTA) integrate complex inputs to encode multiple signals that influence motivated behaviors via diverse projections. Here, we combine axon-initiated viral transduction with rabies-mediated trans-synaptic tracing and Cre-based cell-type-specific targeting to systematically map input-output relationships of VTA-DA neurons. We found that VTA-DA (and VTA-GABA) neurons receive excitatory, inhibitory, and modulatory input from diverse sources. VTA-DA neurons projecting to different forebrain regions exhibit specific biases in their input selection. VTA-DA neurons projecting to lateral and medial nucleus accumbens innervate largely non-overlapping striatal targets, with the latter also sending extensive extra-striatal axon collaterals. Using electrophysiology and behavior, we validated new circuits identified in our tracing studies, including a previously unappreciated top-down reinforcing circuit from anterior cortex to lateral nucleus accumbens via VTA-DA neurons. This study highlights the utility of our viral-genetic tracing strategies to elucidate the complex neural substrates that underlie motivated behaviors.

  15. Sufficiency of Mesolimbic Dopamine Neuron Stimulation for the Progression to Addiction.

    Science.gov (United States)

    Pascoli, Vincent; Terrier, Jean; Hiver, Agnès; Lüscher, Christian

    2015-12-01

    The factors causing the transition from recreational drug consumption to addiction remain largely unknown. It has not been tested whether dopamine (DA) is sufficient to trigger this process. Here we use optogenetic self-stimulation of DA neurons of the ventral tegmental area (VTA) to selectively mimic the defining commonality of addictive drugs. All mice readily acquired self-stimulation. After weeks of abstinence, cue-induced relapse was observed in parallel with a potentiation of excitatory afferents onto D1 receptor-expressing neurons of the nucleus accumbens (NAc). When the mice had to endure a mild electric foot shock to obtain a stimulation, some stopped while others persevered. The resistance to punishment was associated with enhanced neural activity in the orbitofrontal cortex (OFC) while chemogenetic inhibition of the OFC reduced compulsivity. Together, these results show that stimulating VTA DA neurons induces behavioral and cellular hallmarks of addiction, indicating sufficiency for the induction and progression of the disease.

  16. Microinjections of a nicotinic agonist into dopamine terminal fields: effects on locomotion.

    Science.gov (United States)

    Museo, E; Wise, R A

    1990-09-01

    Nicotine induces locomotion, a behavior associated with the mesocorticolimbic dopamine system. The present study determined the effects on locomotion of direct microinjections of the nicotinic agonist cytisine into four DA terminal fields were nicotinic receptors have been localized: nucleus accumbens (NAS, n = 20), caudate putamen (CPU, n = 9), olfactory tubercle (OT, n = 8), and medial prefrontal cortex (MPC, n = 12). Male Long-Evans rats were injected with cytisine (0.1, 1, 10 and 100 nanomoles per 0.5 microliters per side) or vehicle through indwelling cannulae, and locomotor activity was recorded during a 60-minute test session; each animal was tested with each dose in counterbalanced order. NAS injections of the three highest doses of cytisine increased locomotion relative to vehicle injections; injections in the CPU, dorsal to the NAS, were ineffective, as were MPC and OT injections. The data support the notion that systemic nicotine may interact with dopaminergic projections to the NAS to produce increases in locomotor activity.

  17. Role for the mesocortical dopamine system in the motivating effects of cocaine.

    Science.gov (United States)

    Koob, G F; Caine, B; Markou, A; Pulvirenti, L; Weiss, F

    1994-01-01

    The search for a neurobiological substrate for the stimulant and reinforcing properties of cocaine has focused for some time on a particular part of the forebrain, the mesocorticolimbic dopamine (DA) system. This mesocorticolimbic DA system innervates the region of the nucleus accumbens (NACC) (ventral striatum) in the anterior part of the basal forebrain and appears to play a critical role in mediating the acute reinforcing effects of cocaine and amphetamine. This chapter reviews the role of mesocorticolimbic DA in the reinforcing properties of psychomotor stimulants as measured by intravenous (IV) drug self-administration in rats. In addition, the primary neuropharmacological mechanism for cocaine reinforcement provides a rich substrate for studying nondopaminergic modulation of the reinforcing actions of cocaine.

  18. 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.

  19. 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.

  20. 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.

  1. Chronic alcohol consumption leads to neurochemical changes in the nucleus accumbens that are not fully reversed by withdrawal.

    Science.gov (United States)

    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.

  2. Toward isolating the role of dopamine in the acquisition of incentive salience attribution.

    Science.gov (United States)

    Chow, Jonathan J; Nickell, Justin R; Darna, Mahesh; Beckmann, Joshua S

    2016-10-01

    Stimulus-reward learning has been heavily linked to the reward-prediction error learning hypothesis and dopaminergic function. However, some evidence suggests dopaminergic function may not strictly underlie reward-prediction error learning, but may be specific to incentive salience attribution. Utilizing a Pavlovian conditioned approach procedure consisting of two stimuli that were equally reward-predictive (both undergoing reward-prediction error learning) but functionally distinct in regard to incentive salience (levers that elicited sign-tracking and tones that elicited goal-tracking), we tested the differential role of D1 and D2 dopamine receptors and nucleus accumbens dopamine in the acquisition of sign- and goal-tracking behavior and their associated conditioned reinforcing value within individuals. Overall, the results revealed that both D1 and D2 inhibition disrupted performance of sign- and goal-tracking. However, D1 inhibition specifically prevented the acquisition of sign-tracking to a lever, instead promoting goal-tracking and decreasing its conditioned reinforcing value, while neither D1 nor D2 signaling was required for goal-tracking in response to a tone. Likewise, nucleus accumbens dopaminergic lesions disrupted acquisition of sign-tracking to a lever, while leaving goal-tracking in response to a tone unaffected. Collectively, these results are the first evidence of an intraindividual dissociation of dopaminergic function in incentive salience attribution from reward-prediction error learning, indicating that incentive sal