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Sample records for striatal dopamine function

  1. Does human presynaptic striatal dopamine function predict social conformity?

    Science.gov (United States)

    Stokes, Paul R A; Benecke, Aaf; Puraite, Julita; Bloomfield, Michael A P; Shotbolt, Paul; Reeves, Suzanne J; Lingford-Hughes, Anne R; Howes, Oliver; Egerton, Alice

    2014-03-01

    Socially desirable responding (SDR) is a personality trait which reflects either a tendency to present oneself in an overly positive manner to others, consistent with social conformity (impression management (IM)), or the tendency to view one's own behaviour in an overly positive light (self-deceptive enhancement (SDE)). Neurochemical imaging studies report an inverse relationship between SDR and dorsal striatal dopamine D₂/₃ receptor availability. This may reflect an association between SDR and D₂/₃ receptor expression, synaptic dopamine levels or a combination of the two. In this study, we used a [¹⁸F]-DOPA positron emission tomography (PET) image database to investigate whether SDR is associated with presynaptic dopamine function. Striatal [¹⁸F]-DOPA uptake, (k(i)(cer), min⁻¹), was determined in two independent healthy participant cohorts (n=27 and 19), by Patlak analysis using a cerebellar reference region. SDR was assessed using the revised Eysenck Personality Questionnaire (EPQ-R) Lie scale, and IM and SDE were measured using the Paulhus Deception Scales. No significant associations were detected between Lie, SDE or IM scores and striatal [¹⁸F]-DOPA k(i)(cer). These results indicate that presynaptic striatal dopamine function is not associated with social conformity and suggests that social conformity may be associated with striatal D₂/₃ receptor expression rather than with synaptic dopamine levels.

  2. Speech-induced striatal dopamine release is left lateralized and coupled to functional striatal circuits in healthy humans: A combined PET, fMRI and DTI study

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    Simonyan, Kristina; Herscovitch, Peter; Horwitz, Barry

    2013-01-01

    Considerable progress has been recently made in understanding the brain mechanisms underlying speech and language control. However, the neurochemical underpinnings of normal speech production remain largely unknown. We investigated the extent of striatal endogenous dopamine release and its influences on the organization of functional striatal speech networks during production of meaningful English sentences using a combination of positron emission tomography (PET) with the dopamine D2/D3 receptor radioligand [11C]raclopride and functional MRI (fMRI). In addition, we used diffusion tensor tractography (DTI) to examine the extent of dopaminergic modulatory influences on striatal structural network organization. We found that, during sentence production, endogenous dopamine was released in the ventromedial portion of the dorsal striatum, in its both associative and sensorimotor functional divisions. In the associative striatum, speech-induced dopamine release established a significant relationship with neural activity and influenced the left-hemispheric lateralization of striatal functional networks. In contrast, there were no significant effects of endogenous dopamine release on the lateralization of striatal structural networks. Our data provide the first evidence for endogenous dopamine release in the dorsal striatum during normal speaking and point to the possible mechanisms behind the modulatory influences of dopamine on the organization of functional brain circuits controlling normal human speech. PMID:23277111

  3. 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...

  4. Striatal Dopamine D2/D3 Receptor Availability Is Associated with Executive Function in Healthy Controls but Not Methamphetamine Users.

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    Michael E Ballard

    Full Text Available Dopamine D2/D3 receptor availability in the striatum has been linked with executive function in healthy individuals, and is below control levels among drug addicts, possibly contributing to diminished executive function in the latter group. This study tested for an association of striatal D2/D3 receptor availability with a measure of executive function among research participants who met DSM-IV criteria for methamphetamine dependence.Methamphetamine users and non-user controls (n = 18 per group completed the Wisconsin Card Sorting Test and positron emission tomography with [18F]fallypride.The methamphetamine users displayed significantly lower striatal D2/D3 receptor availability on average than controls after controlling for age and education (p = 0.008, but they did not register greater proportions of either perseverative or non-perseverative errors when controlling for education (both ps ≥ 0.622. The proportion of non-perseverative, but not perseverative, errors was negatively correlated with striatal D2/D3 receptor availability among controls (r = -0.588, p = 0.010, but not methamphetamine users (r = 0.281, p = 0.258, and the group-wise interaction was significant (p = 0.030.These results suggest that cognitive flexibility, as measured by perseverative errors on the Wisconsin Card Sorting Test, is not determined by signaling through striatal D2/D3 receptors in healthy controls, and that in stimulant abusers, who have lower D2/D3 receptor availability, compensation can effectively maintain other executive functions, which are associated with D2/D3 receptor signaling in controls.

  5. 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...... 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 [11C]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...

  6. Keep focussing: striatal dopamine multiple functions resolved in a single mechanism tested in a simulated humanoid robot

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    Vincenzo G. Fiore

    2014-02-01

    Full Text Available The effects of striatal dopamine (DA on behavior have been widely investigated over the past decades, with ``phasic'' burst firings considered as the key expression of a reward prediction error responsible for reinforcement learning. Less well studied is tonic DA, where putative functions include the idea that it is a regulator of vigor, incentive salience, disposition to exert an effort and a modulator of approach strategies. We present a preliminary model combining tonic and phasic DA to show how different outflows triggered by either intrinsically or extrinsically motivating stimuli dynamically affect the basal ganglia by impacting on a selection process that this system performs on the inputs provided by the targeted cortex.The model, which has been tested on the simulated humanoid robot iCub in the interaction with a mechatronic board, shows the putative functions ascribed to DA emerging from the combination of a standard computational mechanism coupled to a differential sensitivity to the presence of DA across the striatum.

  7. Striatal dopamine in Parkinson disease: A meta-analysis of imaging studies.

    Science.gov (United States)

    Kaasinen, Valtteri; Vahlberg, Tero

    2017-12-01

    A meta-analysis of 142 positron emission tomography and single photon emission computed tomography studies that have investigated striatal presynaptic dopamine function in Parkinson disease (PD) was performed. Subregional estimates of striatal dopamine metabolism are presented. The aromatic L-amino-acid decarboxylase (AADC) defect appears to be consistently smaller than the dopamine transporter and vesicular monoamine transporter 2 defects, suggesting upregulation of AADC function in PD. The correlation between disease severity and dopamine loss appears linear, but the majority of longitudinal studies point to a negative exponential progression pattern of dopamine loss in PD. Ann Neurol 2017;82:873-882. © 2017 American Neurological Association.

  8. Fractal analysis of striatal dopamine re-uptake sites

    International Nuclear Information System (INIS)

    Kuikka, J.T.; Bergstroem, K.A.; Tiihonen, J.; Raesaenen, P.; Karhu, J.

    1997-01-01

    Spatial variation in regional blood flow, metabolism and receptor density within the brain and in other organs is measurable even with a low spatial resolution technique such as emission tomography. It has been previously shown that the observed variance increases with increasing number of subregions in the organ/tissue studied. This resolution-dependent variance can be described by fractal analysis. We studied striatal dopamine re-uptake sites in 39 healthy volunteers with high-resolution single-photon emission tomography using iodine-123 labelled 2β-carbomethoxy-3β-(4-iodophenyl)tropane ([ 123 I]β-CIT). The mean fractal dimension was 1.15±0.07. The results indicate that regional striatal dopamine re-uptake sites involve considerable spatial heterogeneity which is higher than the uniform density (dimension=1.00) but much lower than complete randomness (dimension=1.50). There was a gender difference, with females having a higher heterogeneity in both the left and the right striatum. In addition, we found striatal asymmetry (left-to-right heterogeneity ratio of 1.19±0.15; P<0.001), suggesting functional hemispheric lateralization consistent with the control of motor behaviour and integrative functions. (orig.). With 5 figs., 1 tab

  9. In vivo neurochemical characterization of clothianidin induced striatal dopamine release.

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    Faro, L R F; Oliveira, I M; Durán, R; Alfonso, M

    2012-12-16

    Clothianidin (CLO) is a neonicotinoid insecticide with selective action on nicotinic acetylcholine receptors. The aim of this study was to determine the neurochemical basis for CLO-induced striatal dopamine release using the microdialysis technique in freely moving and conscious rats. Intrastriatal administration of CLO (3.5mM), produced an increase in both spontaneous (2462 ± 627% with respect to basal values) and KCl-evoked (4672 ± 706% with respect to basal values) dopamine release. This effect was attenuated in Ca(2+)-free medium, and was prevented in reserpine pre-treated animals or in presence of tetrodotoxin (TTX). To investigate the involvement of dopamine transporter (DAT), the effect of CLO was observed in presence of nomifensine. The coadministration of CLO and nomifensine produced an additive effect on striatal dopamine release. The results suggest that the effect of CLO on striatal dopamine release is predominantly mediated by an exocytotic mechanism, Ca(2+), vesicular and TTX-dependent and not by a mechanism mediated by dopamine transporter. Published by Elsevier Ireland Ltd.

  10. Dorsal striatal dopamine, food preference and health perception in humans

    NARCIS (Netherlands)

    Wallace, D.L.; Aarts, E.; Dang, L.C.; Greer, S.M.; Jagust, W.J.; D'Esposito, M.

    2014-01-01

    To date, few studies have explored the neurochemical mechanisms supporting individual differences in food preference in humans. Here we investigate how dorsal striatal dopamine, as measured by the positron emission tomography (PET) tracer [(18)F]fluorometatyrosine (FMT), correlates with food-related

  11. Impaired striatal Akt signaling disrupts dopamine homeostasis and increases feeding.

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    Nicole Speed

    Full Text Available The prevalence of obesity has increased dramatically worldwide. The obesity epidemic begs for novel concepts and therapeutic targets that cohesively address "food-abuse" disorders. We demonstrate a molecular link between impairment of a central kinase (Akt involved in insulin signaling induced by exposure to a high-fat (HF diet and dysregulation of higher order circuitry involved in feeding. Dopamine (DA rich brain structures, such as striatum, provide motivation stimuli for feeding. In these central circuitries, DA dysfunction is posited to contribute to obesity pathogenesis. We identified a mechanistic link between metabolic dysregulation and the maladaptive behaviors that potentiate weight gain. Insulin, a hormone in the periphery, also acts centrally to regulate both homeostatic and reward-based HF feeding. It regulates DA homeostasis, in part, by controlling a key element in DA clearance, the DA transporter (DAT. Upon HF feeding, nigro-striatal neurons rapidly develop insulin signaling deficiencies, causing increased HF calorie intake.We show that consumption of fat-rich food impairs striatal activation of the insulin-activated signaling kinase, Akt. HF-induced Akt impairment, in turn, reduces DAT cell surface expression and function, thereby decreasing DA homeostasis and amphetamine (AMPH-induced DA efflux. In addition, HF-mediated dysregulation of Akt signaling impairs DA-related behaviors such as (AMPH-induced locomotion and increased caloric intake. We restored nigro-striatal Akt phosphorylation using recombinant viral vector expression technology. We observed a rescue of DAT expression in HF fed rats, which was associated with a return of locomotor responses to AMPH and normalization of HF diet-induced hyperphagia.Acquired disruption of brain insulin action may confer risk for and/or underlie "food-abuse" disorders and the recalcitrance of obesity. This molecular model, thus, explains how even short-term exposure to "the fast food

  12. Striatal dopamine transporter binding correlates with serum BDNF levels in patients with striatal dopaminergic neurodegeneration

    DEFF Research Database (Denmark)

    Ziebell, Morten; Khalid, Usman; Klein, Anders B

    2012-01-01

    BDNF levels in patients with parkinsonism. Twenty-one patients with abnormal in vivo striatal dopamine transporter (DAT) binding as evidenced with [(123)I]PE2I SPECT brain scanning were included. Samples for serum BDNF levels were collected at the time of the SPECT scanning, and BDNF was measured...

  13. Cannabinoid-1 receptor antagonist rimonabant (SR141716) increases striatal dopamine D2 receptor availability

    NARCIS (Netherlands)

    Crunelle, Cleo L.; van de Giessen, Elsmarieke; Schulz, Sybille; Vanderschuren, Louk J. M. J.; de Bruin, Kora; van den Brink, Wim; Booij, Jan

    2013-01-01

    The cannabinoid 1 receptor antagonist rimonabant (SR141716) alters rewarding properties and intake of food and drugs. Additionally, striatal dopamine D2 receptor (DRD2) availability has been implicated in reward function. This study shows that chronic treatment of rats with rimonabant (1.0 and

  14. Contribution of vesicular and cytosolic dopamine to the increased striatal dopamine efflux elicited by intrastriatal injection of SKF38393.

    NARCIS (Netherlands)

    Saigusa, T.; Aono, Y.; Sekino, R.; Uchida, T.; Takada, K.; Oi, Y.; Koshikawa, N.; Cools, A.R.

    2009-01-01

    Like dexamphetamine, SKF38393 induces an increase in striatal dopamine efflux which is insensitive for tetrodotoxin, Ca(2+) independent and prevented by a dopamine transporter inhibitor. The dexamphetamine-induced striatal dopamine efflux originates from both the reserpine-sensitive vesicular

  15. Regulation of bat echolocation pulse acoustics by striatal dopamine.

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    Tressler, Jedediah; Schwartz, Christine; Wellman, Paul; Hughes, Samuel; Smotherman, Michael

    2011-10-01

    The ability to control the bandwidth, amplitude and duration of echolocation pulses is a crucial aspect of echolocation performance but few details are known about the neural mechanisms underlying the control of these voice parameters in any mammal. The basal ganglia (BG) are a suite of forebrain nuclei centrally involved in sensory-motor control and are characterized by their dependence on dopamine. We hypothesized that pharmacological manipulation of brain dopamine levels could reveal how BG circuits might influence the acoustic structure of bat echolocation pulses. A single intraperitoneal injection of a low dose (5 mg kg(-1)) of the neurotoxin 1-methyl-4-phenylpyridine (MPTP), which selectively targets dopamine-producing cells of the substantia nigra, produced a rapid degradation in pulse acoustic structure and eliminated the bat's ability to make compensatory changes in pulse amplitude in response to background noise, i.e. the Lombard response. However, high-performance liquid chromatography (HPLC) measurements of striatal dopamine concentrations revealed that the main effect of MPTP was a fourfold increase rather than the predicted decrease in striatal dopamine levels. After first using autoradiographic methods to confirm the presence and location of D(1)- and D(2)-type dopamine receptors in the bat striatum, systemic injections of receptor subtype-specific agonists showed that MPTP's effects on pulse acoustics were mimicked by a D(2)-type dopamine receptor agonist (Quinpirole) but not by a D(1)-type dopamine receptor agonist (SKF82958). The results suggest that BG circuits have the capacity to influence echolocation pulse acoustics, particularly via D(2)-type dopamine receptor-mediated pathways, and may therefore represent an important mechanism for vocal control in bats.

  16. Decreased spontaneous eye blink rates in chronic cannabis users: evidence for striatal cannabinoid-dopamine interactions.

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    Mikael A Kowal

    Full Text Available Chronic cannabis use has been shown to block long-term depression of GABA-glutamate synapses in the striatum, which is likely to reduce the extent to which endogenous cannabinoids modulate GABA- and glutamate-related neuronal activity. The current study aimed at investigating the effect of this process on striatal dopamine levels by studying the spontaneous eye blink rate (EBR, a clinical marker of dopamine level in the striatum. 25 adult regular cannabis users and 25 non-user controls matched for age, gender, race, and IQ were compared. Results show a significant reduction in EBR in chronic users as compared to non-users, suggesting an indirect detrimental effect of chronic cannabis use on striatal dopaminergic functioning. Additionally, EBR correlated negatively with years of cannabis exposure, monthly peak cannabis consumption, and lifetime cannabis consumption, pointing to a relationship between the degree of impairment of striatal dopaminergic transmission and cannabis consumption history.

  17. Phasic dopamine release drives rapid activation of striatal D2-receptors

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    Marcott, Pamela F; Mamaligas, Aphroditi A; Ford, Christopher P

    2014-01-01

    Summary Striatal dopamine transmission underlies numerous goal-directed behaviors. Medium spiny neurons (MSNs) are a major target of dopamine in the striatum. However, as dopamine does not directly evoke a synaptic event in MSNs, the time course of dopamine signaling in these cells remains unclear. To examine how dopamine release activates D2-receptors on MSNs, G-protein activated inwardly rectifying potassium (GIRK2; Kir 3.2) channels were virally overexpressed in the striatum and the resulting outward currents were used as a sensor of D2-receptor activation. Electrical and optogenetic stimulation of dopamine terminals evoked robust D2-receptor inhibitory post-synaptic currents (IPSCs) in GIRK2-expressing MSNs that occurred in under a second. Evoked D2-IPSCs could be driven by repetitive stimulation and were not occluded by background dopamine tone. Together, the results indicate that D2-receptors on MSNs exhibit functional low affinity and suggest that striatal D2-receptors can encode both tonic and phasic dopamine signals. PMID:25242218

  18. No association between striatal dopamine transporter binding and body mass index

    DEFF Research Database (Denmark)

    van de Giessen, Elsmarieke; Hesse, Swen; Caan, Matthan W A

    2013-01-01

    Dopamine is one among several neurotransmitters that regulate food intake and overeating. Thus, it has been linked to the pathophysiology of obesity and high body mass index (BMI). Striatal dopamine D(2) receptor availability is lower in obesity and there are indications that striatal dopamine tr...

  19. Dopamine D(1) receptor-mediated control of striatal acetylcholine release by endogenous dopamine.

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    Acquas, E; Di Chiara, G

    1999-10-27

    The role of dopamine D(1) and D(2) receptors in the control of acetylcholine release in the dorsal striatum by endogenous dopamine was investigated by monitoring with microdialysis the effect of the separate or combined administration of the dopamine D(1) receptor antagonist, SCH 39166 ¿(-)-trans-6,7,7a,8,9, 13b-exahydro-3-chloro-2-hydroxy-N-methyl-5H-benzo-[d]-nap hto-[2, 1b]-azepine hydrochloride¿ (50 microg/kg subcutaneous (s.c.)), of the dopamine D(2)/D(3) receptor agonist, quinpirole (trans-(-)-4aR, 4a,5,6,7,8,8a,9-octahydro-5-propyl-1H-pyrazolo-(3,4-g)-quinoline hydrochloride) (5 and 10 microg/kg s.c.), and of the D(3) receptor selective agonist, PD 128,907 [S(+)-(4aR,10bR)-3,4,4a, 10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano-[4,3-b]-1,4-oxazin -9-ol hydrochloride] (50 microg/kg s.c.), on in vivo dopamine and acetylcholine release. Microdialysis was performed with a Ringer containing low concentrations (0.01 microM) of the acetylcholinesterase inhibitor, neostigmine. Quinpirole (10 microg/kg s.c.) decreased striatal dopamine and acetylcholine release. Administration of PD 128,907 (50 microg/kg) decreased dopamine but failed to affect acetylcholine release. SCH 39166 (50 microg/kg s.c.) stimulated dopamine release and reduced acetylcholine release. Pretreatment with quinpirole reduced (5 microg/kg s.c.) or completely prevented (10 microg/kg s.c.) the stimulation of dopamine release elicited by SCH 39166 (50 microg/kg s.c.); on the other hand, pretreatment with quinpirole (5 and 10 microg/kg) potentiated the reduction of striatal acetylcholine release induced by SCH 39166 (50 microg/kg s.c.). Similarly, pretreatment with PD 128,907 (50 microg/kg) which prevented the increase of dopamine release induced by SCH 39166 (50 microg/kg), potentiated the reduction of striatal acetylcholine transmission elicited by SCH 39166. Thus, pretreatment with low doses of quinpirole or PD 128,907 influences in opposite manner the effect of SCH 39166 on striatal dopamine and

  20. Further human evidence for striatal dopamine release induced by administration of ∆9-tetrahydrocannabinol (THC): selectivity to limbic striatum.

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    Bossong, Matthijs G; Mehta, Mitul A; van Berckel, Bart N M; Howes, Oliver D; Kahn, René S; Stokes, Paul R A

    2015-08-01

    Elevated dopamine function is thought to play a key role in both the rewarding effects of addictive drugs and the pathophysiology of schizophrenia. Accumulating epidemiological evidence indicates that cannabis use is a risk factor for the development of schizophrenia. However, human neurochemical imaging studies that examined the impact of ∆9-tetrahydrocannabinol (THC), the main psychoactive component in cannabis, on striatal dopamine release have provided inconsistent results. The objective of this study is to assess the effect of a THC challenge on human striatal dopamine release in a large sample of healthy participants. We combined human neurochemical imaging data from two previous studies that used [(11)C]raclopride positron emission tomography (PET) (n = 7 and n = 13, respectively) to examine the effect of THC on striatal dopamine neurotransmission in humans. PET images were re-analysed to overcome differences in PET data analysis. THC administration induced a significant reduction in [(11)C]raclopride binding in the limbic striatum (-3.65 %, from 2.39 ± 0.26 to 2.30 ± 0.23, p = 0.023). This is consistent with increased dopamine levels in this region. No significant differences between THC and placebo were found in other striatal subdivisions. In the largest data set of healthy participants so far, we provide evidence for a modest increase in human striatal dopamine transmission after administration of THC compared to other drugs of abuse. This finding suggests limited involvement of the endocannabinoid system in regulating human striatal dopamine release and thereby challenges the hypothesis that an increase in striatal dopamine levels after cannabis use is the primary biological mechanism underlying the associated higher risk of schizophrenia.

  1. Single cocaine exposure does not alter striatal pre-synaptic dopamine function in mice: an [18 F]-FDOPA PET study.

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    Bonsall, David R; Kokkinou, Michelle; Veronese, Mattia; Coello, Christopher; Wells, Lisa A; Howes, Oliver D

    2017-12-01

    Cocaine is a recreational drug of abuse that binds to the dopamine transporter, preventing reuptake of dopamine into pre-synaptic terminals. The increased presence of synaptic dopamine results in stimulation of both pre- and post-synaptic dopamine receptors, considered an important mechanism by which cocaine elicits its reinforcing properties. However, the effects of acute cocaine administration on pre-synaptic dopamine function remain unclear. Non-invasive imaging techniques such as positron emission tomography have revealed impaired pre-synaptic dopamine function in chronic cocaine users. Similar impairments have been seen in animal studies, with microdialysis experiments indicating decreased basal dopamine release. Here we use micro positron emission tomography imaging techniques in mice to measure dopamine synthesis capacity and determine the effect of acute cocaine administration of pre-synaptic dopamine function. We show that a dose of 20 mg/kg cocaine is sufficient to elicit hyperlocomotor activity, peaking 15-20 min post treatment (p cocaine treatment (KiCer: 0.0097 per min vs. 0.0112 per min in vehicle controls, p > 0.05). Furthermore, expression levels of two key enzymes related to dopamine synthesis, tyrosine hydroxylase and aromatic l-amino acid decarboxylase, within the striatum of scanned mice were not significantly affected by acute cocaine pre-treatment (p > 0.05). Our findings suggest that while the regulation of dopamine synthesis and release in the striatum have been shown to change with chronic cocaine use, leading to a reduced basal tone, these adaptations to pre-synaptic dopaminergic neurons are not initiated following a single exposure to the drug. © 2017 International Society for Neurochemistry.

  2. Endocannabinoid-dopamine interactions in striatal synaptic plasticity

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    Brian Neil Mathur

    2012-04-01

    Full Text Available The nigrostriatal dopaminergic system is implicated in action control and learning. A large body of work has focused on the contribution of this system to modulation of the corticostriatal synapse, the predominant synapse type in the striatum. Signaling through the D2 dopamine receptor is necessary for endocannabinoid-mediated depression of corticostriatal glutamate release. Here we review the known details of this mechanism and discuss newly discovered signaling pathways interacting with this system that ultimately exert dynamic control of cortical input to the striatum and striatal output. This topic is timely with respect to Parkinson’s disease given recent data indicating changes in the striatal endocannabinoid system in patients with this disorder.

  3. Dysregulation of Striatal Dopamine Receptor Binding in Suicide.

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    Fitzgerald, Megan L; Kassir, Suham A; Underwood, Mark D; Bakalian, Mihran J; Mann, J John; Arango, Victoria

    2017-03-01

    Inconsistent evidence implicates disruptions of striatal dopaminergic indices in suicide and major depression. To determine whether there are alterations in the striatal dopamine system in suicide, we conducted a quantitative autoradiographic survey of dopamine transporter (DAT; [ 3 H]mazindol), D1 receptor ([ 3 H]SCH23390), and D2 receptor ([ 3 H]sulpiride) binding in the dorsal striatum postmortem from matched suicides and controls. Axis I and axis II psychiatric diagnosis, recent treatment history, and early life adversity (ELA) were determined by psychological autopsy. Mean DAT, D2, and D1 receptor binding did not differ in suicide. However, there was a positive correlation between D1 and D2 receptor binding in the dorsal striatum of control subjects (R 2 =0.31, p<0.05) that was not present in suicides (R 2 =0.00, p=0.97). In suicides and controls with reported ELA, there was no correlation between striatal DAT and D1 receptor binding (R 2 =0.07, p=0.33), although DAT and D1 receptor binding was positively correlated in subjects with no report of ELA (R 2 =0.32, p<0.05). After controlling for age, there were no significant ELA-related mean differences. Binding of D1 receptors and DAT throughout the striatum correlated negatively with age (D1 receptor: R 2 =0.12, p<0.05; DAT: R 2 =0.36, p<0.001). There appears to be an imbalance in dopaminergic receptor and transporter expression related to suicide that differs from that associated with ELA or age.

  4. Dopamine signaling negatively regulates striatal phosphorylation of Cdk5 at tyrosine 15 in mice.

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    Yukio eYamamura

    2013-02-01

    Full Text Available Striatal functions depend on the activity balance between the dopamine and glutamate neurotransmissions. Glutamate inputs activate cyclin-dependent kinase 5 (Cdk5, which inhibits postsynaptic dopamine signaling by phosphorylating DARPP-32 (dopamine- and cAMP-regulated phosphoprotein, 32 kDa at Thr75 in the striatum. c-Abelson tyrosine kinase (c-Abl is known to phosphorylate Cdk5 at Tyr15 (Tyr15-Cdk5 and thereby facilitates the Cdk5 activity. We here report that Cdk5 with Tyr15 phosphorylation (Cdk5-pTyr15 is enriched in the mouse striatum, where dopaminergic stimulation inhibited phosphorylation of Tyr15-Cdk5 by acting through the D2 class dopamine receptors. Moreover, in the 1-methyl-4-phenyl-1,2,4,6-tetrahydropyridine mouse model, dopamine deficiency caused increased phosphorylation of both Tyr15-Cdk5 and Thr75-DARPP-32 in the striatum, which could be attenuated by administration of L-3,4-dihydroxyphenylalanine and imatinib (STI-571, a selective c-Abl inhibitor. Our results suggest a functional link of Cdk5-pTyr15 with postsynaptic dopamine and glutamate signals through the c-Abl kinase activity in the striatum.

  5. Environmental enrichment enhances synaptic plasticity by internalization of striatal dopamine transporters

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    Kim, Myung-Sun; Yu, Ji Hea; Kim, Chul Hoon; Choi, Jae Yong; Seo, Jung Hwa; Lee, Min-Young; Yi, Chi Hoon; Choi, Tae Hyun; Ryu, Young Hoon; Lee, Jong Eun; Lee, Bae Hwan; Kim, Hyongbum

    2015-01-01

    Environmental enrichment (EE) with a complex combination of physical, cognitive and social stimulations enhances synaptic plasticity and behavioral function. However, the mechanism remains to be elucidated in detail. We aimed to investigate dopamine-related synaptic plasticity underlying functional improvement after EE. For this, six-week-old CD-1 mice were randomly allocated to EE or standard conditions for two months. EE significantly enhanced behavioral functions such as rotarod and ladder walking tests. In a [18F]FPCIT positron emission tomography scan, binding values of striatal DAT were significantly decreased approximately 18% in the EE mice relative to the control mice. DAT inhibitor administrated to establish the relationship of the DAT down-regulation to the treatment effects also improved rotarod performances, suggesting that DAT inhibition recapitulated EE-mediated treatment benefits. Next, EE-induced internalization of DAT was confirmed using a surface biotinylation assay. In situ proximity ligation assay and immunoprecipitation demonstrated that EE significantly increased the phosphorylation of striatal DAT as well as the levels of DAT bound with protein kinase C (PKC). In conclusion, we suggest that EE enables phosphorylation of striatal DAT via a PKC-mediated pathway and causes DAT internalization. This is the first report to suggest an EE-mediated mechanism of synaptic plasticity by internalization of striatal DAT. PMID:26661218

  6. Multicistronic lentiviral vector-mediated striatal gene transfer of aromatic L-amino acid decarboxylase, tyrosine hydroxylase, and GTP cyclohydrolase I induces sustained transgene expression, dopamine production, and functional improvement in a rat model of Parkinson's disease.

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    Azzouz, Mimoun; Martin-Rendon, Enca; Barber, Robert D; Mitrophanous, Kyriacos A; Carter, Emma E; Rohll, Jonathan B; Kingsman, Susan M; Kingsman, Alan J; Mazarakis, Nicholas D

    2002-12-01

    Parkinson's disease (PD) is a neurodegenerative disorder characterized by the selective loss of dopaminergic neurons in the substantia nigra. This loss leads to complete dopamine depletion in the striatum and severe motor impairment. It has been demonstrated previously that a lentiviral vector system based on equine infectious anemia virus (EIAV) gives rise to highly efficient and sustained transduction of neurons in the rat brain. Therefore, a dopamine replacement strategy using EIAV has been investigated as a treatment in the 6-hydroxydopamine (6-OHDA) animal model of PD. A self-inactivating EIAV minimal lentiviral vector that expresses tyrosine hydroxylase (TH), aromatic amino acid dopa decarboxylase (AADC), and GTP cyclohydrolase 1 (CH1) in a single transcription unit has been generated. In cultured striatal neurons transduced with this vector, TH, AADC, and CH1 proteins can all be detected. After stereotactic delivery into the dopamine-denervated striatum of the 6-OHDA-lesioned rat, sustained expression of each enzyme and effective production of catecholamines were detected, resulting in significant reduction of apomorphine-induced motor asymmetry compared with control animals (p < 0.003). Expression of each enzyme in the striatum was observed for up to 5 months after injection. These data indicate that the delivery of three catecholaminergic synthetic enzymes by a single lentiviral vector can achieve functional improvement and thus open the potential for the use of this vector for gene therapy of late-stage PD patients.

  7. Presynaptic Dopamine Synthesis Capacity in Schizophrenia and Striatal Blood Flow Change During Antipsychotic Treatment and Medication-Free Conditions.

    Science.gov (United States)

    Eisenberg, Daniel Paul; Yankowitz, Lisa; Ianni, Angela M; Rubinstein, Dani Y; Kohn, Philip D; Hegarty, Catherine E; Gregory, Michael D; Apud, José A; Berman, Karen F

    2017-10-01

    Standard-of-care biological treatment of schizophrenia remains dependent upon antipsychotic medications, which demonstrate D 2 receptor affinity and elicit variable, partial clinical responses via neural mechanisms that are not entirely understood. In the striatum, where D 2 receptors are abundant, antipsychotic medications may affect neural function in studies of animals, healthy volunteers, and patients, yet the relevance of this to pharmacotherapeutic actions remains unresolved. In this same brain region, some individuals with schizophrenia may demonstrate phenotypes consistent with exaggerated dopaminergic signaling, including alterations in dopamine synthesis capacity; however, the hypothesis that dopamine system characteristics underlie variance in medication-induced regional blood flow changes has not been directly tested. We therefore studied a cohort of 30 individuals with schizophrenia using longitudinal, multi-session [ 15 O]-water and [ 18 F]-FDOPA positron emission tomography to determine striatal blood flow during active atypical antipsychotic medication treatment and after at least 3 weeks of placebo treatment, along with presynaptic dopamine synthesis capacity (ie, DOPA decarboxylase activity). Regional striatal blood flow was significantly higher during active treatment than during the placebo condition. Furthermore, medication-related increases in ventral striatal blood flow were associated with more robust amelioration of excited factor symptoms during active medication and with higher dopamine synthesis capacity. These data indicate that atypical medications enact measureable physiological alterations in limbic striatal circuitry that vary as a function of dopaminergic tone and may have relevance to aspects of therapeutic responses.

  8. [3H]Dopamine accumulation and release from striatal slices in young, mature and senescent rats

    International Nuclear Information System (INIS)

    Thompson, J.M.

    1981-01-01

    Examinations of [ 3 H]dopamine ([ 3 H]DA) release following KCl or amphetamine administration in striatal slices from young (7 month), mature (12 month) and senescent (24 month) Wistar rats showed no age-related changes. Further, the amount of [ 3 H]DA accumulated in the striatal slices showed no changes with age. Thus, previously reported age-related deficits in motor behavior (i.e. rotational) are not produced by changes in striatal DA accumulation or release. (Auth.)

  9. Role of DARPP-32 and ARPP-21 in the Emergence of Temporal Constraints on Striatal Calcium and Dopamine Integration

    Science.gov (United States)

    Bhalla, Upinder S.; Hellgren Kotaleski, Jeanette

    2016-01-01

    In reward learning, the integration of NMDA-dependent calcium and dopamine by striatal projection neurons leads to potentiation of corticostriatal synapses through CaMKII/PP1 signaling. In order to elicit the CaMKII/PP1-dependent response, the calcium and dopamine inputs should arrive in temporal proximity and must follow a specific (dopamine after calcium) order. However, little is known about the cellular mechanism which enforces these temporal constraints on the signal integration. In this computational study, we propose that these temporal requirements emerge as a result of the coordinated signaling via two striatal phosphoproteins, DARPP-32 and ARPP-21. Specifically, DARPP-32-mediated signaling could implement an input-interval dependent gating function, via transient PP1 inhibition, thus enforcing the requirement for temporal proximity. Furthermore, ARPP-21 signaling could impose the additional input-order requirement of calcium and dopamine, due to its Ca2+/calmodulin sequestering property when dopamine arrives first. This highlights the possible role of phosphoproteins in the temporal aspects of striatal signal transduction. PMID:27584878

  10. Measurement of striatal dopamine metabolism with 6-[18F]-fluoro-L-dopa and PET

    International Nuclear Information System (INIS)

    Kuwabara, Y.; Otsuka, M.; Ichiya, Y.; Yoshikai, T.; Fukumura, T.; Masuda, K.; Kato, M.; Taniwaki, T.

    1992-01-01

    Striatal dopamine metabolism was studied with 6-[ 18 F]-fluoro-L-dopa ( 18 F-DOPA) and PET. The subjects were normal controls, and patients with Parkinson's disease (PD), parkinsonism, multiple system atrophy (MSA), progressive supranuclear palsy (PSP), Alzheimer's disease (AD), Huntington's disease (HD) and other cerebral disorders. Cerebral glucose metabolism (CMRGlc) was also measured in these patients. Striatal dopamine metabolism was evaluated by the relative striatal uptake of 18 F-DOPA referring cerebellum (S/C ratio). In normal controls, the S/C ratio was 2.82 ± 0.32 (n = 6, mean ± SD) at 120 min after injection of 18 F-DOPA. The S/C ratio was low in patients with PD, parkinsonism, MSA and PSP compared to the normal controls and thus coincident with the symptoms of parkinsonism due to decrease in striatal dopamine concentration. The decrease in the striatal CMRGlc was also observed in patients with parkinsonism and PSP, and it was preserved in patients with PD, thus representing that more neurons were damaged in patients with parkinsonism and PSP than in patients with PD. A patient with AD having symptoms of parkinsonism also showed a decrease in S/C ratio. In a patient with HD, the striatal CMRGlc sharply decreased, but the S/C ratio was normal. The measurements of striatal dopamine and glucose metabolism with PET may be useful for studying the pathophysiological mechanism in patients with cerebral disorders. (author)

  11. Differences in striatal dopamine transporter density between tremor dominant and non-tremor Parkinson's disease

    Energy Technology Data Exchange (ETDEWEB)

    Kaasinen, Valtteri; Kinos, Maija; Joutsa, Juho [University of Turku and Turku University Hospital, Division of Clinical Neurosciences, Turku (Finland); University of Turku and Turku University Hospital, Turku PET Centre, Turku (Finland); Seppaenen, Marko [University of Turku and Turku University Hospital, Turku PET Centre, Turku (Finland); University of Turku and Turku University Hospital, Department of Clinical Physiology and Nuclear Medicine, Turku (Finland); Noponen, Tommi [University of Turku and Turku University Hospital, Department of Clinical Physiology and Nuclear Medicine, Turku (Finland)

    2014-10-15

    Parkinson's disease (PD) can manifest with a tremor-dominant or a non-tremor (akinetic-rigid) phenotype. Although the tremor-dominant subtype may show a better prognosis, there is limited information on the phenotypic differences regarding the level of striatal dopamine transmission. The present study investigated striatal dopamine transporter (DAT) binding characteristics in a large sample of patients with and without tremor. [{sup 123}I]FP-CIT SPECT scans of 231 patients with a clinical diagnosis of PD and abnormal FP-CIT binding (157 with tremor, 74 without tremor) and 230 control patients with normal FP-CIT binding (148 with tremor, 82 without tremor) were analysed using an automated region-of-interest analysis of the scans (BRASS). Specific striatal binding ratios were compared between phenotypes and groups using age, sex, and symptom duration, predominant side of symptoms, dopaminergic medications and scanner as covariates. Patients with PD had 28.1 - 65.0 % lower binding in all striatal regions compared to controls (p < 0.001). The mean FP-CIT caudate nucleus uptake and the left caudate nucleus uptake were higher in PD patients with tremor than in PD patients without tremor (mean 9.0 % higher, left 10.5 % higher; p < 0.05), whereas there were no differences between tremor and non-tremor control patients. No significant effects of tremor on DAT binding were observed in the anterior or posterior putamen. The motor phenotype is associated with the extent of caudate dopamine terminal loss in PD, as dopamine function is relatively more preserved in tremor patients. Symptom type is related to caudate dopamine function only in association with Parkinsonian dopaminergic degeneration, not in intact dopamine systems in patients with non-PD tremor. (orig.)

  12. Reduced Striatal Dopamine Transporters in People with Internet Addiction Disorder

    Directory of Open Access Journals (Sweden)

    Haifeng Hou

    2012-01-01

    Full Text Available In recent years, internet addiction disorder (IAD has become more prevalent worldwide and the recognition of its devastating impact on the users and society has rapidly increased. However, the neurobiological mechanism of IAD has not bee fully expressed. The present study was designed to determine if the striatal dopamine transporter (DAT levels measured by T99mc-TRODAT-1 single photon emission computed tomography (SPECT brain scans were altered in individuals with IAD. SPECT brain scans were acquired on 5 male IAD subjects and 9 healthy age-matched controls. The volume (V and weight (W of bilateral corpus striatum as well as the T99mc-TRODAT-1 uptake ratio of corpus striatum/the whole brain (Ra were calculated using mathematical models. It was displayed that DAT expression level of striatum was significantly decreased and the V, W, and Ra were greatly reduced in the individuals with IAD compared to controls. Taken together, these results suggest that IAD may cause serious damages to the brain and the neuroimaging findings further illustrate IAD is associated with dysfunctions in the dopaminergic brain systems. Our findings also support the claim that IAD may share similar neurobiological abnormalities with other addictive disorders.

  13. Effects of isomers of apomorphines on dopamine receptors in striatal and limbic tissue of rat brain

    Energy Technology Data Exchange (ETDEWEB)

    Kula, N.S.; Baldessarini, R.J.; Bromley, S.; Neumeyer, J.L.

    1985-09-16

    The optical isomers of apomorphine (APO) and N-propylnorapomorphine (NPA) were interacted with three biochemical indices of dopamine (Da) receptors in extrapyramidal and limbic preparations of rat brain tissues. There were consistent isomeric preferences for the R(-) configuration of both DA analogs in stimulation adenylate cyclase (D-1 sites) and in competing for high affinity binding of /sup 3/H-spiroperidol (D-2 sites) and of /sup 3/H-ADTN (DA agonist binding sites) in striatal tissue, with lesser isomeric differences in the limbic tissue. The S(+) apomorphines did not inhibit stimulation of adenylate cyclase by DA. The tendency for greater activity of higher apparent affinity of R(-) apomorphines in striatum may reflect the evidently greater abundance of receptor sites in that region. There were only small regional differences in interactions of the apomorphine isomers with all three receptor sites, except for a strong preference of (-)NPA for striatal D-2 sites. These results do not parallel our recent observations indicating potent and selective antidopaminergic actions of S(+) apomorphines in the rat limbic system. They suggest caution in assuming close parallels between current biochemical functional, especially behavioral, methods of evaluating dopamine receptors of mammalian brain.

  14. Revisiting the 'self-medication' hypothesis in light of the new data linking low striatal dopamine to comorbid addictive behavior.

    Science.gov (United States)

    Awad, A George; Voruganti, Lakshmi L N P

    2015-06-01

    Persons with schizophrenia are at a high risk, almost 4.6 times more likely, of having drug abuse problems than persons without psychiatric illness. Among the influential proposals to explain such a high comorbidity rate, the 'self-medication hypothesis' proposed that persons with schizophrenia take to drugs in an effort to cope with the illness and medication side effects. In support of the self-medication hypothesis, data from our earlier clinical study confirmed the strong association between neuroleptic dysphoria and negative subjective responses and comorbid drug abuse. Though dopamine has been consistently suspected as one of the major culprits for the development of neuroleptic dysphoria, it is only recently our neuroimaging studies correlated the emergence of neuroleptic dysphoria to the low level of striatal dopamine functioning. Similarly, more evidence has recently emerged linking low striatal dopamine with the development of vulnerability for drug addictive states in schizophrenia. The convergence of evidence from both the dysphoria and comorbidity research, implicating the role of low striatal dopamine in both conditions, has led us to propose that the person with schizophrenia who develops dysphoria and comorbid addictive disorder is likely to be one and the same.

  15. Declines in stimulated striatal dopamine release over the first 32 h following microdialysis probe insertion: generalization across releasing mechanisms.

    Science.gov (United States)

    Holson, R R; Gazzara, R A; Gough, B

    1998-10-19

    In a recent paper [R.R. Holson, J.F. Bowyer, P. Clausing, B. Gough, Methamphetamine-stimulated striatal dopamine release declines rapidly over time following microdialysis probe insertion, Brain Res. 739 (1996) 301-307] we reported that methamphetamine-stimulated striatal dopamine release declined rapidly over the first eight hours following microdialysis probe insertion. This decline was strictly a function of time post-probe implantation, and not due to tolerance or desensitization. To further examine this phenomenon, we subjected rats to three brief pulses of several DA-releasing compounds at 2, 4 and 6 h post-probe insertion, and compared these results to those caused by a single pulse 6 h post-insertion, or in some cases to pulses given more than 24 h post-insertion. We found that when buproprion, a dopamine reuptake blocker, was infused briefly into the striatum via the microdialysis probe, there was a pronounced drop in the amount of dopamine released at 6 h vs. 2 h post-insertion; this drop was not due to repeated exposure, since dopamine release at 6 h post-insertion was the same for a single pulse, or when preceded by two earlier pulses. Twenty-four hours later, buproprion-stimulated dopamine release was still lower, but did not appear to drop further thereafter. Potassium-stimulated dopamine release, on the other hand, dropped rapidly over the first 8 h post-insertion, and this decline continued throughout the 24-32 h interval post-insertion. Similarly, a single i.p. injection of 0.5 mg/kg haloperidol released three times as much dopamine when given two compared to six hours post-implantation. Both bupropion- and potassium-stimulated dopamine release were accompanied by declines in extracellular DOPAC concentrations, and these declines were the same 2 or 26 h post-insertion. In contrast, haloperidol exposure increased extracellular DOPAC, and this haloperidol-stimulated DOPAC increase was also greatly attenuated at 6 compared to 2 h post-insertion. We

  16. Phasic Dopamine Modifies Sensory-Driven Output of Striatal Neurons through Synaptic Plasticity.

    Science.gov (United States)

    Wieland, Sebastian; Schindler, Sebastian; Huber, Cathrin; Köhr, Georg; Oswald, Manfred J; Kelsch, Wolfgang

    2015-07-08

    Animals are facing a complex sensory world in which only few stimuli are relevant to guide behavior. Value has to be assigned to relevant stimuli such as odors to select them over concurring information. Phasic dopamine is involved in the value assignment to stimuli in the ventral striatum. The underlying cellular mechanisms are incompletely understood. In striatal projection neurons of the ventral striatum in adult mice, we therefore examined the features and dynamics of phasic dopamine-induced synaptic plasticity and how this plasticity may modify the striatal output. Phasic dopamine is predicted to tag inputs that occur in temporal proximity. Indeed, we observed D1 receptor-dependent synaptic potentiation only when odor-like bursts and optogenetically evoked phasic dopamine release were paired within a time window of synaptic potentiation persisted after the phasic dopamine signal had ceased, but gradually reversed when odor-like bursts continued to be presented. The synaptic plasticity depended on the sensory input rate and was input specific. Importantly, synaptic plasticity amplified the firing response to a given olfactory input as the dendritic integration and the firing threshold remained unchanged during synaptic potentiation. Thus, phasic dopamine-induced synaptic plasticity can change information transfer through dynamic increases of the output of striatal projection neurons to specific sensory inputs. This plasticity may provide a neural substrate for dynamic value assignment in the striatum. Copyright © 2015 the authors 0270-6474/15/359946-11$15.00/0.

  17. Is there a relation between novelty seeking, striatal dopamine release and frontal cortical thickness?

    Directory of Open Access Journals (Sweden)

    Natalia Jaworska

    Full Text Available Novelty-seeking (NS and impulsive personality traits have been proposed to reflect an interplay between fronto-cortical and limbic systems, including the limbic striatum (LS. Although neuroimaging studies have provided some evidence for this, most are comprised of small samples and many report surprisingly large effects given the challenges of trying to relate a snapshot of brain function or structure to an entity as complex as personality. The current work tested a priori hypotheses about associations between striatal dopamine (DA release, cortical thickness (CT, and NS in a large sample of healthy adults.Fifty-two healthy adults (45M/7F; age: 23.8±4.93 underwent two positron emission tomography scans with [11C]raclopride (specific for striatal DA D2/3 receptors with or without amphetamine (0.3 mg/kg, p.o.. Structural magnetic resonance image scans were acquired, as were Tridimensional Personality Questionnaire data. Amphetamine-induced changes in [11C]raclopride binding potential values (ΔBPND were examined in the limbic, sensorimotor (SMS and associative (AST striatum. CT measures, adjusted for whole brain volume, were extracted from the dorsolateral sensorimotor and ventromedial/limbic cortices.BPND values were lower in the amphetamine vs. no-drug sessions, with the largest effect in the LS. When comparing low vs. high LS ΔBPND groups (median split, higher NS2 (impulsiveness scores were found in the high ΔBPND group. Partial correlations (age and gender as covariates yielded a negative relation between ASTS ΔBPND and sensorimotor CT; trends for inverse associations existed between ΔBPND values in other striatal regions and frontal CT. In other words, the greater the amphetamine-induced striatal DA response, the thinner the frontal cortex.These data expand upon previously reported associations between striatal DA release in the LS and both NS related impulsiveness and CT in the largest sample reported to date. The findings add to the

  18. Reduced striatal dopamine D2/3 receptor availability in Body Dysmorphic Disorder

    NARCIS (Netherlands)

    Vulink, Nienke C; Planting, Robin S; Figee, Martijn; Booij, Jan; Denys, D.

    Though the dopaminergic system is implicated in Obsessive Compulsive and Related Disorders (OCRD), the dopaminergic system has never been investigated in-vivo in Body Dysmorphic Disorder (BDD). In line with consistent findings of reduced striatal dopamine D2/3 receptor availability in Obsessive

  19. Reduced striatal dopamine D2/3 receptor availability in Body Dysmorphic Disorder

    NARCIS (Netherlands)

    Vulink, Nienke C.; Planting, Robin S.; Figee, Martijn; Booij, Jan; Denys, Damiaan

    2016-01-01

    Though the dopaminergic system is implicated in Obsessive Compulsive and Related Disorders (OCRD), the dopaminergic system has never been investigated in-vivo in Body Dysmorphic Disorder (BDD). In line with consistent findings of reduced striatal dopamine D2/3 receptor availability in Obsessive

  20. Apathy and striatal dopamine transporter levels in de-novo, untreated Parkinson's disease patients.

    Science.gov (United States)

    Santangelo, Gabriella; Vitale, Carmine; Picillo, Marina; Cuoco, Sofia; Moccia, Marcello; Pezzella, Domenica; Erro, Roberto; Longo, Katia; Vicidomini, Caterina; Pellecchia, Maria Teresa; Amboni, Marianna; Brunetti, Arturo; Salvatore, Marco; Barone, Paolo; Pappatà, Sabina

    2015-05-01

    Apathy is a neuropsychiatric symptom in Parkinson's Disease (PD) which has a negative impact on quality of life and might be related in part to damage of presynaptic dopaminergic system. Little is known about relationship between striatal dopamine levels and apathy in PD patients without dementia and/or depression. The aim of the present study was to investigate the relationship between "pure apathy" and striatal dopamine uptake in untreated, drug-naïve PD patients without clinically significant dementia and/or depression. Fourteen PD patients with pure apathy and 14 PD patients without apathy, matched for age, side of motor symptoms at onset, motor disability and disease duration, underwent both neuropsychological and behavioral examination including self-rated version of the Apathy Evaluation Scale (AES-S). All patients underwent 123 I-FP-CIT (DaT-SCAN) SPECT to assess dopamine transporter (DAT) striatal uptake. PD patients with apathy showed lower DAT levels in the striatum than non-apathetic patients. After Bonferroni correction the difference between groups was significant in the right caudate. Apathy is associated with reduced striatal dopamine transporter levels, independent of motor disability and depression in non-demented PD patients. These findings suggest that dysfunction of dopaminergic innervation in the striatum and particularly in the right caudate may contribute to development of apathy in early PD. Copyright © 2015 Elsevier Ltd. All rights reserved.

  1. Striatal dopamine release and genetic variation of the serotonin 2C receptor in humans.

    Science.gov (United States)

    Mickey, Brian J; Sanford, Benjamin J; Love, Tiffany M; Shen, Pei-Hong; Hodgkinson, Colin A; Stohler, Christian S; Goldman, David; Zubieta, Jon-Kar

    2012-07-04

    Mesoaccumbal and nigrostriatal projections are sensitive to stress, and heightened stress sensitivity is thought to confer risk for neuropsychiatric disorders. Serotonin 2C (5-HT(2C)) receptors mediate the inhibitory effects of serotonin on dopaminergic circuitry in experimental animals, and preclinical findings have implicated 5-HT(2C) receptors in motivated behaviors and psychotropic drug mechanisms. In humans, a common missense single-nucleotide change (rs6318, Cys23Ser) in the 5-HT(2C) receptor gene (HTR2C) has been associated with altered activity in vitro and with clinical mood disorders. We hypothesized that dopaminergic circuitry would be more sensitive to stress in humans carrying the Ser23 variant. To test this hypothesis, we studied 54 healthy humans using positron emission tomography and the displaceable D(2)/D(3) receptor radiotracer [(11)C]raclopride. Binding potential (BP(ND)) was quantified before and after a standardized stress challenge consisting of 20 min of moderate deep muscular pain, and reduction in BP(ND) served as an index of dopamine release. The Cys23Ser variant was genotyped on a custom array, and ancestry informative markers were used to control for population stratification. We found greater dopamine release in the nucleus accumbens, caudate nucleus, and putamen among Ser23 carriers, after controlling for sex, age, and ancestry. Genotype accounted for 12% of the variance in dopamine release in the nucleus accumbens. There was no association of Cys23Ser with baseline BP(ND). These findings indicate that a putatively functional HTR2C variant (Ser23) is associated with greater striatal dopamine release during pain in healthy humans. Mesoaccumbal stress sensitivity may mediate the effects of HTR2C variation on risk of neuropsychiatric disorders.

  2. Dopamine D1-histamine H3 Receptor Heteromers Provide a Selective Link to MAPK Signaling in GABAergic Neurons of the Direct Striatal Pathway*

    Science.gov (United States)

    Moreno, Estefanía; Hoffmann, Hanne; Gonzalez-Sepúlveda, Marta; Navarro, Gemma; Casadó, Vicent; Cortés, Antoni; Mallol, Josefa; Vignes, Michel; McCormick, Peter J.; Canela, Enric I.; Lluís, Carme; Moratalla, Rosario; Ferré, Sergi; Ortiz, Jordi; Franco, Rafael

    2011-01-01

    Previously, using artificial cell systems, we identified receptor heteromers between the dopamine D1 or D2 receptors and the histamine H3 receptor. In addition, we demonstrated two biochemical characteristics of the dopamine D1 receptor-histamine H3 receptor heteromer. We have now extended this work to show the dopamine D1 receptor-histamine H3 receptor heteromer exists in the brain and serves to provide a novel link between the MAPK pathway and the GABAergic neurons in the direct striatal efferent pathway. Using the biochemical characteristics identified previously, we found that the ability of H3 receptor activation to stimulate p44 and p42 extracellular signal-regulated MAPK (ERK 1/2) phosphorylation was only observed in striatal slices of mice expressing D1 receptors but not in D1 receptor-deficient mice. On the other hand, the ability of both D1 and H3 receptor antagonists to block MAPK activation induced by either D1 or H3 receptor agonists was also found in striatal slices. Taken together, these data indicate the occurrence of D1-H3 receptor complexes in the striatum and, more importantly, that H3 receptor agonist-induced ERK 1/2 phosphorylation in striatal slices is mediated by D1-H3 receptor heteromers. Moreover, H3 receptor-mediated phospho-ERK 1/2 labeling co-distributed with D1 receptor-containing but not with D2 receptor-containing striatal neurons. These results indicate that D1-H3 receptor heteromers work as processors integrating dopamine- and histamine-related signals involved in controlling the function of striatal neurons of the direct striatal pathway. PMID:21173143

  3. Apathy and striatal dopamine defects in non-demented patients with Parkinson's disease.

    Science.gov (United States)

    Chung, Su Jin; Lee, Jae Jung; Ham, Jee Hyun; Lee, Phil Hyu; Sohn, Young H

    2016-02-01

    Apathy is a common, disabling symptom in Parkinson's disease (PD). The mechanisms underlying apathy in PD are still unclear, although they may be related to dysfunction in the meso-cortico-limbic circuit, including the ventral striatum. Thus, we performed this study to investigate whether dopamine depletion in the ventral striatum contributes to apathy in PD. We conducted a survey of the degree of apathy (using the Korean version of the Apathy Evaluation Scale, AES-S) in 108 non-demented patients with PD who underwent dopamine transporter (DAT) positron emission tomography scans as an initial diagnostic work-up. Patients with AES-S scores of 37 or higher were defined as having apathetic PD. The Beck Depression Inventory (BDI) was administered to assess the severity of depression. Patients with BDI scores of 15 or higher were regarded as having depression. Apathetic patients (n = 34) tended to exhibit higher BDI scores than non-apathetic patients (n = 74); however, other clinical variables were comparable between the two groups. DAT activity in the striatal sub-regions was also similar between the two groups. Selecting only non-depressed patients, including 20 apathetic and 47 non-apathetic patients, did not alter the results. This study demonstrated that the pattern of striatal dopamine depletion does not contribute to the degree of apathy in early PD. Apathy in PD may be associated with extra-striatal lesions that accompany PD rather than striatal dopaminergic deficits. Copyright © 2015 Elsevier Ltd. All rights reserved.

  4. Reduced striatal dopamine D2/3 receptor availability in Body Dysmorphic Disorder.

    Science.gov (United States)

    Vulink, Nienke C; Planting, Robin S; Figee, Martijn; Booij, Jan; Denys, Damiaan

    2016-02-01

    Though the dopaminergic system is implicated in Obsessive Compulsive and Related Disorders (OCRD), the dopaminergic system has never been investigated in-vivo in Body Dysmorphic Disorder (BDD). In line with consistent findings of reduced striatal dopamine D2/3 receptor availability in Obsessive Compulsive Disorder (OCD), we hypothesized that the dopamine D2/3 receptor availability in the striatum will be lower in patients with BDD in comparison to healthy subjects. Striatal dopamine D2/3 receptor Binding Potential (BPND) was examined in 12 drug-free BDD patients and 12 control subjects pairwise matched by age, sex, and handedness using [(123)I]iodobenzamide Single Photon Emission Computed Tomography (SPECT; bolus/constant infusion technique). Regions of interest were the caudate nucleus and the putamen. BPND was calculated as the ratio of specific striatal to binding in the occipital cortex (representing nonspecific binding). Compared to controls, dopamine D2/3 receptor BPND was significantly lower in BDD, both in the putamen (p=0.017) and caudate nucleus (p=0.022). This study provides the first evidence of a disturbed dopaminergic system in BDD patients. Although previously BDD was classified as a separate disorder (somatoform disorder), our findings give pathophysiological support for the recent reclassification of BDD to the OCRD in DSM-5. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.

  5. Chronic exposure to dopamine agonists affects the integrity of striatal D2 receptors in Parkinson's patients

    Directory of Open Access Journals (Sweden)

    Marios Politis

    2017-01-01

    Full Text Available We aimed to investigate the integrity and clinical relevance of striatal dopamine receptor type-2 (D2R availability in Parkinson's disease (PD patients. We studied 68 PD patients, spanning from early to advanced disease stages, and 12 healthy controls. All participants received one [11C]raclopride PET scan in an OFF medication condition for quantification of striatal D2R availability in vivo. Parametric images of [11C]raclopride non-displaceable binding potential were generated from the dynamic [11C]raclopride scans using implementation of the simplified reference tissue model with cerebellum as the reference tissue. PET data were interrogated for correlations with clinical data related to disease burden and dopaminergic treatment. PD patients showed a mean 16.7% decrease in caudate D2R and a mean 3.5% increase in putaminal D2R availability compared to healthy controls. Lower caudate [11C]raclopride BPND correlated with longer PD duration. PD patients on dopamine agonist treatment had 9.2% reduced D2R availability in the caudate and 12.8% in the putamen compared to PD patients who never received treatment with dopamine agonists. Higher amounts of lifetime dopamine agonist therapy correlated with reduced D2Rs availability in both caudate and putamen. No associations between striatal D2R availability and levodopa treatment and dyskinesias were found. In advancing PD the caudate and putamen D2R availability are differentially affected. Chronic exposure to treatment with dopamine agonists, but no levodopa, suppresses striatal D2R availability, which may have relevance to output signaling to frontal lobes and the occurrence of executive deficits, but not dyskinesias.

  6. 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.

  7. Effect of in vitro inorganic lead on dopamine release from superfused rat striatal synaptosomes

    International Nuclear Information System (INIS)

    Minnema, D.J.; Greenland, R.D.; Michaelson, I.A.

    1986-01-01

    The effect of inorganic lead in vitro in several aspects of [ 3 H]dopamine release from superfused rat striatal synaptosomes was examined. Under conditions of spontaneous release, lead (1-30 microM) induced dopamine release in a concentration-dependent manner. The onset of the lead-induced release was delayed by approximately 15-30 sec. The magnitude of dopamine release induced by lead was increased when calcium was removed from the superfusing buffer. Lead-induced release was unaffected in the presence of putative calcium, sodium, and/or potassium channel blockers (nickel, tetrodotoxin, tetraethylammonium, respectively). Depolarization-evoked dopamine release, produced by a 1-sec exposure to 61 mM potassium, was diminished at calcium concentrations below 0.254 mM. The onset of depolarization-evoked release was essentially immediate following exposure of the synaptosomes to high potassium. The combination of lead (3 or 10 microM) with high potassium reduced the magnitude of depolarization-evoked dopamine release. This depression of depolarization-evoked release by lead was greater in the presence of 0.25 mM than 2.54 mM calcium in the superfusing buffer. These findings demonstrate multiple actions of lead on synaptosomal dopamine release. Lead can induce dopamine release by yet unidentified neuronal mechanisms independent of external calcium. Lead can also reduce depolarization-evoked dopamine release by apparent competition with calcium influx at the neuronal membrane calcium channel

  8. Overeating Behavior and Striatal Dopamine with 6-[18F]-Fluoro-L--Tyrosine PET

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    Claire E. Wilcox

    2010-01-01

    Full Text Available Eating behavior may be affected by dopamine synthesis capacity. In this study, 6-[18F]-fluoro-L--tyrosine (FMT positron emission tomography (PET uptake in striatal subregions was correlated with BMI (kg/m2 and an estimate of the frequency of prior weight loss attempts in 15 healthy subjects. BMI was negatively correlated with FMT uptake in the dorsal caudate. Although the association between BMI and FMT uptake in the dorsal caudate was not significant upon correction for age and sex, the association fell within the range of a statistical trend. Weight loss attempts divided by years trying was also negatively correlated with FMT uptake in the dorsal putamen (=.05. These results suggest an association between low dorsal striatal presynaptic dopamine synthesis capacity and overeating behavior.

  9. Cortico-striatal oxidative status, dopamine turnover and relation with stereotypy in the deer mouse.

    Science.gov (United States)

    Güldenpfennig, Marianne; Wolmarans, De Wet; du Preez, Jan L; Stein, Dan J; Harvey, Brian H

    2011-06-01

    The deer mouse presents with spontaneous stereotypic movements that resemble the repetitive behaviours of obsessive-compulsive disorder (OCD), and demonstrates a selective response to serotonin reuptake inhibitors. OCD has been linked to altered redox status and since increased dopamine signalling can promote stereotypies as well as oxidative stress, we investigated whether the severity of deer mouse stereotypy may be associated with altered dopamine turnover and cortico-striatal redox status. Deer mice were separated into high (HSB), low (LSB) and non-stereotypy (NS) groups. Frontal cortical and striatal dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), as well as superoxide dismutase (SOD) activity, reduced (GSH) and oxidised (GSSG) glutathione and glutathione redox index, were analysed as markers for regional dopamine turnover and oxidative stress, respectively. Dopamine and its metabolites and SOD activity did not differ across the stereotypy groups. Significantly reduced GSH and GSSG and increased glutathione redox index were only observed in the frontal cortex of HSB animals. Frontal cortical GSH and GSSG were inversely correlated while glutathione redox index was positively correlated with stereotypy. Deer mouse stereotypy is thus characterised by a deficient glutathione system in the frontal cortex but not striatum, and provides a therapeutic rationale for using glutathione-active antioxidants in OCD. The evidence for a primary frontal lesion has importance for future OCD research. Copyright © 2011 Elsevier Inc. All rights reserved.

  10. Ventral striatal dopamine synthesis capacity predicts financial extravagance in Parkinson’s Disease

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    Andrew David Lawrence

    2013-02-01

    Full Text Available Impulse control disorders (ICDs, including disordered gambling, can occur in a significant number of patients with Parkinson’s disease (PD receiving dopaminergic therapy. The neurobiology underlying susceptibility to such problems is unclear, but risk likely results from an interaction between dopaminergic medication and a pre-existing trait vulnerability. Impulse control and addictive disorders form part of a broader psychopathological spectrum of disorders, which share a common underlying genetic vulnerability, referred to as externalizing. The broad externalizing risk factor is a continuously varying trait reflecting vulnerability to various impulse control problems, manifested at the overt level by disinhibitory symptoms and at the personality level by antecedent traits such as impulsivity and novelty/sensation seeking. Trait ‘disinhibition’ is thus a core endophenotype of ICDs, and a key target for neurobiological investigation. The ventral striatal dopamine system has been hypothesized to underlie individual variation in behavioural disinhibition. Here, we examined whether individual differences in ventral striatal dopamine synthesis capacity predicted individual variation in disinhibitory temperament traits in individuals with PD. Eighteen early-stage male PD patients underwent 6-[18F]Fluoro-L-DOPA (FDOPA positron emission tomography (PET scanning to measure striatal dopamine synthesis capacity, and completed a measure of disinhibited personality. Consistent with our predictions, we found that levels of ventral, but not dorsal, striatal dopamine synthesis capacity predicted disinhibited personality, particularly a propensity for financial extravagance. Our results are consistent with recent preclinical models of vulnerability to behavioural disinhibition and addiction proneness, and provide novel insights into the neurobiology of potential vulnerability to impulse control problems in PD and other disorders.

  11. Rapid eye movement sleep behaviour disorder and striatal dopamine depletion in patients with Parkinson's disease.

    Science.gov (United States)

    Chung, S J; Lee, Y; Lee, J J; Lee, P H; Sohn, Y H

    2017-10-01

    Rapid eye movement sleep behaviour disorder (RBD) is related to striatal dopamine depletion. This study was performed to confirm whether clinically probable RBD (cpRBD) in patients with Parkinson's disease (PD) is associated with a specific pattern of striatal dopamine depletion. A prospective survey was conducted using the RBD Screening Questionnaire (RBDSQ) in 122 patients with PD who had undergone dopamine transporter (DAT) positron emission tomography scan. Patients with cpRBD (RBDSQ ≥ 7) exhibited greater motor deficits, predominantly in the less-affected side and axial symptoms, and were prescribed higher levodopa-equivalent doses at follow-up than those without cpRBD (RBDSQ ≤ 4), despite their similar disease and treatment durations. Compared to patients without cpRBD, those with cpRBD showed lower DAT activities in the putamen, particularly in the less-affected side in all putaminal subregions, and a tendency to be lower in the ventral striatum. In addition, greater motor deficits in patients with cpRBD than in those without cpRBD remained significant after controlling for DAT binding in the putamen and other confounding variables. These results demonstrated that the presence of RBD in patients with PD is associated with different patterns of both motor deficit distribution and striatal DAT depletion, suggesting that the presence of RBD represents a distinct PD subtype with a malignant motor parkinsonism. © 2017 EAN.

  12. Striatal and extra-striatal dopamine transporter in cannabis and tobacco addiction: a high resolution PET study

    International Nuclear Information System (INIS)

    Leroy, C.; Martinot, J.L.; Duchesnay, E.; Artiges, E.; Ribeiro, M.J.; Trichard, Ch.; Karila, L.; Lukasiewicz, M.; Benyamina, A.; Reynaud, M.; Martinot, J.L.; Duchesnay, E.; Artiges, E.; Comtat, C.; Artiges, E.; Trichard, Ch.

    2011-01-01

    The dopamine (DA) system is known to be involved in the reward and dependence mechanisms of addiction. However, modifications in dopaminergic neurotransmission associated with long-term tobacco and cannabis use have been poorly documented in vivo. In order to assess striatal and extra-striatal dopamine transporter (DAT) availability in tobacco and cannabis addiction, three groups of male age-matched subjects were compared: 11 healthy non-smoker subjects, 14 tobacco-dependent smokers (17.6 ± 5.3 cigarettes/day for 12.1 ± 8.5 years) and 13 cannabis and tobacco smokers (CTS) (4.8 ± 5.3 cannabis joints/day for 8.7 ± 3.9 years). DAT availability was examined in positron emission tomography (HRRT) with a high resolution research tomograph after injection of [ 11 C]PE2I, a selective DAT radioligand. Region of interest and voxel-by-voxel approaches using a simplified reference tissue model were performed for the between-group comparison of DAT availability. Measurements in the dorsal striatum from both analyses were concordant and showed a mean 20% lower DAT availability in drug users compared with controls. Whole-brain analysis also revealed lower DAT availability in the ventral striatum, the midbrain, the middle cingulate and the thalamus (ranging from -15 to -30%). The DAT availability was slightly lower in all regions in CTS than in subjects who smoke tobacco only, but the difference does not reach a significant level. These results support the existence of a decrease in DAT availability associated with tobacco and cannabis addictions involving all dopaminergic brain circuits. These findings are consistent with the idea of a global decrease in cerebral DA activity in dependent subjects. (authors)

  13. Somatostatin regulates dopamine release in rat striatal slices and cat caudate nuclei

    International Nuclear Information System (INIS)

    Chesselet, M.F.; Reisine, T.D.

    1983-01-01

    The effects of somatostatin on the release of tritiated dopamine (DA) formed continuously from tritiated tyrosine were studied in vitro in superfused striatal slices and in vivo in both caudate nuclei and both substantiae nigrae of halothane-anesthetized cats using a push-pull cannula technique. Somatostatin (3 X 10(-10) to 3 X 10(-7) M) increased the spontaneous tritiated dopamine release from rat striatal slices. This effect was dose dependent and was completely prevented by tetrodotoxin (5 X 10(-7) M). When applied for 30 min in one cat caudate nucleus, somatostatin (10(-7) M) immediately increased the local release of tritiated DA, while a gradual inhibition of the tritiated amine's efflux was observed in the contralateral caudate nucleus. No changes in tritiated dopamine were seen in either substantia nigra during or after the peptide's application in the caudate nucleus. These results suggest that somatostatin in the striatum may play a role in the local and the distal control of dopamine release from the terminals of dopaminergic nigrostriatal neurons

  14. Adenosine Receptor Heteromers and their Integrative Role in Striatal Function

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    Sergi Ferré

    2007-01-01

    Full Text Available By analyzing the functional role of adenosine receptor heteromers, we review a series of new concepts that should modify our classical views of neurotransmission in the central nervous system (CNS. Neurotransmitter receptors cannot be considered as single functional units anymore. Heteromerization of neurotransmitter receptors confers functional entities that possess different biochemical characteristics with respect to the individual components of the heteromer. Some of these characteristics can be used as a “biochemical fingerprint” to identify neurotransmitter receptor heteromers in the CNS. This is exemplified by changes in binding characteristics that are dependent on coactivation of the receptor units of different adenosine receptor heteromers. Neurotransmitter receptor heteromers can act as “processors” of computations that modulate cell signaling, sometimes critically involved in the control of pre- and postsynaptic neurotransmission. For instance, the adenosine A1-A2A receptor heteromer acts as a concentration-dependent switch that controls striatal glutamatergic neurotransmission. Neurotransmitter receptor heteromers play a particularly important integrative role in the “local module” (the minimal portion of one or more neurons and/or one or more glial cells that operates as an independent integrative unit, where they act as processors mediating computations that convey information from diverse volume-transmitted signals. For instance, the adenosine A2A-dopamine D2 receptor heteromers work as integrators of two different neurotransmitters in the striatal spine module.

  15. Striatal dopamine transmission is subtly modified in human A53Tα-synuclein overexpressing mice.

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    Nicola J Platt

    Full Text Available Mutations in, or elevated dosage of, SNCA, the gene for α-synuclein (α-syn, cause familial Parkinson's disease (PD. Mouse lines overexpressing the mutant human A53Tα-syn may represent a model of early PD. They display progressive motor deficits, abnormal cellular accumulation of α-syn, and deficits in dopamine-dependent corticostriatal plasticity, which, in the absence of overt nigrostriatal degeneration, suggest there are age-related deficits in striatal dopamine (DA signalling. In addition A53Tα-syn overexpression in cultured rodent neurons has been reported to inhibit transmitter release. Therefore here we have characterized for the first time DA release in the striatum of mice overexpressing human A53Tα-syn, and explored whether A53Tα-syn overexpression causes deficits in the release of DA. We used fast-scan cyclic voltammetry to detect DA release at carbon-fibre microelectrodes in acute striatal slices from two different lines of A53Tα-syn-overexpressing mice, at up to 24 months. In A53Tα-syn overexpressors, mean DA release evoked by a single stimulus pulse was not different from wild-types, in either dorsal striatum or nucleus accumbens. However the frequency responsiveness of DA release was slightly modified in A53Tα-syn overexpressors, and in particular showed slight deficiency when the confounding effects of striatal ACh acting at presynaptic nicotinic receptors (nAChRs were antagonized. The re-release of DA was unmodified after single-pulse stimuli, but after prolonged stimulation trains, A53Tα-syn overexpressors showed enhanced recovery of DA release at old age, in keeping with elevated striatal DA content. In summary, A53Tα-syn overexpression in mice causes subtle changes in the regulation of DA release in the striatum. While modest, these modifications may indicate or contribute to striatal dysfunction.

  16. Dopamine D1-like receptors depress excitatory synaptic transmissions in striatal neurons after transient forebrain ischemia.

    Science.gov (United States)

    Zhang, Yuchun; Deng, Ping; Ruan, Yiwen; Xu, Zao C

    2008-08-01

    Spiny neurons in the neostriatum are highly vulnerable to ischemia. Despite an enormous body of research suggesting that dopamine is involved in ischemia-induced neuronal loss in the striatum, it remains unclear how dopamine interacts with the glutamatergic excitotoxicity that is widely accepted as a major cause of ischemic cell death. Our study was designed to investigate the effects of dopamine D1 receptor (D1R) activation on excitatory neurotransmission in postischemic striatal neurons. We used the 4-vessel occlusion ischemia model and brain slice preparations. Whole-cell voltage-clamp recording was performed on striatal neurons to measure excitatory postsynaptic currents (EPSCs). Systemic administration of a D1R agonist after ischemia and hematoxylin/eosin staining were performed to evaluate the effects of D1R activation on ischemia-induced neuronal degeneration in the striatum. D1R activation depressed EPSCs in postischemic striatal neurons. The depression was attributable to inhibition of presynaptic release. An activator of cAMP-dependent protein kinase A (PKA) mimicked the depressive effects of D1R activation. Bath application of a PKA inhibitor blocked the depression of EPSCs, whereas intracellular postsynaptic application of the PKA inhibitor had no effect. The D1R agonist failed to reduce EPSC amplitude in the presence of an adenosine A1 receptor antagonist. Systemic administration of a D1R agonist after ischemia significantly attenuated ischemia-induced cell death in the striatum. These results indicate that D1R activation presynaptically depresses excitatory synaptic transmission in striatal neurons after ischemia through activation of PKA and adenosine A1 receptors and thus demonstrate a novel mechanism of D1R-mediated protection against ischemia.

  17. Effects of mercuric chloride on [3H]dopamine release from rat brain striatal synaptosomes

    International Nuclear Information System (INIS)

    Hare, M.F.; Minnema, D.J.; Cooper, G.P.; Michaelson, I.A.

    1989-01-01

    Electrophysiological studies employing amphibian neuromuscular preparations have shown that mercuric chloride (HgCl2) in vitro increases both spontaneous and evoked neurotransmitter release. The present study examines the effect of HgCl2 on the release of [ 3 H]dopamine from synaptosomes prepared from mammalian brain tissue. Mercuric chloride (3-10 microM) produces a concentration-dependent increase in spontaneous [ 3 H]dopamine release from ''purified'' rat striatal synaptosomes, in both the presence and absence of extra-synaptosomal calcium. The effects of HgCl2 on transmitter release from amphibian neuromuscular junction preparations resemble those produced by the Na+, K+-ATPase inhibitor ouabain. Experiments were performed to determine whether the HgCl2 effects on mammalian synaptosomal dopamine release are a consequence of Na+, K+-ATPase inhibition. Na+, K+-ATPase activity in lysed synaptosomal membranes is inhibited by HgCl2 (IC50 = 160 nM). However, mercuric chloride in the presence of 1 mM ouabain still increased [3H]dopamine release. The specific inhibitor of Na+-dependent, high-affinity dopamine transport, RMI81,182 inhibited ouabain-induced [3H]dopamine release whereas it had no effect on HgCl2-induced [ 3 H]dopamine release. These data suggest that augmentation of spontaneous [ 3 H]dopamine release by HgCl2 probably is not mediated by an inhibition of Na+, K+-ATPase and HgCl2 does not act directly on the dopamine transporter

  18. Striatal dopamine D2/3 receptor availability in treatment resistant depression.

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    Bart P de Kwaasteniet

    Full Text Available Several studies demonstrated improvement of depressive symptoms in treatment resistant depression (TRD after administering dopamine agonists which suggest abnormal dopaminergic neurotransmission in TRD. However, the role of dopaminergic signaling through measurement of striatal dopamine D(2/3 receptor (D2/3R binding has not been investigated in TRD subjects. We used [(123I]IBZM single photon emission computed tomography (SPECT to investigate striatal D2/3R binding in TRD. We included 6 severe TRD patients, 11 severe TRD patients on antipsychotics (TRD AP group and 15 matched healthy controls. Results showed no significant difference (p = 0.75 in striatal D2/3R availability was found between TRD patients and healthy controls. In the TRD AP group D2/3R availability was significantly decreased (reflecting occupancy of D2/3Rs by antipsychotics relative to TRD patients and healthy controls (p<0.001 but there were no differences in clinical symptoms between TRD AP and TRD patients. This preliminary study therefore does not provide evidence for large differences in D2/3 availability in severe TRD patients and suggests this TRD subgroup is not characterized by altered dopaminergic transmission. Atypical antipsychotics appear to have no clinical benefit in severe TRD patients who remain depressed, despite their strong occupancy of D2/3Rs.

  19. Striatal and Extrastriatal Dopamine Transporter Availability in Schizophrenia and Its Clinical Correlates: A Voxel-Based and High-Resolution PET Study.

    Science.gov (United States)

    Artiges, Eric; Leroy, Claire; Dubol, Manon; Prat, Marie; Pepin, Audrey; Mabondo, Audrey; de Beaurepaire, Renaud; Beaufils, Béatrice; Korwin, Jean-Pierre; Galinowski, André; D'Albis, Marc-Antoine; Santiago-Ribeiro, Maria-João; Granger, Bernard; Tzavara, Eleni T; Martinot, Jean-Luc; Trichard, Christian

    2017-09-01

    Neuroimaging studies investigating dopamine (DA) function widely support the hypothesis of presynaptic striatal DA hyperactivity in schizophrenia. However, published data on the striatal DA transporter (DAT) appear less consistent with this hypothesis, probably partly due to methodological limitations. Moreover, DAT in extrastriatal regions has been very poorly investigated in the context of schizophrenia. In order to address these issues, we used a high resolution positron emission tomograph and the selective DAT radioligand [11C]PE2I, coupled with a whole brain voxel-based analysis method to investigate DAT availability in striatal but also extra-striatal regions in 21 male chronic schizophrenia patients compared to 30 healthy male controls matched by age. We found higher DAT availability in schizophrenia patients in midbrain, striatal, and limbic regions. DAT availability in amygdala/hippocampus and putamen/pallidum was positively correlated with hallucinations and suspiciousness/persecution, respectively. These results are consistent with an increase of presynaptic DA function in patients with schizophrenia, and support the involvement of both striatal and extrastriatal DA dysfunction in positive psychotic symptoms. The study also highlights the whole brain voxel-based analysis method to explore DA dysfunction in schizophrenia. © The Author 2017. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  20. Repeated cocaine administration results in supersensitivity of striatal D-2 dopamine autoreceptors to pergolide

    International Nuclear Information System (INIS)

    Dwoskin, L.P.; Peris, J.; Yasuda, R.P.; Philpott, K.; Zahniser, N.R.

    1988-01-01

    Groups of rats administered cocaine-HCl (10 mg/kg, i.p.) or saline either acutely or once daily for 8 or 14 days were killed 24 hrs after the last dose. In striatal slices prelabelled with [ 3 H]DA, modulation of [ 3 H]-overflow by pergolide was used to measure D-2 autoreceptor activity. Compared to the contemporaneous control group pergolide produced a greater inhibition only in striatal slices from rats treated repeatedly with cocaine. In radioligand binding studies using striatal membranes from control rats, pergolide had a 500-fold greater affinity for the D-2, as opposed to the D-1, dopamine (DA) receptor subtype. These results indicate that repeated treatment with cocaine produces supersensitive striatal D-2 release-modulating autoreceptors consistent with a compensatory change to diminish the effect of elevated synaptic concentrations of DA produced by cocaine. In contrast, supersensitivity of D-2 receptors was not detected in [ 3 H]spiperone binding assays. 31 references, 2 figures, 1 table

  1. Increased impulsivity retards the transition to dorsolateral striatal dopamine control of cocaine seeking.

    Science.gov (United States)

    Murray, Jennifer E; Dilleen, Ruth; Pelloux, Yann; Economidou, Daina; Dalley, Jeffrey W; Belin, David; Everitt, Barry J

    2014-07-01

    Development of maladaptive drug-seeking habits occurs in conjunction with a ventral-to-dorsal striatal shift in dopaminergic control over behavior. Although these habits readily develop as drug use continues, high impulsivity predicts loss of control over drug seeking and taking. However, whether impulsivity facilitates the transition to dorsolateral striatum (DLS) dopamine-dependent cocaine-seeking habits or whether impulsivity and cocaine-induced intrastriatal shifts are additive processes is unknown. High- and low-impulsive rats identified in the five-choice serial reaction-time task were trained to self-administer cocaine (.25 mg/infusion) with infusions occurring in the presence of a cue-light conditioned stimulus. Dopamine transmission was blocked in the DLS after three stages of training: early, transition, and late-stage, by bilateral intracranial infusions of α-flupenthixol (0, 5, 10, or 15 μg/side) during 15-min cocaine-seeking test sessions in which each response was reinforced by a cocaine-associated conditioned stimulus presentation. In early-stage tests, neither group was affected by DLS dopamine receptor blockade. In transition-stage tests, low-impulsive rats showed a significant dose-dependent reduction in cocaine seeking, whereas high-impulsive rats were still unaffected by α-flupenthixol infusions. In the final, late-stage seeking test, both groups showed dose-dependent sensitivity to dopamine receptor blockade. The results demonstrate that high impulsivity is associated with a delayed transition to DLS-dopamine-dependent control over cocaine seeking. This suggests that, if impulsivity confers an increased propensity to addiction, it is not simply through a more rapid development of habits but instead through interacting corticostriatal and striato-striatal processes that result ultimately in maladaptive drug-seeking habits. © 2013 Society of Biological Psychiatry Published by Society of Biological Psychiatry All rights reserved.

  2. Disrupted functional connectivity of striatal sub-regions in Bell's palsy patients

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    Wenwen Song

    2017-01-01

    Full Text Available The striatum plays an important role in controlling motor function in humans, and its degeneration has the ability to cause severe motor disorders. More specifically, previous studies have demonstrated a disruption in the connectivity of the cortico-striatal loop in patients suffering from motor disorders caused by dopamine dysregulation, such as Parkinson's disease. However, little is known about striatal functional connectivity in patients with motor dysfunction not caused by dopamine dysregulation. In this study, we used early-state Bell's palsy (BP patients (within 14 days of onset to investigate how functional connectivity between the striatum and motor cortex is affected by peripheral nerve injury in which the dopamine system remains fully functional. We found a significant increase in the connectivity between the contralateral putamen, and the ipsilateral primary sensory (S1 and motor cortex (M1 in BP patients compared to healthy controls. We also found increased connectivity between the ventral striatum and supplementary motor area (SMA, and the dorsal caudate and medial prefrontal lobe in BP patients compared to healthy controls. Our results demonstrate that the entirety of the striatum is affected following acute peripheral nerve injury, and suggests that this disrupted striatal functional connectivity may reflect a compensatory mechanism for the sensory-motor mismatch caused by BP.

  3. A C-terminal PDZ domain-binding sequence is required for striatal distribution of the dopamine transporter

    DEFF Research Database (Denmark)

    Rickhag, Karl Mattias; Hansen, Freja Herborg; Sørensen, Gunnar

    2013-01-01

    transporter expression in the striatum, causing hyperlocomotion and attenuated response to amphetamine. In cultured dopaminergic neurons and striatal slices from dopamine transporter-AAA mice, we find markedly reduced dopamine transporter surface levels and evidence for enhanced constitutive internalization....... In dopamine transporter-AAA neurons, but not in wild-type neurons, surface levels are rescued in part by expression of a dominant-negative dynamin mutation (K44A). Our findings suggest that PDZ-domain interactions are critical for synaptic distribution of dopamine transporter in vivo and thereby for proper...

  4. Mechanism of action of nitrogen pressure in controlling striatal dopamine level of freely moving rats is changed by recurrent exposures to nitrogen narcosis.

    Science.gov (United States)

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

    2012-03-01

    In rats, a single exposure to 3 MPa nitrogen induces change in motor processes, a sedative action and a decrease in dopamine release in the striatum. These changes due to a narcotic effect of nitrogen have been attributed to a decrease in glutamatergic control and the facilitation of GABAergic neurotransmission involving NMDA and GABA(A) receptors, respectively. After repeated exposure to nitrogen narcosis, a second exposure to 3 MPa increased dopamine levels suggesting a change in the control of the dopaminergic pathway. We investigated the role of the nigral NMDA and GABA(A) receptors in changes in the striatal dopamine levels. Dopamine-sensitive electrodes were implanted into the striatum under general anesthesia, together with a guide-cannula for drug injections into the SNc. Dopamine level was monitored by in vivo voltammetry. The effects of NMDA/GABA(A) receptor agonists (NMDA/muscimol) and antagonists (AP7/gabazine) on dopamine levels were investigated. Rats were exposed to 3 MPa nitrogen before and after five daily exposures to 1 MPa. After these exposures to nitrogen narcosis, gabazine, NMDA and AP7 had no effect on the nitrogen-induced increase in dopamine levels. By contrast, muscimol strongly enhanced the increase in dopamine level induced by nitrogen. Our findings suggest that repeated nitrogen exposure disrupted NMDA receptor function and decreased GABAergic input by modifying GABA(A) receptor sensitivity. These findings demonstrated a change in the mechanism of action of nitrogen at pressure.

  5. Pre-Existing Differences and Diet-Induced Alterations in Striatal Dopamine Systems of Obesity-Prone Rats

    Science.gov (United States)

    Vollbrecht, Peter J.; Mabrouk, Omar S.; Nelson, Andrew D.; Kennedy, Robert T.; Ferrario, Carrie R.

    2016-01-01

    Objective Interactions between pre-existing differences in mesolimbic function and neuroadaptations induced by consumption of fatty, sugary foods are thought to contribute to human obesity. This study examined basal and cocaine-induced changes in striatal neurotransmitter levels without diet manipulation and D2/D3 dopamine receptor-mediated transmission prior to and after consumption of “junk-foods” in obesity-prone and obesity-resistant rats. Methods Microdialysis and liquid chromatography-mass spectrometry were used to determine basal and cocaine-induced changes in neurotransmitter levels in real time with cocaine-induced locomotor activity. Sensitivity to the D2/D3 dopamine receptor agonist quinpirole was examined before and after restricted junk-food exposure. Selectively bred obesity-prone and obesity-resistant rats were used. Results Cocaine-induced locomotion was greater in obesity-prone rats versus obesity-resistant rats prior to diet manipulation. Basal and cocaine-induced increases in dopamine and serotonin levels did not differ. Obesity-prone rats were more sensitive to the D2 receptor-mediated effects of quinpirole, and junk-food produced modest alterations in quinpirole sensitivity in obesity-resistant rats. Conclusions These data show that mesolimbic systems differ prior to diet manipulation in susceptible versus resistant rats, and that consumption of fatty, sugary foods produce different neuroadaptations in these populations. These differences may contribute to enhanced food craving and an inability to limit food intake in susceptible individuals. PMID:26847484

  6. Striatal dopamine D1 and D2 receptors are differentially regulated following buprenorphine or methadone treatment.

    Science.gov (United States)

    Allouche, Stéphane; Le Marec, Thierry; Coquerel, Antoine; Noble, Florence; Marie, Nicolas

    2015-05-01

    Chronic administration of morphine induces adaptations in neurotransmission system such as the dopamine pathway, and these modifications could be influenced by the drug administration pattern. Methadone and buprenorphine are the two main opioid substitution therapies, and despite their protracted use in humans, no study has investigated their ability to regulate dopamine system after chronic exposure/withdrawal. We evaluated the consequences of two administration patterns of methadone and buprenorphine on striatal dopamine D1 (D1R) and D2 (D2R) receptor levels. Mice were treated with escalating doses of methadone or buprenorphine for 5 days either once daily (binge) or three times a day (TTD). D1R and D2R density in striatum was measured by autoradiography using [(3)H]-SCH23390 and [(3)H]-raclopride, respectively, at 1 (WD1), 14 (WD14), and 35 (WD35) days after the last opioid injection. A downregulation of D1R was observed upon TTD administration of buprenorphine and binge methadone treatment while an increase of those receptor levels was detected both with binge buprenorphine and TTD methadone treatments. Concerning the D2R, we rather measured an early or late downregulation with both agonists and administration patterns. Our results demonstrated that methadone and buprenorphine were able to differentially regulate dopamine receptor density depending on the withdrawal period and the administration pattern.

  7. Tamoxifen counteracts estradiol induced effects on striatal and hypophyseal dopamine receptors

    International Nuclear Information System (INIS)

    Ferretti, C.; Blengio, M.; Ghi, P.; Racca, S.; Genazzani, E.; Portaleone, P.

    1988-01-01

    We investigated the ability of Tamoxifen (TAM), an antiestrogen drug, to counteract the modification induced by estrogens on dopamine (DA) receptors on striatum and on adenohypophysis of ovex female rats. Subacute treatment with 17β-estradiol (E 2 ) at both low (0.1 μg/kg) and high (20 μg/kg) doses confirmed its ability to increase the number of striatal 3 H-Spiperone ( 3 H-SPI) binding sites in a dose dependent manner. By contrast in the pituitary, only high doses of estrogen were effective in reducing the number of DA receptors. We treated ovex female rats for 15 days with TAM alone or associated with E 2 , to see if these estrogenic effects could be suppressed by an antiestrogenic drug. TAM did not affect the number of striatal DA receptors, but significantly increased the adenohypophy-seal DA binding sites, without varying their affinity. No changes were observed in pituitary and striatal DA receptor density, even when TAM was injected in association with estradiol. In conclusions: TAM is able to counteract the effects estrogens have on DA receptors. However there is some evidence that it could influence the pituitary DA systems independently of it antiestrogenic activity

  8. Tamoxifen counteracts estradiol induced effects on striatal and hypophyseal dopamine receptors

    Energy Technology Data Exchange (ETDEWEB)

    Ferretti, C.; Blengio, M.; Ghi, P.; Racca, S.; Genazzani, E.; Portaleone, P.

    1988-01-01

    We investigated the ability of Tamoxifen (TAM), an antiestrogen drug, to counteract the modification induced by estrogens on dopamine (DA) receptors on striatum and on adenohypophysis of ovex female rats. Subacute treatment with 17..beta..-estradiol (E/sub 2/) at both low (0.1 ..mu..g/kg) and high (20 ..mu..g/kg) doses confirmed its ability to increase the number of striatal /sup 3/H-Spiperone (/sup 3/H-SPI) binding sites in a dose dependent manner. By contrast in the pituitary, only high doses of estrogen were effective in reducing the number of DA receptors. We treated ovex female rats for 15 days with TAM alone or associated with E/sub 2/, to see if these estrogenic effects could be suppressed by an antiestrogenic drug. TAM did not affect the number of striatal DA receptors, but significantly increased the adenohypophy-seal DA binding sites, without varying their affinity. No changes were observed in pituitary and striatal DA receptor density, even when TAM was injected in association with estradiol. In conclusions: TAM is able to counteract the effects estrogens have on DA receptors. However there is some evidence that it could influence the pituitary DA systems independently of it antiestrogenic activity.

  9. The effects of gestational and chronic atrazine exposure on motor behaviors and striatal dopamine in male Sprague-Dawley rats

    International Nuclear Information System (INIS)

    Walters, Jennifer L.; Lansdell, Theresa A.; Lookingland, Keith J.; Baker, Lisa E.

    2015-01-01

    This study sought to investigate the effects of environmentally relevant gestational followed by continued chronic exposure to the herbicide, atrazine, on motor function, cognition, and neurochemical indices of nigrostriatal dopamine (DA) activity in male rats. Dams were treated with 100 μg/kg atrazine, 10 mg/kg atrazine, or vehicle on gestational day 1 through postnatal day 21. Upon weaning, male offspring continued daily vehicle or atrazine gavage treatments for an additional six months. Subjects were tested in a series of behavioral assays, and 24 h after the last treatment, tissue samples from the striatum were analyzed for DA and 3,4-dihydroxyphenylacetic acid (DOPAC). At 10 mg/kg, this herbicide was found to produce modest disruptions in motor functioning, and at both dose levels it significantly lowered striatal DA and DOPAC concentrations. These results suggest that exposures to atrazine have the potential to disrupt nigrostriatal DA neurons and behaviors associated with motor functioning. - Highlights: • Male rats received gestational and chronic exposure to ATZ (10 mg/kg and 100 μg/kg). • ATZ altered locomotor activity and impaired motor coordination. • ATZ lowered striatal DA and DOPAC concentrations. • ATZ produced a potential anxiogenic effect. • ATZ did not impair performance in learning and memory assessments.

  10. Prenatal stress induces increased striatal dopamine transporter binding in adult nonhuman primates.

    Science.gov (United States)

    Converse, Alexander K; Moore, Colleen F; Moirano, Jeffrey M; Ahlers, Elizabeth O; Larson, Julie A; Engle, Jonathan W; Barnhart, Todd E; Murali, Dhanabalan; Christian, Bradley T; DeJesus, Onofre T; Holden, James E; Nickles, Robert J; Schneider, Mary L

    2013-10-01

    To determine the effects in adult offspring of maternal exposure to stress and alcohol during pregnancy, we imaged striatal and midbrain dopamine transporter (DAT) binding by positron emission tomography in rhesus monkeys (Macaca mulatta). We also evaluated the relationship between DAT binding and behavioral responses previously found to relate to dopamine D2 receptor density (responsivity to tactile stimuli, performance on a learning task, and behavior during a learning task). Subjects were adult offspring derived from a 2 × 2 experiment in which pregnant monkeys were randomly assigned to control, daily mild stress exposure (acoustic startle), voluntary consumption of moderate-level alcohol, or both daily stress and alcohol. Adult offspring (n = 38) were imaged by positron emission tomography with the DAT ligand [(18)F]2β-carbomethoxy-3β-(4-chlorophenyl)-8-(2-fluoroethyl)-nortropane ([(18)F]FECNT). Results showed that prenatal stress yielded an overall increase of 15% in [(18)F]FECNT binding in the striatum (p = .016), 17% greater binding in the putamen (p = .012), and 13% greater binding in the head of the caudate (p = .028) relative to animals not exposed to prenatal stress. Striatal [(18)F]FECNT binding correlated negatively with habituation to repeated tactile stimulation and positively with tactile responsivity. There were no significant effects of prenatal alcohol exposure on [(18)F]FECNT binding. Maternal exposure to mild daily stress during pregnancy yielded increases in striatal DAT availability that were apparent in adult offspring and were associated with behavioral characteristics reflecting tactile hyperresponsivity, a condition associated with problem behaviors in children. © 2013 Society of Biological Psychiatry.

  11. Greater ethanol-induced locomotor activation in DBA/2J versus C57BL/6J mice is not predicted by presynaptic striatal dopamine dynamics.

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    Jamie H Rose

    Full Text Available A large body of research has aimed to determine the neurochemical factors driving differential sensitivity to ethanol between individuals in an attempt to find predictors of ethanol abuse vulnerability. Here we find that the locomotor activating effects of ethanol are markedly greater in DBA/2J compared to C57BL/6J mice, although it is unclear as to what neurochemical differences between strains mediate this behavior. Dopamine elevations in the nucleus accumbens and caudate-putamen regulate locomotor behavior for most drugs, including ethanol; thus, we aimed to determine if differences in these regions predict strain differences in ethanol-induced locomotor activity. Previous studies suggest that ethanol interacts with the dopamine transporter, potentially mediating its locomotor activating effects; however, we found that ethanol had no effects on dopamine uptake in either strain. Ex vivo voltammetry allows for the determination of ethanol effects on presynaptic dopamine terminals, independent of drug-induced changes in firing rates of afferent inputs from either dopamine neurons or other neurotransmitter systems. However, differences in striatal dopamine dynamics did not predict the locomotor-activating effects of ethanol, since the inhibitory effects of ethanol on dopamine release were similar between strains. There were differences in presynaptic dopamine function between strains, with faster dopamine clearance in the caudate-putamen of DBA/2J mice; however, it is unclear how this difference relates to locomotor behavior. Because of the role of the dopamine system in reinforcement and reward learning, differences in dopamine signaling between the strains could have implications for addiction-related behaviors that extend beyond ethanol effects in the striatum.

  12. Amphetamine and Dopamine-Induced Immediate Early Gene Expression in Striatal Neurons Depends on Postsynaptic NMDA Receptors and Calcium

    Science.gov (United States)

    Konradi, Christine; Leveque, Jean-Christophe; Hyman, Steven E.

    2014-01-01

    Amphetamine and cocaine induce the expression of both immediate early genes (IEGs) and neuropeptide genes in rat striatum. Despite the demonstrated dependence of these effects on D1 dopamine receptors, which activate the cyclic AMP pathway, there are several reports that amphetamine and cocaine-induced IEG expression can be inhibited in striatum in vivo by NMDA receptor antagonists. We find that in vivo, the NMDA receptor antagonist MK-801 inhibits amphetamine induction of c-fos acutely and also prevents downregulation of IEG expression with chronic amphetamine administration. Such observations raise the question of whether dopamine/glutamate interactions occur at the level of corticostriatal and mesostriatal circuitry or within striatal neurons. Therefore, we studied dissociated striatal cultures in which midbrain and cortical presynaptic inputs are removed. In these cultures, we find that dopamine- or forskolin-mediated IEG induction requires Ca2+ entry via NMDA receptors but not via L-type Ca2+ channels. Moreover, blockade of NMDA receptors diminishes the ability of dopamine to induce phosphorylation of the cyclic AMP responsive element binding protein CREB. Although these results do not rule out a role for circuit-level dopamine/glutamate interactions, they demonstrate a requirement at the cellular level for interactions between the cyclic AMP and NMDA receptor pathways in dopamine-regulated gene expression in striatal neurons. PMID:8753884

  13. The Feasibility of Using CT-Guided ROI for Semiquantifying Striatal Dopamine Transporter Availability in a Hybrid SPECT/CT System

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    Chien-Chin Hsu

    2014-01-01

    Full Text Available A hybrid SPECT/CT system provides accurate coregistration of functional and morphological images. CT-guided region of interest (ROI for semiquantifying striatal dopamine transporter (DAT availability may be a feasible method. We therefore assessed the intra- and interobserver reproducibility of manual SPECT and CT-guided ROI methods and compared their semiquantitative data with data from MRI-guided ROIs. We enrolled twenty-eight patients who underwent Tc-99m TRODAT-1 brain SPECT/CT and brain MRI. ROIs of the striatal, caudate, putamen, and occipital cortex were manually delineated on the SPECT, CT, and MRI. ROIs from CT and MRI were transferred to the coregistered SPECT for semiquantification. The striatal, caudate, and putamen nondisplaceable binding potential (BPND were calculated. Using CT-guided ROIs had higher intra- and interobserver concordance correlation coefficients, closer Bland-Altman biases to zero, and narrower limits of agreement than using manual SPECT ROIs. The correlation coefficients of striatal, caudate, and putamen BPND were good between manual SPECT and MRI-guided ROI methods and even better between CT-guided and MRI-guided ROI methods. Conclusively, CT-guided ROI delineation for semiquantifying striatal DAT availability in a hybrid SPECT/CT system is highly reproducible, and the semiquantitative data correlate well with data from MRI-guided ROIs.

  14. Cue-induced striatal dopamine release in Parkinson's disease-associated impulsive-compulsive behaviours.

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    O'Sullivan, Sean S; Wu, Kit; Politis, Marios; Lawrence, Andrew D; Evans, Andrew H; Bose, Subrata K; Djamshidian, Atbin; Lees, Andrew J; Piccini, Paola

    2011-04-01

    Impulsive-compulsive behaviours are a significant source of morbidity for patients with Parkinson's disease receiving dopaminergic therapy. The development of these behaviours may reflect sensitization of the neural response to non-drug rewards, similar to that proposed for sensitization to drug rewards in addiction. Here, by using (11)C-raclopride positron emission tomography imaging, we investigated the effects of reward-related cues and L-dopa challenge in patients with Parkinson's disease with and without impulsive-compulsive behaviours on striatal levels of synaptic dopamine. Eighteen patients (11 with and seven without impulsive-compulsive behaviours) underwent three (11)C-raclopride positron emission tomography scans. The impulsive-compulsive behaviours included hypersexuality, binge eating, punding, compulsive use of dopamine replacement therapy, compulsive buying and pathological gambling, with eight patients exhibiting more than one impulsive-compulsive behaviour. There were no significant differences in baseline dopamine D2 receptor availability between the Parkinson's disease groups. No differences were found when comparing the percentage change of raclopride binding potential between the two Parkinson's disease groups following L-dopa challenge with neutral cues. The group with Parkinson's disease with impulsive-compulsive behaviours had a greater reduction of ventral striatum (11)C-raclopride binding potential following reward-related cue exposure, relative to neutral cue exposure, following L-dopa challenge (16.3% compared with 5.8% in Parkinson's disease controls, P = 0.016). The heightened response of striatal reward circuitry to heterogeneous reward-related visual cues among a group of patients with different impulsive-compulsive behaviours is consistent with a global sensitization to appetitive behaviours with dopaminergic therapy in vulnerable individuals. Our findings are relevant for the broader debate on the relation between impulsive

  15. Glutamatergic Tuning of Hyperactive Striatal Projection Neurons Controls the Motor Response to Dopamine Replacement in Parkinsonian Primates.

    Science.gov (United States)

    Singh, Arun; Jenkins, Meagan A; Burke, Kenneth J; Beck, Goichi; Jenkins, Andrew; Scimemi, Annalisa; Traynelis, Stephen F; Papa, Stella M

    2018-01-23

    Dopamine (DA) loss in Parkinson's disease (PD) alters the function of striatal projection neurons (SPNs) and causes motor deficits, but DA replacement can induce further abnormalities. A key pathological change in animal models and patients is SPN hyperactivity; however, the role of glutamate in altered DA responses remains elusive. We tested the effect of locally applied AMPAR or NMDAR antagonists on glutamatergic signaling in SPNs of parkinsonian primates. Following a reduction in basal hyperactivity by antagonists at either receptor, DA inputs induced SPN firing changes that were stable during the entire motor response, in clear contrast with the typically unstable effects. The SPN activity reduction over an extended putamenal area controlled the release of involuntary movements in the "on" state and therefore improved motor responses to DA replacement. These results demonstrate the pathophysiological role of upregulated SPN activity and support strategies to reduce striatal glutamate signaling for PD therapy. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  16. Imaging of striatal dopamine transporters in rat brain with single pinhole SPECT and co-aligned MRI is highly reproducible

    International Nuclear Information System (INIS)

    Booij, Jan; Bruin, Kora de; Win, Maartje M.L. de; Lavini, Cristina Mphil; Heeten, Gerard J. den; Habraken, Jan

    2003-01-01

    A recently developed pinhole high-resolution SPECT system was used to measure striatal to non-specific binding ratios in rats (n = 9), after injection of the dopamine transporter ligand 123 I-FP-CIT, and to assess its test/retest reproducibility. For co-alignment purposes, the rat brain was imaged on a 1.5 Tesla clinical MRI scanner using a specially developed surface coil. The SPECT images showed clear striatal uptake. On the MR images, cerebral and extra-cerebral structures could be easily delineated. The mean striatal to non-specific [ 123 I]FP-CIT binding ratios of the test/retest studies were 1.7 ± 0.2 and 1.6 ± 0.2, respectively. The test/retest variability was approximately 9%. We conclude that the assessment of striatal [ 123 I]FP-CIT binding ratios in rats is highly reproducible

  17. Dietary Tyrosine Protects Striatal Dopamine Receptors from the Adverse Effects of REM Sleep Deprivation.

    Science.gov (United States)

    Hamdi, A; Brock, J W; Payne, S; Ross, K D; Bond, S P; Prasad, C

    1998-01-01

    L-Tyrosine is a non-essential amino acid that is produced as an intermediary metabolite in the conversion of phenylalanine to 3,4-dihyroxyphenylalanine (DOPA), and is a precursor of the neurotransmitter dopamine. In previous studies, tyrosine pretreatment was shown to protect against the neurochemical and behavioral deficits of acute stress caused by tail shock or cold exposure in rodents. The present study addressed the hypothesis that tyrosine administration may be an effective counter-measure to dopamine-mediated behaviors induced by rapid eye-movement sleep deprivation (RSD). In order to test the hypothesis, Sprague-Dawley rats were divided into 9 treatment groups: RSD-treated rats on normal-protein diet (20% casein: 1% tyrosine, 1% valine); tank control (TC) rats on a normal diet; cage control (CC) rats on normal diet; RSD-treated rats on 4% tyrosine diet; TC rats on 4% tyrosine diet; CC rats on 4% tyrosine diet; RSD-treated rats on 4% valine diet; TC rats on 4% valine diet; CC rats on 4% valine diet. In the RSD group receiving tyrosine, there was no apparent change in Bmax for binding of the dopamine D2 receptor ligand [(3)H]YM-09151-2 in the striata as compared to the respective TC and CC groups; whereas RSD-treated rats maintained on the normal diet and valine supplementation demonstrated expected increases in Bmax for ligand binding. The TC group on the tyrosine diet showed attenuated catalepsy compared to the corresponding CC group, while the RSD group consuming tyrosine showed a catalepsy that was significantly increased, and similar to that of cage control animais on a control diet. These data suggest that the tyrosine-supplemented diet significantly attenuated RSD-induced changes in striatal dopamine D2 receptors, and the effect appeared sufficient to influence RSD-induced behaviors.

  18. Lower levels of uric acid and striatal dopamine in non-tremor dominant Parkinson's disease subtype.

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    Ismael Huertas

    Full Text Available Parkinson's disease (PD patients who present with tremor and maintain a predominance of tremor have a better prognosis. Similarly, PD patients with high levels of uric acid (UA, a natural neuroprotectant, have also a better disease course. Our aim was to investigate whether PD motor subtypes differ in their levels of UA, and if these differences correlate with the degree of dopamine transporter (DAT availability. We included 75 PD patients from whom we collected information about their motor symptoms, DAT imaging and UA concentration levels. Based on the predominance of their motor symptoms, patients were classified into postural instability and gait disorder (PIGD, n = 36, intermediate (I, n = 22, and tremor-dominant (TD, n = 17 subtypes. The levels of UA and striatal DAT were compared across subtypes and the correlation between these two measures was also explored. We found that PIGD patients had lower levels of UA (3.7 vs 4.5 vs 5.3 mg/dL; P<0.001 and striatal DAT than patients with an intermediate or TD phenotype. Furthermore, UA levels significantly correlated with the levels of striatal DAT. We also observed that some PIGD (25% and I (45% patients had a predominance of tremor at disease onset. We speculate that UA might be involved in the maintenance of the less damaging TD phenotype and thus also in the conversion from TD to PIGD. Low levels of this natural antioxidant could lead to a major neuronal damage and therefore influence the conversion to a more severe motor phenotype.

  19. Lower levels of uric acid and striatal dopamine in non-tremor dominant Parkinson's disease subtype.

    Science.gov (United States)

    Huertas, Ismael; Jesús, Silvia; Lojo, José Antonio; García-Gómez, Francisco Javier; Cáceres-Redondo, María Teresa; Oropesa-Ruiz, Juan Manuel; Carrillo, Fátima; Vargas-Gonzalez, Laura; Martín Rodríguez, Juan Francisco; Gómez-Garre, Pilar; García-Solís, David; Mir, Pablo

    2017-01-01

    Parkinson's disease (PD) patients who present with tremor and maintain a predominance of tremor have a better prognosis. Similarly, PD patients with high levels of uric acid (UA), a natural neuroprotectant, have also a better disease course. Our aim was to investigate whether PD motor subtypes differ in their levels of UA, and if these differences correlate with the degree of dopamine transporter (DAT) availability. We included 75 PD patients from whom we collected information about their motor symptoms, DAT imaging and UA concentration levels. Based on the predominance of their motor symptoms, patients were classified into postural instability and gait disorder (PIGD, n = 36), intermediate (I, n = 22), and tremor-dominant (TD, n = 17) subtypes. The levels of UA and striatal DAT were compared across subtypes and the correlation between these two measures was also explored. We found that PIGD patients had lower levels of UA (3.7 vs 4.5 vs 5.3 mg/dL; P<0.001) and striatal DAT than patients with an intermediate or TD phenotype. Furthermore, UA levels significantly correlated with the levels of striatal DAT. We also observed that some PIGD (25%) and I (45%) patients had a predominance of tremor at disease onset. We speculate that UA might be involved in the maintenance of the less damaging TD phenotype and thus also in the conversion from TD to PIGD. Low levels of this natural antioxidant could lead to a major neuronal damage and therefore influence the conversion to a more severe motor phenotype.

  20. Convergence of dopamine and glutamate signalling onto striatal ERK activation in response to drugs of abuse.

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    Emma eCahill

    2014-01-01

    Full Text Available Despite their distinct targets, all addictive drugs commonly abused by humans evoke increases in dopamine (DA concentration within the striatum. The main DA G-Protein Coupled Receptors (GPCRs expressed by medium-sized spiny neurons (MSNs of the striatum are the D1R and D2R, which are positively and negatively coupled to cAMP/protein kinase A (PKA signalling, respectively. These two DA GPCRs are largely segregated into distinct neuronal populations, where they are co-expressed with glutamate receptors in dendritic spines. Direct and indirect interactions between DA GPCRs and glutamate receptors are the molecular basis by which DA modulates glutamate transmission and controls striatal plasticity and behaviour induced by drugs of abuse. A major downstream target of striatal D1R is the Extracellular signal-Regulated Kinase (ERK kinase pathway. ERK activation by drugs of abuse behaves as a key integrator of D1R and glutamate NMDAR signalling. Once activated, ERK can trigger chromatin remodelling and induce gene expression that permits long-term cellular alterations and drug-induced morphological and behavioural changes. Besides the classical cAMP/PKA pathway, downstream of D1R, recent evidence implicates a cAMP-independent crosstalk mechanism by which the D1R potentiates NMDAR-mediated calcium influx and ERK activation. The mounting evidence of reciprocal modulation of DA and glutamate receptors adds further intricacy to striatal synaptic signalling and is liable to prove relevant for addictive drug-induced signalling, plasticity and behaviour. Herein, we review the evidence that built our understanding of the consequences of this synergistic signalling for the actions of drugs of abuse.

  1. Pergolide inhibition of calcium-induced 3H-dopamine release from striatal synaptosomes

    International Nuclear Information System (INIS)

    Bowyer, J.F.; Weiner, N.

    1986-01-01

    Several investigators have reported that dopamine agonists or antagonists are unable to modulate the K + -evoked release of 3 H-dopamine ( 3 H-DA) from striatal synaptosomes. To further assess the role of DA in regulating its release, they have examined the effects of pergolide on Ca ++ (1.25 mM)-evoked release of 3 H-DA from partially K + -depolarized striatal synaptosomes. Synaptosomes (P2 pellet) were isolated from rat striatum and incubated for 5 min at 37 0 C in a Ca ++ -free Krebs-Ringer buffer containing 25 nM 3 H-DA. After radiolabeling, the synaptosomes were superfused for 12 min with Ca ++ -free 6 mM Krebs-Ringer buffer to determine basal release of 3 H-DA. Synaptosomes were then exposed to test drugs for 8 min prior to Ca ++ challenge. Ca ++ addition resulted in a 3-fold increase in 3 H-DA release within 2-4 min. Pergolide inhibited the release of 3 H-DA in a concentration-dependent manner. Release was inhibited to 56% of control by 10 nM pergolide. This was largely reversed by 0.1 μM S-sulpiride. Ca ++ -evoked release was inhibited over 70% by 1 μM tetrodotoxin (TTX), indicating that voltage-dependent Na + channels may play a role in the release process. The combination of pergolide and TTX inhibited release to a degree similar to TTX alone. These results suggest that pergolide may inhibit 3 H-DA release by a TTX-sensitive mechanism and that the dopaminergic autoreceptors may be linked to voltage-sensitive Na + channels

  2. The effect of amperozide on uptake and release of [3H]-dopamine in vitro from perfused rat striatal and limbic brain areas

    International Nuclear Information System (INIS)

    Eriksson, E.; Christensson, E.

    1990-01-01

    Amperozide, a putatively antipsychotic drug, was studied for its effects on uptake and release of [ 3 H]-dopamine in rat brain in vitro. Amperozide inhibited uptake of [ 3 H]-dopamine in striatal chopped tissue in vitro with an IC 50 of 18 μM. It also increased basal release of [ 3 H]-dopamine from perfused rat striatal and limbic tissue in vitro at concentrations above 5 μM. Release of [ 3 H]-dopamine from perfused rat striatal and limbic tissue stimulated with 5 μM amphetamine, was inhibited by 1 μM amperozide to 46%. No significant difference was found for the effect of amperozide on in vitro release of [ 3 H]-dopamine from corpus striatum compared to tissue from limbic grain regions; neither on basal release nor on amphetamine-stimulated release of dopamine. (author)

  3. Correlation of individual differences in schizotypal personality traits with amphetamine-induced dopamine release in striatal and extrastriatal brain regions.

    Science.gov (United States)

    Woodward, Neil D; Cowan, Ronald L; Park, Sohee; Ansari, M Sib; Baldwin, Ronald M; Li, Rui; Doop, Mikisha; Kessler, Robert M; Zald, David H

    2011-04-01

    Schizotypal personality traits are associated with schizophrenia spectrum disorders, and individuals with schizophrenia spectrum disorders demonstrate increased dopamine transmission in the striatum. The authors sought to determine whether individual differences in normal variation in schizotypal traits are correlated with dopamine transmission in the striatum and in extrastriatal brain regions. Sixty-three healthy volunteers with no history of psychiatric illness completed the Schizotypal Personality Questionnaire and underwent positron emission tomography imaging with [(18)F]fallypride at baseline and after administration of oral d-amphetamine (0.43 mg/kg). Dopamine release, quantified by subtracting each participant's d-amphetamine scan from his or her baseline scan, was correlated with Schizotypal Personality Questionnaire total and factor scores using region-of-interest and voxel-wise analyses. Dopamine release in the striatum was positively correlated with overall schizotypal traits. The association was especially robust in the associative subdivision of the striatum. Voxel-wise analyses identified additional correlations between dopamine release and schizotypal traits in the left middle frontal gyrus and left supramarginal gyrus. Exploratory analyses of Schizotypal Personality Questionnaire factor scores revealed correlations between dopamine release and disorganized schizotypal traits in the striatum, thalamus, medial prefrontal cortex, temporal lobe, insula, and inferior frontal cortex. The association between dopamine signaling and psychosis phenotypes extends to individual differences in normal variation in schizotypal traits and involves dopamine transmission in both striatal and extrastriatal brain regions. Amphetamine-induced dopamine release may be a useful endophenotype for investigating the genetic basis of schizophrenia spectrum disorders.

  4. Dopamine

    International Nuclear Information System (INIS)

    Walters, L.

    1983-01-01

    Dopamine is an important neurotransmittor in the central nervous system. The physiological function of the peripheral dopamine receptors is unknown, but they are of therapeutic importance as dopamine is used to improve renal blood flow in shocked patients. There are 4 dopamine receptors. The classification of these dopamine receptors has been made possible by research with radiopharmaceuticals. Dopamine sensitive adenylate cyclase is an inherent part of the dopamine-1-receptor. Dopamine-1-receptors are stimulated by micromolar (physiological) concentrations of dopamine and inhibited by micromolar (supratherapeutic) concentrations of the antipsychotic drugs. The vascular effect of dopamine is mediated through the dopamine-1-receptors. Dopamine-2-receptors are responsible for the effect of dopamine at the mesolimbic, nigrostriatal and chemoreceptortrigger areas. It is activated by micromolar concentrations of dopamine and blocked by nanomolar (therapeutic) concentrations of the anti-psychotic drugs. Dopamine-3-receptors are activated by nanomolar concentrations of dopamine and inhibited by micromolar concentrations of the antipsychotic drugs. They occur on presynaptic nerve terminals and have a negative feedback effect on the liberation of dopamine, noradrenaline and serotonin. The dopamine-4-receptors are activated by nanomolar concentrations of dopamine. These are the only dopamine receptors that could be responsible for effects in the hypophysis as only nanomolar concentrations of dopamine occur there. These receptors are blocked by nanomolar concentrations of the antipsychotic drugs

  5. Membrane properties of striatal direct and indirect pathway neurons in mouse and rat slices and their modulation by dopamine.

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    Henrike Planert

    Full Text Available D1 and D2 receptor expressing striatal medium spiny neurons (MSNs are ascribed to striatonigral ("direct" and striatopallidal ("indirect" pathways, respectively, that are believed to function antagonistically in motor control. Glutamatergic synaptic transmission onto the two types is differentially affected by Dopamine (DA, however, less is known about the effects on MSN intrinsic electrical properties. Using patch clamp recordings, we comprehensively characterized the two pathways in rats and mice, and investigated their DA modulation. We identified the direct pathway by retrograde labeling in rats, and in mice we used transgenic animals in which EGFP is expressed in D1 MSNs. MSNs were subjected to a series of current injections to pinpoint differences between the populations, and in mice also following bath application of DA. In both animal models, most electrical properties were similar, however, membrane excitability as measured by step and ramp current injections consistently differed, with direct pathway MSNs being less excitable than their counterparts. DA had opposite effects on excitability of D1 and D2 MSNs, counteracting the initial differences. Pronounced changes in AP shape were seen in D2 MSNs. In direct pathway MSNs, excitability increased across experimental conditions and parameters, and also when applying DA or the D1 agonist SKF-81297 in presence of blockers of cholinergic, GABAergic, and glutamatergic receptors. Thus, DA induced changes in excitability were D1 R mediated and intrinsic to direct pathway MSNs, and not a secondary network effect of altered synaptic transmission. DAergic modulation of intrinsic properties therefore acts in a synergistic manner with previously reported effects of DA on afferent synaptic transmission and dendritic processing, supporting the antagonistic model for direct vs. indirect striatal pathway function.

  6. Effects of Ketamine and Ketamine Metabolites on Evoked Striatal Dopamine Release, Dopamine Receptors, and Monoamine Transporters

    Science.gov (United States)

    Can, Adem; Zanos, Panos; Moaddel, Ruin; Kang, Hye Jin; Dossou, Katinia S. S.; Wainer, Irving W.; Cheer, Joseph F.; Frost, Douglas O.; Huang, Xi-Ping

    2016-01-01

    Following administration at subanesthetic doses, (R,S)-ketamine (ketamine) induces rapid and robust relief from symptoms of depression in treatment-refractory depressed patients. Previous studies suggest that ketamine’s antidepressant properties involve enhancement of dopamine (DA) neurotransmission. Ketamine is rapidly metabolized to (2S,6S)- and (2R,6R)-hydroxynorketamine (HNK), which have antidepressant actions independent of N-methyl-d-aspartate glutamate receptor inhibition. These antidepressant actions of (2S,6S;2R,6R)-HNK, or other metabolites, as well as ketamine’s side effects, including abuse potential, may be related to direct effects on components of the dopaminergic (DAergic) system. Here, brain and blood distribution/clearance and pharmacodynamic analyses at DA receptors (D1–D5) and the DA, norepinephrine, and serotonin transporters were assessed for ketamine and its major metabolites (norketamine, dehydronorketamine, and HNKs). Additionally, we measured electrically evoked mesolimbic DA release and decay using fast-scan cyclic voltammetry following acute administration of subanesthetic doses of ketamine (2, 10, and 50 mg/kg, i.p.). Following ketamine injection, ketamine, norketamine, and multiple hydroxynorketamines were detected in the plasma and brain of mice. Dehydronorketamine was detectable in plasma, but concentrations were below detectable limits in the brain. Ketamine did not alter the magnitude or kinetics of evoked DA release in the nucleus accumbens in anesthetized mice. Neither ketamine’s enantiomers nor its metabolites had affinity for DA receptors or the DA, noradrenaline, and serotonin transporters (up to 10 μM). These results suggest that neither the side effects nor antidepressant actions of ketamine or ketamine metabolites are associated with direct effects on mesolimbic DAergic neurotransmission. Previously observed in vivo changes in DAergic neurotransmission following ketamine administration are likely indirect. PMID

  7. Effects of the modern food environment on striatal function, cognition and regulation of ingestive behavior.

    Science.gov (United States)

    Burke, Mary V; Small, Dana M

    2016-06-01

    Emerging evidence from human and animal studies suggest that consumption of palatable foods rich in fat and/or carbohydrates may produce deleterious influences on brain function independently of body weight or metabolic disease. Here we consider two mechanisms by which diet can impact striatal circuits to amplify food cue reactivity and impair inhibitory control. First, we review findings demonstrating that the energetic properties of foods regulate nucleus accumbens food cue reactivity, a demonstrated predictor of weight gain susceptibility, which is then sensitized by chronic consumption of an energy dense diet. Second, we consider evidence for diet-induced adaptations in dorsal striatal dopamine signaling that is associated with impaired inhibitory control and negative outcome learning.

  8. A53T-alpha-synuclein overexpression impairs dopamine signaling and striatal synaptic plasticity in old mice.

    Directory of Open Access Journals (Sweden)

    Alexander Kurz

    2010-07-01

    Full Text Available Parkinson's disease (PD, the second most frequent neurodegenerative disorder at old age, can be caused by elevated expression or the A53T missense mutation of the presynaptic protein alpha-synuclein (SNCA. PD is characterized pathologically by the preferential vulnerability of the dopaminergic nigrostriatal projection neurons.Here, we used two mouse lines overexpressing human A53T-SNCA and studied striatal dysfunction in the absence of neurodegeneration to understand early disease mechanisms. To characterize the progression, we employed young adult as well as old mice. Analysis of striatal neurotransmitter content demonstrated that dopamine (DA levels correlated directly with the level of expression of SNCA, an observation also made in SNCA-deficient (knockout, KO mice. However, the elevated DA levels in the striatum of old A53T-SNCA overexpressing mice may not be transmitted appropriately, in view of three observations. First, a transcriptional downregulation of the extraneural DA degradation enzyme catechol-ortho-methytransferase (COMT was found. Second, an upregulation of DA receptors was detected by immunoblots and autoradiography. Third, extensive transcriptome studies via microarrays and quantitative real-time RT-PCR (qPCR of altered transcript levels of the DA-inducible genes Atf2, Cb1, Freq, Homer1 and Pde7b indicated a progressive and genotype-dependent reduction in the postsynaptic DA response. As a functional consequence, long term depression (LTD was absent in corticostriatal slices from old transgenic mice.Taken together, the dysfunctional neurotransmission and impaired synaptic plasticity seen in the A53T-SNCA overexpressing mice reflect early changes within the basal ganglia prior to frank neurodegeneration. As a model of preclinical stages of PD, such insights may help to develop neuroprotective therapeutic approaches.

  9. Effect of cocaine on striatal dopamine clearance in a rat model of developmental stress and attention-deficit/hyperactivity disorder.

    Science.gov (United States)

    Womersley, Jacqueline S; Kellaway, Lauriston A; Stein, Dan J; Gerhardt, Greg A; Russell, Vivienne A

    2016-01-01

    Attention-deficit/hyperactivity disorder (ADHD) and developmental stress are considered risk factors for the development of drug abuse. Though the physiological mechanisms underlying this risk are not yet clear, ADHD, developmental stress and drug abuse are known to share underlying disturbances in dopaminergic neurotransmission. Thus, we hypothesized that clearance of cocaine-induced elevations in striatal dopamine would be prolonged in a rat model of ADHD and that this would be further increased by exposure to developmental stress. In the current study, male spontaneously hypertensive rats (SHRs), a well-validated model of ADHD, and control Wistar-Kyoto (WKY) rats were exposed to either standard rearing (nMS) or a maternal separation (MS) paradigm involving removal of the pups from the dam for 180 min/day over 13 days. This produced a 2 × 2 factorial design (SHR/WKY × nMS/MS) with 5-6 rats/group. Striatal clearance of exogenously applied dopamine was measured via in vivo chronoamperometry, and the difference in dopamine uptake parameters before and after cocaine administration was compared between experimental groups. Cocaine, a potent dopamine transporter inhibitor, reliably increased the clearance time of dopamine though no difference in this parameter was found between SHR and WKY strains. However, developmental stress elevated the cocaine-induced increase in time to clear 50% of exogenously applied dopamine (T50) in SHR but had no effect in WKY rats. These findings suggest that a strain × environment interaction prolongs elevated levels of dopamine thereby potentially increasing the rewarding properties of this drug in SHR.

  10. Suppression of serotonin hyperinnervation does not alter the dysregulatory influences of dopamine depletion on striatal neuropeptide gene expression in rodent neonates.

    Science.gov (United States)

    Basura, G J; Walker, P D

    1999-10-15

    Sixty days following neonatal dopamine depletion (>98%) with 6-hydroxydopamine, preprotachykinin and preprodynorphin mRNA levels were significantly reduced (67 and 78% of vehicle controls, respectively) in the anterior striatum as determined by in situ hybridization while preproenkephalin mRNA expression was elevated (133% of vehicle controls). Suppression of the serotonin hyperinnervation phenomenon in the dopamine-depleted rat with 5,7-dihydroxytryptamine yielded no significant alterations in reduced striatal preprotachykinin (66%) or preprodynorphin (64%) mRNA levels, while preproenkephalin mRNA expression remained significantly elevated (140%). These data suggest that striatal serotonin hyperinnervation does not contribute to the development of dysregulated striatal neuropeptide transmission in either direct or indirect striatal output pathways following neonatal dopamine depletion.

  11. In vivo evaluation of striatal dopamine reuptake sites using 11C-nomifensine and positron emission tomography

    International Nuclear Information System (INIS)

    Aquilonius, S.-M.; Bergstroem, K.; Eckernaes, S.-Aa.; Leenders, K.L.; Hartvig, P.; Lundquist, H.; Antoni, G.; Gee, A.; Rimland, A.; Uhlin, J.; Langstroem, B.

    1987-01-01

    In vitro nomifensine demonstrates high affinity and specificity for dopamine reuptake sites in the brain. In the present study 11 C-nomifensine was administered i.v. in trace amounts (10-50 μg) to ketamine anaesthetized Rhesus monkeys (6-10 kg b.w.) and the timecourse of radioactivity within different brain regions was measured by positron emission tomography (PET). Six base-line experiments lasting for 60-80 min were performed. The procedure was repeated after pretreatment with nomifensine (2-6 mg/kg i.v.), another reuptake inhibitor, mazindol (0.3 mg/kg i.v.), desipramine (0.5 mg/kg i.v.) or spiperone (0.3 mg/kg i.v.) before the administration of a second 11 C-nomifensine dose. The highest radioactivity uptake was found in the dopamine innervated striatum and the lowest in a region containing the cerebellum, known to be almost devoid of dopaminergic neurons. The difference between striatal and cerebellar uptake of 11 C-nomifensine derived radioactivity was markedly reduced after nomifensine and mazindol but not after desipramine and spiperone. These results indicate that in vivo the striatal uptake of 11 C-nomifensine, as measured with PET, involves specific binding with the dopamine reuptake sites. In the first human applications of 11 C-nomifensine and PET in a healthy volunteer, the regional uptake of radioactivity was similar to that in base-line experiments with Rhesus monkeys. In the healthy subject the striatal/cerebellar ratio was 1.6, 50 min after the injection of 11 C-nomifensine. In a hemi-parkinsonian patient this ratio was 1.1 contralaterally and 1.3 ipsilaterally to the affected side. 11 C-nomifensine and PET seems to be an auspicious method to measure the striatal dopaminergic nerve terminals of man in vivo. (author)

  12. In vivo evaluation of striatal dopamine reuptake sites using /sup 11/C-nomifensine and positron emission tomography

    Energy Technology Data Exchange (ETDEWEB)

    Aquilonius, S.-M.; Bergstroem, K.; Eckernaes, S.-Aa.; Leenders, K.L.; Hartvig, P.; Lundquist, H.; Antoni, G.; Gee, A.; Rimland, A.; Uhlin, J.

    1987-01-01

    In vitro nomifensine demonstrates high affinity and specificity for dopamine reuptake sites in the brain. In the present study /sup 11/C-nomifensine was administered i.v. in trace amounts (10-50 ..mu..g) to ketamine anaesthetized Rhesus monkeys (6-10 kg b.w.) and the timecourse of radioactivity within different brain regions was measured by positron emission tomography (PET). Six base-line experiments lasting for 60-80 min were performed. The procedure was repeated after pretreatment with nomifensine (2-6 mg/kg i.v.), another reuptake inhibitor, mazindol (0.3 mg/kg i.v.), desipramine (0.5 mg/kg i.v.) or spiperone (0.3 mg/kg i.v.) before the administration of a second /sup 11/C-nomifensine dose. The highest radioactivity uptake was found in the dopamine innervated striatum and the lowest in a region containing the cerebellum, known to be almost devoid of dopaminergic neurons. The difference between striatal and cerebellar uptake of /sup 11/C-nomifensine derived radioactivity was markedly reduced after nomifensine and mazindol but not after desipramine and spiperone. These results indicate that in vivo the striatal uptake of /sup 11/C-nomifensine, as measured with PET, involves specific binding with the dopamine reuptake sites. In the first human applications of /sup 11/C-nomifensine and PET in a healthy volunteer, the regional uptake of radioactivity was similar to that in base-line experiments with Rhesus monkeys. In the healthy subject the striatal/cerebellar ratio was 1.6, 50 min after the injection of /sup 11/C-nomifensine. In a hemi-parkinsonian patient this ratio was 1.1 contralaterally and 1.3 ipsilaterally to the affected side. /sup 11/C-nomifensine and PET seems to be an auspicious method to measure the striatal dopaminergic nerve terminals of man in vivo.

  13. Timing of caloric intake during weight loss differentially affects striatal dopamine transporter and thalamic serotonin transporter binding.

    Science.gov (United States)

    Versteeg, Ruth I; Schrantee, Anouk; Adriaanse, Sofie M; Unmehopa, Unga A; Booij, Jan; Reneman, Liesbeth; Fliers, Eric; la Fleur, Susanne E; Serlie, Mireille J

    2017-10-01

    Recent studies have shown that meal timing throughout the day contributes to maintaining or regaining weight after hypocaloric diets. Although brain serotonin and dopamine are well known to be involved in regulating feeding, it is unknown whether meal timing during energy restriction affects these neurotransmitter systems. We studied the effect of a 4 wk hypocaloric diet with either 50% of daily calories consumed at breakfast (BF group) or at dinner (D group) on hypothalamic and thalamic serotonin transporter (SERT) binding and on striatal dopamine transporter (DAT) binding. The BF and D groups lost a similar amount of weight. Striatal DAT and thalamic SERT binding increased in the BF group, while decreasing in the D group after the diet (ΔDAT 0.37 ± 0.63 vs. -0.53 ± 0.77, respectively; P = 0.005; ΔSERT 0.12 ± 0.25 vs. -0.13 ± 0.26 respectively, P = 0.032). Additional voxel-based analysis showed an increase in DAT binding in the ventral striatum in the BF group and a decrease in the dorsal striatum in the D group. During weight loss, striatal DAT and thalamic SERT binding increased weight independently when 50% of daily calories were consumed at breakfast, whereas it decreased when caloric intake was highest at dinner. These findings may contribute to the earlier reported favorable effect of meal timing on weight maintenance after hypocaloric diets.-Versteeg, R. I., Schrantee, A., Adriaanse, S. M., Unmehopa, U. A., Booij, J., Reneman, L., Fliers, E., la Fleur, S. E., Serlie, M. J. Timing of caloric intake during weight loss differentially affects striatal dopamine transporter and thalamic serotonin transporter binding. © FASEB.

  14. Differences in the time course of haloperidol-induced up-regulation of rat striatal and mesolimbic dopamine receptors

    International Nuclear Information System (INIS)

    Prosser, E.S.; Csernansky, J.G.; Hollister, L.E.

    1988-01-01

    Regional differences in the onset and persistence of increased dopamine D2 receptor density in rat brain were studied following daily injections of haloperidol for 3, 7, 14, or 28 days. Striatal [ 3 H]-spiroperidol Bmax values were significantly increased following 3 - 28 days of haloperidol treatment, as compared to saline controls. Olfactory tubercle Bmax values were significantly increased only after 14 or 28 days of haloperidol treatment. Nucleus accumbens Bmax values were significantly increased only in the 14-day drug treatment group, suggesting that dopamine D2 receptor up-regulation in nucleus accumbens may reverse during ongoing neuroleptic treatment. These findings suggest that important differences in adaptive responses to chronic dopamine blockade may exist between dopaminergic synapses located in various rat brain regions

  15. Impairment of striatal mitochondrial function by acute paraquat poisoning.

    Science.gov (United States)

    Czerniczyniec, Analía; Lanza, E M; Karadayian, A G; Bustamante, J; Lores-Arnaiz, S

    2015-10-01

    Mitochondria are essential for survival. Their primary function is to support aerobic respiration and to provide energy for intracellular metabolic pathways. Paraquat is a redox cycling agent capable of generating reactive oxygen species. The aim of the present study was to evaluate changes in cortical and striatal mitochondrial function in an experimental model of acute paraquat toxicity and to compare if the brain areas and the molecular mechanisms involved were similar to those observed after chronic exposure. Sprague-Dawley rats received paraquat (25 mg/Kg i.p.) or saline and were sacrificed after 24 h. Paraquat treatment decreased complex I and IV activity by 37 and 21 % respectively in striatal mitochondria. Paraquat inhibited striatal state 4 and state 3 KCN-sensitive respiration by 80 % and 62 % respectively, indicating a direct effect on respiratory chain. An increase of 2.2 fold in state 4 and 2.3 fold in state 3 in KCN-insensitive respiration was observed in striatal mitochondria from paraquat animals, suggesting that paraquat redox cycling also consumed oxygen. Paraquat treatment increased hydrogen peroxide production (150 %), TBARS production (42 %) and cardiolipin oxidation/depletion (12 %) in striatal mitochondria. Also, changes in mitochondrial polarization was induced after paraquat treatment. However, no changes were observed in any of these parameters in cortical mitochondria from paraquat treated-animals. These results suggest that paraquat treatment induced a clear striatal mitochondrial dysfunction due to both paraquat redox cycling reactions and impairment of the mitochondrial electron transport, causing oxidative damage. As a consequence, mitochondrial dysfunction could probably lead to alterations in cellular bioenergetics.

  16. Inhibition of [3H]dopamine uptake into rat striatal slices by quaternary N-methylated nicotine metabolites

    International Nuclear Information System (INIS)

    Dwoskin, L.P.; Leibee, L.L.; Jewell, A.L.; Fang, Zhaoxia; Crooks, P.A.

    1992-01-01

    The effects of quaternary N-methylated nicotine derivatives were examined on in vitro uptake of [ 3 H]dopamine ([ 3 H]DA) in rat striatal slices. Striatal slices were incubated with a 10 μM concentration of the following compounds: N-methylnicotinium, N-methylnornicotinium, N-methylcotininium, N,N'-dimethylnicotinium and N'-methylnicotinium salts. The results clearly indicated that significant inhibition of [ 3 H]DA uptake occurred with those compounds possessing a N-methylpyridinium group; whereas, compounds that were methylated at the N'-pyrrolidinium position were less effective or exhibited no inhibition of [ 3 H]DA uptake. The results suggest that high concentrations of quaternary N-methylated nicotine metabolites which are structurally related to the neurotoxin MPP + , and which may be formed in the CNS, may protect against Parkinson's Disease and explain the inverse relationship between smoking and Parkinsonism reported in epidemiologic studies

  17. Contribution of vesicular and cytosolic dopamine to the increased striatal dopamine efflux elicited by intrastriatal injection of dexamphetamine.

    NARCIS (Netherlands)

    Watanabe, S.; Aono, Y.; Fusa, K.; Takada, K.; Saigusa, T.; Koshikawa, N.; Cools, A.R.

    2005-01-01

    Systemic administration of high doses of dexamphetamine induces a dopamine efflux that has its intracellular origin in both the vesicular, reserpine-sensitive dopamine pool and the cytosolic, alpha-methyl-para-tyrosine-sensitive, newly synthesized dopamine pool. It remains unknown whether locally

  18. Monetary discounting and ventral striatal dopamine receptor availability in nontreatment-seeking alcoholics and social drinkers.

    Science.gov (United States)

    Oberlin, Brandon G; Albrecht, Daniel S; Herring, Christine M; Walters, James W; Hile, Karen L; Kareken, David A; Yoder, Karmen K

    2015-06-01

    Dopamine (DA) in the ventral striatum (VST) has long been implicated in addiction pathologies, yet its role in temporal decision-making is not well-understood. To determine if VST DA D2 receptor availability corresponds with greater impulsive choice in both nontreatment-seeking alcoholics (NTS) and social drinkers (SD). NTS subjects (n = 10) and SD (n = 13) received PET scans at baseline with the D2/D3 radioligand [(11)C]raclopride (RAC). Outside the scanner, subjects performed a delay discounting procedure with monetary rewards. RAC binding potential (BPND) was estimated voxelwise, and correlations were performed to test for relationships between VST BPND and delay discounting performance. Self-reported impulsivity was also tested for correlations with BPND. Across all subjects, greater impulsive choice for $20 correlated with lower BPND in the right VST. NTS showed greater impulsive choice than SD and were more impulsive by self-report. Across all subjects, the capacity of larger rewards to reduce impulsive choice (the magnitude effect) correlated negatively (p = 0.028) with problematic alcohol use (AUDIT) scores. Self-reported impulsivity did not correlate with BPND in VST. Preference for immediate reinforcement may reflect greater endogenous striatal DA or lower D2 number, or both. Alcoholic status did not mediate significant effects on VST BPND, suggesting minimal effects from alcohol exposure. The apparent lack of BPND correlation with self-reported impulsivity highlights the need for objective behavioral assays in the study of the neurochemical substrates of behavior. Finally, our results suggest that the magnitude effect may be more sensitive to alcohol-induced problems than single discounting measures.

  19. New Repeat Polymorphism in theAKT1Gene Predicts Striatal Dopamine D2/D3 Receptor Availability and Stimulant-Induced Dopamine Release in the Healthy Human Brain.

    Science.gov (United States)

    Shumay, Elena; Wiers, Corinde E; Shokri-Kojori, Ehsan; Kim, Sung Won; Hodgkinson, Colin A; Sun, Hui; Tomasi, Dardo; Wong, Christopher T; Weinberger, Daniel R; Wang, Gene-Jack; Fowler, Joanna S; Volkow, Nora D

    2017-05-10

    The role of the protein kinase Akt1 in dopamine neurotransmission is well recognized and has been implicated in schizophrenia and psychosis. However, the extent to which variants in the AKT1 gene influence dopamine neurotransmission is not well understood. Here we investigated the effect of a newly characterized variant number tandem repeat (VNTR) polymorphism in AKT1 [major alleles: L- (eight repeats) and H- (nine repeats)] on striatal dopamine D2/D3 receptor (DRD2) availability and on dopamine release in healthy volunteers. We used PET and [ 11 C]raclopride to assess baseline DRD2 availability in 91 participants. In 54 of these participants, we also measured intravenous methylphenidate-induced dopamine release to measure dopamine release. Dopamine release was quantified as the difference in specific binding of [ 11 C]raclopride (nondisplaceable binding potential) between baseline values and values following methylphenidate injection. There was an effect of AKT1 genotype on DRD2 availability at baseline for the caudate ( F (2,90) = 8.2, p = 0.001) and putamen ( F (2,90) = 6.6, p = 0.002), but not the ventral striatum ( p = 0.3). For the caudate and putamen, LL showed higher DRD2 availability than HH; HL were in between. There was also a significant effect of AKT1 genotype on dopamine increases in the ventral striatum ( F (2,53) = 5.3, p = 0.009), with increases being stronger in HH > HL > LL. However, no dopamine increases were observed in the caudate ( p = 0.1) or putamen ( p = 0.8) following methylphenidate injection. Our results provide evidence that the AKT1 gene modulates both striatal DRD2 availability and dopamine release in the human brain, which could account for its association with schizophrenia and psychosis. The clinical relevance of the newly characterized AKT1 VNTR merits investigation. SIGNIFICANCE STATEMENT The AKT1 gene has been implicated in schizophrenia and psychosis. This association is likely to reflect modulation of dopamine signaling by

  20. Ascorbic acid and striatal transport of [3H]1-methyl-4-phenylpyridine (MPP+) and [3H]dopamine

    International Nuclear Information System (INIS)

    Debler, E.A.; Hashim, A.; Lajtha, A.; Sershen, H.

    1988-01-01

    The inhibition of uptake of [ 3 H]dopamine and [ 3 H]1-methyl-4-phenylpyridine (MPP + ) was examined in mouse striatal synaptosomal preparations. Kinetic analysis indicated that ascorbic acid is a noncompetitive inhibitor of [ 3 H]MPP + uptake. No inhibition of [ 3 H]dopamine uptake is observed. The dopamine uptake blockers, GBR-12909, cocaine, and mazindol strongly inhibit (IC 50 3 H]dopamine and [ 3 H]MPP + transport. Nicotine, its metabolites, and other tobacco alkaloids are weak inhibitors except 4-phenylpyridine and lobeline, which are moderate inhibitors of both [ 3 H]dopamine and [ 3 H]MPP + uptake. These similarities in potencies are in agreement with the suggestion that [ 3 H]MPP + and [ 3 H] are transported by the same carrier. The differences observed in the alteration of dopaminergic transport and mazindol binding by ascorbic acid suggest that ascorbic acid's effects on [ 3 H]MPP + transport are related to translocation and/or dissociation processes occurring subsequent to the initial binding event

  1. Adenosine–cannabinoid receptor interactions. Implications for striatal function

    Science.gov (United States)

    Ferré, Sergi; Lluís, Carme; Justinova, Zuzana; Quiroz, César; Orru, Marco; Navarro, Gemma; Canela, Enric I; Franco, Rafael; Goldberg, Steven R

    2010-01-01

    Adenosine and endocannabinoids are very ubiquitous non-classical neurotransmitters that exert a modulatory role on the transmission of other more ‘classical’ neurotransmitters. In this review we will focus on their common role as modulators of dopamine and glutamate neurotransmission in the striatum, the main input structure of the basal ganglia. We will pay particular attention to the role of adenosine A2A receptors and cannabinoid CB1 receptors. Experimental results suggest that presynaptic CB1 receptors interacting with A2A receptors in cortico-striatal glutamatergic terminals that make synaptic contact with dynorphinergic medium-sized spiny neurons (MSNs) are involved in the motor-depressant and addictive effects of cannabinoids. On the other hand, postsynaptic CB1 receptors interacting with A2A and D2 receptors in the dendritic spines of enkephalinergic MSNs and postsynaptic CB1 receptors in the dendritic spines of dynorphinergic MSN are probably involved in the cataleptogenic effects of cannabinoids. These receptor interactions most probably depend on the existence of a variety of heteromers of A2A, CB1 and D2 receptors in different elements of striatal spine modules. Drugs selective for the different striatal A2A and CB1 receptor heteromers could be used for the treatment of neuropsychiatric disorders and drug addiction and they could provide effective drugs with fewer side effects than currently used drugs. This article is part of a themed issue on Cannabinoids. To view the editorial for this themed issue visit http://dx.doi.org/10.1111/j.1476-5381.2010.00831.x PMID:20590556

  2. Extrasynaptic neurotransmission in the modulation of brain function. Focus on the striatal neuronal-glial networks

    Directory of Open Access Journals (Sweden)

    Kjell eFuxe

    2012-06-01

    Full Text Available Extrasynaptic neurotransmission is an important short distance form of volume transmission (VT and describes the extracellular diffusion of transmitters and modulators after synaptic spillover or extrasynaptic release in the local circuit regions binding to and activating mainly extrasynaptic neuronal and glial receptors in the neuroglial networks of the brain. Receptor-receptor interactions in G protein-coupled receptor (GPCR heteromers play a major role, on dendritic spines and nerve terminals including glutamate synapses, in the integrative processes of the extrasynaptic signaling. Heteromeric complexes between GPCR and ion-channel receptors play a special role in the integration of the synaptic and extrasynaptic signals. Changes in extracellular concentrations of the classical synaptic neurotransmitters glutamate and GABA found with microdialysis is likely an expression of the activity of the neuron-astrocyte unit of the brain and can be used as an index of VT-mediated actions of these two neurotransmitters in the brain. Thus, the activity of neurons may be functionally linked to the activity of astrocytes, which may release glutamate and GABA to the extracellular space where extrasynaptic glutamate and GABA receptors do exist. Wiring transmission (WT and VT are fundamental properties of all neurons of the CNS but the balance between WT and VT varies from one nerve cell population to the other. The focus is on the striatal cellular networks, and the WT and VT and their integration via receptor heteromers are described in the GABA projection neurons, the glutamate, dopamine, 5-hydroxytryptamine (5-HT and histamine striatal afferents, the cholinergic interneurons and different types of GABA interneurons. In addition, the role in these networks of VT signaling of the energy-dependent modulator adenosine and of endocannabinoids mainly formed in the striatal projection neurons will be underlined to understand the communication in the striatal

  3. Exploring personality traits related to dopamine D2/3 receptor availability in striatal subregions of humans.

    Science.gov (United States)

    Caravaggio, Fernando; Fervaha, Gagan; Chung, Jun Ku; Gerretsen, Philip; Nakajima, Shinichiro; Plitman, Eric; Iwata, Yusuke; Wilson, Alan; Graff-Guerrero, Ariel

    2016-04-01

    While several studies have examined how particular personality traits are related to dopamine D2/3 receptor (D2/3R) availability in the striatum of humans, few studies have reported how multiple traits measured in the same persons are differentially related to D2/3R availability in different striatal sub-regions. We examined how personality traits measured with the Karolinska Scales of Personality are related to striatal D2/3R availability measured with [(11)C]-raclopride in 30 healthy humans. Based on previous the literature, five personality traits were hypothesized to be most likely related to D2/3R availability: impulsiveness, monotony avoidance, detachment, social desirability, and socialization. We found self-reported impulsiveness was negatively correlated with D2/3R availability in the ventral striatum and globus pallidus. After controlling for age and gender, monotony avoidance was also negatively correlated with D2/3R availability in the ventral striatum and globus pallidus. Socialization was positively correlated with D2/3R availability in the ventral striatum and putamen. After controlling for age and gender, the relationship between socialization and D2/3R availability in these regions survived correction for multiple comparisons (p-threshold=.003). Thus, within the same persons, different personality traits are differentially related to in vivo D2/3R availability in different striatal sub-regions. Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.

  4. Caffeine and a selective adenosine A2A receptor antagonist induce sensitization and cross-sensitization behavior associated with increased striatal dopamine in mice

    Directory of Open Access Journals (Sweden)

    Hsu Chih W

    2010-01-01

    Full Text Available Abstract Background Caffeine, a nonselective adenosine A1 and A2A receptor antagonist, is the most widely used psychoactive substance in the world. Evidence demonstrates that caffeine and selective adenosine A2A antagonists interact with the neuronal systems involved in drug reinforcement, locomotor sensitization, and therapeutic effect in Parkinson's disease (PD. Evidence also indicates that low doses of caffeine and a selective adenosine A2A antagonist SCH58261 elicit locomotor stimulation whereas high doses of these drugs exert locomotor inhibition. Since these behavioral and therapeutic effects are mediated by the mesolimbic and nigrostriatal dopaminergic pathways which project to the striatum, we hypothesize that low doses of caffeine and SCH58261 may modulate the functions of dopaminergic neurons in the striatum. Methods In this study, we evaluated the neuroadaptations in the striatum by using reverse-phase high performance liquid chromatography (HPLC to quantitate the concentrations of striatal dopamine and its metabolites, dihydroxylphenylacetic acid (DOPAC and homovanilic acid (HVA, and using immunoblotting to measure the level of phosphorylation of tyrosine hydroxylase (TH at Ser31, following chronic caffeine and SCH58261 sensitization in mice. Moreover, to validate further that the behavior sensitization of caffeine is through antagonism at the adenosine A2A receptor, we also evaluate whether chronic pretreatment with a selective adenosine A2A antagonist SCH58261 or a selective adenosine A1 antagonist DPCPX can sensitize the locomotor stimulating effects of caffeine. Results Chronic treatments with low dose caffeine (10 mg/kg or SCH58261 (2 mg/kg increased the concentrations of dopamine, DOPAC and HVA, concomitant with increased TH phosphorylation at Ser31 and consequently enhanced TH activity in the striatal tissues in both caffeine- and SCH58261-sensitized mice. In addition, chronic caffeine or SCH58261 administration induced

  5. 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.

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

    International Nuclear Information System (INIS)

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

    2011-01-01

    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.

  7. Centrality of striatal cholinergic transmission in basal ganglia function

    Directory of Open Access Journals (Sweden)

    Paola eBonsi

    2011-02-01

    Full Text Available Work over the past two decades revealed a previously unexpected role for striatal cholinergic interneurons in the context of basal ganglia function. The recognition that these interneurons are essential in synaptic plasticity and motor learning represents a significant step ahead in deciphering how the striatum processes cortical inputs, and why pathological circumstances cause motor dysfunction.Loss of the reciprocal modulation between dopaminergic inputs and the intrinsic cholinergic innervation within the striatum appears to be the trigger for pathophysiological changes occurring in basal ganglia disorders. Accordingly, there is now compelling evidence showing profound changes in cholinergic markers in these disorders, in particular Parkinson’s disease and dystonia.Based on converging experimental and clinical evidence, we provide an overview of the role of striatal cholinergic transmission in physiological and pathological conditions, in the context of the pathogenesis of movement disorders.

  8. Striatal dopamine D2 receptor availability predicts the thalamic and medial prefrontal responses to reward in cocaine abusers three years later

    Energy Technology Data Exchange (ETDEWEB)

    Asensio, S.; Goldstein, R.; Asensio, S.; Romero, M.J.; Romero, F.J.; Wong, C.T.; Alia-Klein, N.; Tomasi, D.; Wang, G.-J.; Telang, F..; Volkow, N.D.; Goldstein, R.Z.

    2010-05-01

    Low levels of dopamine (DA) D2 receptor availability at a resting baseline have been previously reported in drug addicted individuals and have been associated with reduced ventral and dorsal prefrontal metabolism. The reduction in DA D2 receptor availability along with the reduced ventral frontal metabolism is thought to underlie compromised sensitivity to nondrug reward, a core characteristic of drug addiction. We therefore hypothesized that variability in DA D2 receptor availability at baseline will covary with dynamic responses to monetary reward in addicted individuals. Striatal DA D2 receptor availability was measured with [{sup 11}C]raclopride and positron emission tomography and response to monetary reward was measured (an average of three years later) with functional magnetic resonance imaging in seven cocaine-addicted individuals. Results show that low DA D2 receptor availability in the dorsal striatum was associated with decreased thalamic response to monetary reward; while low availability in ventral striatum was associated with increased medial prefrontal (Brodmann Area 6/8/32) response to monetary reward. These preliminary results, that need to be replicated in larger sample sizes and validated with healthy controls, suggest that resting striatal DA D2 receptor availability predicts variability in functional responses to a nondrug reinforcer (money) in prefrontal cortex, implicated in behavioral monitoring, and in thalamus, implicated in conditioned responses and expectation, in cocaine-addicted individuals.

  9. Striatal dopamine D2 receptor availability predicts the thalamic and medial prefrontal responses to reward in cocaine abusers three years later

    International Nuclear Information System (INIS)

    Asensio, S.; Goldstein, R.; Romero, M.J.; Romero, F.J.; Wong, C.T.; Alia-Klein, N.; Tomasi, D.; Wang, G.-J.; Telang, F.; Volkow, N.D.; Goldstein, R.Z.

    2010-01-01

    Low levels of dopamine (DA) D2 receptor availability at a resting baseline have been previously reported in drug addicted individuals and have been associated with reduced ventral and dorsal prefrontal metabolism. The reduction in DA D2 receptor availability along with the reduced ventral frontal metabolism is thought to underlie compromised sensitivity to nondrug reward, a core characteristic of drug addiction. We therefore hypothesized that variability in DA D2 receptor availability at baseline will covary with dynamic responses to monetary reward in addicted individuals. Striatal DA D2 receptor availability was measured with ( 11 C)raclopride and positron emission tomography and response to monetary reward was measured (an average of three years later) with functional magnetic resonance imaging in seven cocaine-addicted individuals. Results show that low DA D2 receptor availability in the dorsal striatum was associated with decreased thalamic response to monetary reward; while low availability in ventral striatum was associated with increased medial prefrontal (Brodmann Area 6/8/32) response to monetary reward. These preliminary results, that need to be replicated in larger sample sizes and validated with healthy controls, suggest that resting striatal DA D2 receptor availability predicts variability in functional responses to a nondrug reinforcer (money) in prefrontal cortex, implicated in behavioral monitoring, and in thalamus, implicated in conditioned responses and expectation, in cocaine-addicted individuals.

  10. Striatal dopamine D2 receptor availability predicts the thalamic and medial prefrontal responses to reward in cocaine abusers three years later

    Science.gov (United States)

    Asensio, Samuel; Romero, Maria J.; Romero, Francisco J.; Wong, Christopher; Alia-Klein, Nelly; Tomasi, Dardo; Wang, Gene-Jack; Telang, Frank; Volkow, Nora D.; Goldstein, Rita Z.

    2009-01-01

    Low levels of dopamine (DA) D2 receptor availability at a resting baseline have been previously reported in drug addicted individuals and have been associated with reduced ventral and dorsal prefrontal metabolism. The reduction in DA D2 receptor availability along with the reduced ventral frontal metabolism is thought to underlie compromised sensitivity to non-drug reward, a core characteristic of drug addiction. We therefore hypothesized that variability in DA D2 receptor availability at baseline will covary with dynamic responses to monetary reward in addicted individuals. Striatal DA D2 receptor availability was measured with [11C]raclopride and positron emission tomography and response to monetary reward was measured (an average of 3 years later) with functional magnetic resonance imaging in seven cocaine addicted individuals. Results show that low DA D2 receptor availability in the dorsal striatum was associated with decreased thalamic response to monetary reward; while low availability in ventral striatum was associated with increased medial prefrontal (Brodmann Area 6/8/32) response to monetary reward. These preliminary results, that need to be replicated in larger sample sizes and validated with healthy controls, suggest that resting striatal DA D2 receptor availability predicts variability in functional responses to a non-drug reinforcer (money) in prefrontal cortex, implicated in behavioral monitoring, and in thalamus, implicated in conditioned responses and expectation, in cocaine addicted individuals. PMID:20034014

  11. Long-term changes of striatal dopamine D-2 receptors in patients with Parkinson's disease : A study with positron emission tomography and [C-11]Raclopride

    NARCIS (Netherlands)

    Antonini, A; Schwarz, J; Oertel, WH; Pogarell, O; Leenders, KL

    We used [C-11]raclopride (RACLO) and positron emission tomography (PET) to study longitudinally striatal dopamine D-2 receptor binding in nine patients with Parkinson's disease (PD) at an early drug-naive stage and 3-5 years later, when motor fluctuations had appeared in seven of them. Patients were

  12. No difference in striatal dopamine transporter availability between active smokers, ex-smokers and non-smokers using (123I)FP-CIT (DaTSCAN) and SPECT

    DEFF Research Database (Denmark)

    Thomsen, G; Knudsen, Gitte Moos; Jensen, PS

    2013-01-01

    BACKGROUND: Mesolimbic and nigrostriatal dopaminergic pathways play important roles in both the rewarding and conditioning effects of drugs. The dopamine transporter (DAT) is of central importance in regulating dopaminergic neurotransmission and in particular in activating the striatal D2-like re...

  13. Pharmacological modifications of dopamine transmission do not influence the striatal in vivo binding of [3H]mazindol or [3H]cocaine in mice.

    Science.gov (United States)

    Thibaut, F; Bonnet, J J; Vaugeois, J M; Costentin, J

    1996-03-01

    We have considered the in vivo striatal binding of two ligands of the neuronal dopamine uptake complex: [3H]cocaine and [3H]mazindol. The [3H]cocaine tracer dose labelled the dopamine uptake complex in striatum but not the noradrenaline complex in cerebellum. On the contrary, the [3H]mazindol tracer dose induced a marked labelling of the noradrenaline uptake complex in cerebellum; its prevention by desipramine (5 mg/kg) increased simultaneously the cerebral bioavailability and thereby the striatal labelling of the dopamine transporter. In mice submitted to treatments modifying dopaminergic transmission either to decrease it (gammabutyrolactone, 750 mg/kg, i.p.) or to increase it (L-DOPA, 200 mg/kg, i.p., dexamphetamine, 4 mg/kg, s.c., or their combination), only dexamphetamine pretreatment significantly reduced [3H]cocaine and [3H]mazindol binding. Thus it appears that the level of dopamine transmission would not interfere with the in vivo quantification of striatal dopamine uptake sites assessed with either ligands.

  14. Dopamine and the management of attentional resources: genetic markers of striatal D2 dopamine predict individual differences in the attentional blink.

    Science.gov (United States)

    Colzato, Lorenza S; Slagter, Heleen A; de Rover, Mischa; Hommel, Bernhard

    2011-11-01

    The attentional blink (AB)--a deficit in reporting the second of two target stimuli presented in close succession in a rapid sequence of distracters--has been related to processing limitations in working memory. Given that dopamine (DA) plays a crucial role working memory, the present study tested whether individual differences in the size of the AB can be predicted by differences in genetic predisposition related to the efficiency of dopaminergic pathways. Polymorphisms related to mesocortical and nigrostriatal dopaminergic pathways were considered, as well as polymorphisms related to norepinephrine (NE), a transmitter system that has also been suspected to play a role in the AB. In a sample of 157 healthy adults, we studied the dependency of the individual magnitude of the AB and the C957T polymorphism at the DRD2 gene (associated with striatal DA/D2 receptors), the DARPP32 polymorphism (associated with striatal DA/D1), the COMT Val(158)Met polymorphism (associated with frontal DA), DBH444 g/a and DBH5'-ins/del polymorphisms (polymorphisms strongly correlated with DA beta hydroxylase, the enzyme catalyzing the DA-NE conversion) and NET T-182C (a polymorphism related to the NE transporter). DRD2 C957T T/T homozygotes showed a significantly smaller AB, whereas polymorphisms associated with frontal DA and NE were unrelated to performance. This outcome pattern suggests a crucial role of the nigrostriatal dopaminergic pathway and of nigrostriatal D2 receptors, in particular, in the management of attentional resources.

  15. Striatal dopamine D2 receptors, metabolism, and volume in preclinical Huntington disease

    NARCIS (Netherlands)

    van Oostrom, JCH; Maguire, RP; Verschuuren-Bemelmans, CC; van der Duin, LV; Pruim, J; Roos, RAC; Leenders, KL

    2005-01-01

    Among 27 preclinical carriers of the Huntington disease mutation (PMC), the authors found normal striatal values for MRI volumetry in 88% and for fluorodesoxyglucose PET metabolic index in 67%. Raclopride PET binding potential (RAC-BP) was decreased in 50% and correlated with increases in the

  16. Striatal Dopamine Transporter Binding Does Not Correlate with Clinical Severity in Dementia with Lewy Bodies

    DEFF Research Database (Denmark)

    Ziebell, Morten; Andersen, Birgitte B; Pinborg, Lars H

    2013-01-01

    cognitively evaluated with the Mini Mental State Examination. RESULTS: There was no correlation between Mini Mental State Examination, Hoehn and Yahr score, fluctuations or hallucinations, and striatal DAT availability as measured with (123)I-PE2I and SPECT. CONCLUSION: In patients with newly diagnosed DLB...

  17. Classification of H2O2 as a Neuromodulator that Regulates Striatal Dopamine Release on a Subsecond Time Scale

    Science.gov (United States)

    2012-01-01

    Here we review evidence that the reactive oxygen species, hydrogen peroxide (H2O2), meets the criteria for classification as a neuromodulator through its effects on striatal dopamine (DA) release. This evidence was obtained using fast-scan cyclic voltammetry to detect evoked DA release in striatal slices, along with whole-cell and fluorescence imaging to monitor cellular activity and H2O2 generation in striatal medium spiny neurons (MSNs). The data show that (1) exogenous H2O2 suppresses DA release in dorsal striatum and nucleus accumbens shell and the same effect is seen with elevation of endogenous H2O2 levels; (2) H2O2 is generated downstream from glutamatergic AMPA receptor activation in MSNs, but not DA axons; (3) generation of modulatory H2O2 is activity dependent; (4) H2O2 generated in MSNs diffuses to DA axons to cause transient DA release suppression by activating ATP-sensitive K+ (KATP) channels on DA axons; and (5) the amplitude of H2O2-dependent inhibition of DA release is attenuated by enzymatic degradation of H2O2, but the subsecond time course is determined by H2O2 diffusion rate and/or KATP-channel kinetics. In the dorsal striatum, neuromodulatory H2O2 is an intermediate in the regulation of DA release by the classical neurotransmitters glutamate and GABA, as well as other neuromodulators, including cannabinoids. However, modulatory actions of H2O2 occur in other regions and cell types, as well, consistent with the widespread expression of KATP and other H2O2-sensitive channels throughout the CNS. PMID:23259034

  18. Leptin Increases Striatal Dopamine D2 Receptor Binding in Leptin-Deficient Obese (ob/ob) Mice

    Energy Technology Data Exchange (ETDEWEB)

    Pfaffly, J.; Michaelides, M.; Wang, G-J.; Pessin, J.E.; Volkow, N.D.; Thanos, P.K.

    2010-06-01

    Peripheral and central leptin administration have been shown to mediate central dopamine (DA) signaling. Leptin-receptor deficient rodents show decreased DA D2 receptor (D2R) binding in striatum and unique DA profiles compared to controls. Leptin-deficient mice show increased DA activity in reward-related brain regions. The objective of this study was to examine whether basal D2R-binding differences contribute to the phenotypic behaviors of leptin-deficient ob/ob mice, and whether D2R binding is altered in response to peripheral leptin treatment in these mice. Leptin decreased body weight, food intake, and plasma insulin concentration in ob/ob mice but not in wild-type mice. Basal striatal D2R binding (measured with autoradiography [{sup 3}H] spiperone) did not differ between ob/ob and wild-type mice but the response to leptin did. In wild-type mice, leptin decreased striatal D2R binding, whereas, in ob/ob mice, leptin increased D2R binding. Our findings provide further evidence that leptin modulates D2R expression in striatum and that these effects are genotype/phenotype dependent.

  19. Developmental profile of the aberrant dopamine D2 receptor response in striatal cholinergic interneurons in DYT1 dystonia.

    Directory of Open Access Journals (Sweden)

    Giuseppe Sciamanna

    Full Text Available DYT1 dystonia, a severe form of genetically determined human dystonia, exhibits reduced penetrance among carriers and begins usually during adolescence. The reasons for such age dependence and variability remain unclear.We characterized the alterations in D2 dopamine receptor (D2R signalling in striatal cholinergic interneurons at different ages in mice overexpressing human mutant torsinA (hMT. An abnormal excitatory response to the D2R agonist quinpirole was recorded at postnatal day 14, consisting of a membrane depolarization coupled to an increase in spiking frequency, and persisted unchanged at 3 and 9 months in hMT mice, compared to mice expressing wild-type human torsinA and non-transgenic mice. This response was blocked by the D2R antagonist sulpiride and depended upon G-proteins, as it was prevented by intrapipette GDP-β-S. Patch-clamp recordings from dissociated interneurons revealed a significant increase in the Cav2.2-mediated current fraction at all ages examined. Consistently, chelation of intracellular calcium abolished the paradoxical response to quinpirole. Finally, no gross morphological changes were observed during development.These results suggest that an imbalanced striatal dopaminergic/cholinergic signaling occurs early in DYT1 dystonia and persists along development, representing a susceptibility factor for symptom generation.

  20. A kinetic model of dopamine- and calcium-dependent striatal synaptic plasticity.

    Directory of Open Access Journals (Sweden)

    Takashi Nakano

    2010-02-01

    Full Text Available Corticostriatal synapse plasticity of medium spiny neurons is regulated by glutamate input from the cortex and dopamine input from the substantia nigra. While cortical stimulation alone results in long-term depression (LTD, the combination with dopamine switches LTD to long-term potentiation (LTP, which is known as dopamine-dependent plasticity. LTP is also induced by cortical stimulation in magnesium-free solution, which leads to massive calcium influx through NMDA-type receptors and is regarded as calcium-dependent plasticity. Signaling cascades in the corticostriatal spines are currently under investigation. However, because of the existence of multiple excitatory and inhibitory pathways with loops, the mechanisms regulating the two types of plasticity remain poorly understood. A signaling pathway model of spines that express D1-type dopamine receptors was constructed to analyze the dynamic mechanisms of dopamine- and calcium-dependent plasticity. The model incorporated all major signaling molecules, including dopamine- and cyclic AMP-regulated phosphoprotein with a molecular weight of 32 kDa (DARPP32, as well as AMPA receptor trafficking in the post-synaptic membrane. Simulations with dopamine and calcium inputs reproduced dopamine- and calcium-dependent plasticity. Further in silico experiments revealed that the positive feedback loop consisted of protein kinase A (PKA, protein phosphatase 2A (PP2A, and the phosphorylation site at threonine 75 of DARPP-32 (Thr75 served as the major switch for inducing LTD and LTP. Calcium input modulated this loop through the PP2B (phosphatase 2B-CK1 (casein kinase 1-Cdk5 (cyclin-dependent kinase 5-Thr75 pathway and PP2A, whereas calcium and dopamine input activated the loop via PKA activation by cyclic AMP (cAMP. The positive feedback loop displayed robust bi-stable responses following changes in the reaction parameters. Increased basal dopamine levels disrupted this dopamine-dependent plasticity. The

  1. Association of Novelty Seeking Scores and Striatal Dopamine D2/D3 Receptor Availability of Healthy Volunteers: Single Photon Emission Computed Tomography With 123I-iodobenzamide

    Directory of Open Access Journals (Sweden)

    Hsiang Yu Huang

    2010-10-01

    Full Text Available It has been speculated that novelty seeking (NS behavior is related to the dopaminergic system. Fifty-two subjects completed the Tridimensional Personality Questionnaire and underwent single photon emission computed tomography with 123I-iodobenzamide. A marginally positive correlation was noted between NS and striatal dopamine D2/D3 receptor availability (r = 0.25, p =0.07. A positive association was noted between the NS scores and left striatal D2/D3 receptor availability (r= 0.29, p =0.04. The results suggest that a relationship might exist between NS score and dopaminergic activity.

  2. Response contingency directs long-term cocaine-induced neuroplasticity in prefrontal and striatal dopamine terminals.

    Science.gov (United States)

    Wiskerke, Joost; Schoffelmeer, Anton N M; De Vries, Taco J

    2016-10-01

    Exposure to addictive substances such as cocaine is well-known to alter brain organisation. Cocaine-induced neuroadaptations depend on several factors, including drug administration paradigm. To date, studies addressing the consequences of cocaine exposure on dopamine transmission have either not been designed to investigate the role of response contingency or focused only on short-term neuroplasticity. We demonstrate a key role of response contingency in directing long-term cocaine-induced neuroplasticity throughout projection areas of the mesocorticolimbic dopamine system. We found enhanced electrically-evoked [(3)H]dopamine release from superfused brain slices of nucleus accumbens shell and core, dorsal striatum and medial prefrontal cortex three weeks after cessation of cocaine self-administration. In yoked cocaine rats receiving the same amount of cocaine passively, sensitised dopamine terminal reactivity was only observed in the nucleus accumbens core. Control sucrose self-administration experiments demonstrated that the observed neuroadaptations were not the result of instrumental learning per se. Thus, long-term withdrawal from cocaine self-administration is associated with widespread sensitisation of dopamine terminals throughout frontostriatal circuitries. Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.

  3. No Correlation Between Body Mass Index and Striatal Dopamine Transporter Availability in Healthy Volunteers Using SPECT and I-123 PE2I

    DEFF Research Database (Denmark)

    Thomsen, G.; Ziebell, M.; Jensen, P. S.

    2013-01-01

    and BMI, age and gender as predictors was performed. We found no correlation between BMI and striatal DAT availability in striatum (P = 0.99), caudate nucleus (P = 0.61), and putamen (P = 0.30). Furthermore, we found no group difference between obese/severely obese (BMI > 30 kg/m(2)) and normal weight......, dopamine is inactivated by reuptake via the dopamine transporter (DAT). The aim of the study was to test the hypothesis of lower DAT availability in obese healthy subjects using a selective DAT radiotracer in a sample of subjects with a wide range of BMI values. Design and Methods: Thirty-three healthy...

  4. Voluntary Exercise Improves Performance of a Discrimination Task through Effects on the Striatal Dopamine System

    Science.gov (United States)

    Eddy, Meghan C.; Stansfield, Katherine J.; Green, John T.

    2014-01-01

    We have previously demonstrated that voluntary exercise facilitates discrimination learning in a modified T-maze. There is evidence implicating the dorsolateral striatum (DLS) as the substrate for this task. The present experiments examined whether changes in DLS dopamine receptors might underlie the exercise-associated facilitation. Infusing a…

  5. 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.

  6. Methamphetamine-induced dopamine-independent alterations in striatal gene expression in the 6-hydroxydopamine hemiparkinsonian rats.

    Directory of Open Access Journals (Sweden)

    Jean Lud Cadet

    Full Text Available Unilateral injections of 6-hydroxydopamine into the medial forebrain bundle are used extensively as a model of Parkinson's disease. The present experiments sought to identify genes that were affected in the dopamine (DA-denervated striatum after 6-hydroxydopamine-induced destruction of the nigrostriatal dopaminergic pathway in the rat. We also examined whether a single injection of methamphetamine (METH (2.5 mg/kg known to cause changes in gene expression in the normally DA-innervated striatum could still influence striatal gene expression in the absence of DA. Unilateral injections of 6-hydroxydopamine into the medial forebrain bundle resulted in METH-induced rotational behaviors ipsilateral to the lesioned side and total striatal DA depletion on the lesioned side. This injection also caused decrease in striatal serotonin (5-HT and 5-hydroxyindoleacetic acid (5-HIAA levels. DA depletion was associated with increases in 5-HIAA/5-HT ratios that were potentiated by the METH injection. Microarray analyses revealed changes (±1.7-fold, p<0.025 in the expression of 67 genes on the lesioned side in comparison to the intact side of the saline-treated hemiparkinsonian animals. These include follistatin, neuromedin U, and tachykinin 2 which were up-regulated. METH administration caused increases in the expression of c-fos, Egr1, and Nor-1 on the intact side. On the DA-depleted side, METH administration also increased the expression of 61 genes including Pdgf-d and Cox-2. There were METH-induced changes in 16 genes that were common in the DA-innervated and DA-depleted sides. These include c-fos and Nor-1 which show greater changes on the normal DA side. Thus, the present study documents, for the first time, that METH mediated DA-independent changes in the levels of transcripts of several genes in the DA-denervated striatum. Our results also implicate 5-HT as a potential player in these METH-induced alterations in gene expression because the METH injection

  7. In vivo imaging of dopamine transporter function in rat striatum using pinhole SPECT and 123I-beta-CIT coregistered with small animal MRI

    CERN Document Server

    Dierkes, K

    2001-01-01

    The aim of this study was to establish in vivo imaging of dopamine transporter function in a small animal model of Parkinson's disease using pinhole SPECT and 123I labeled beta-CIT. Since functional imaging of small animals can hardly be interpreted without localization to related anatomical structures, MRI-SPECT coregistration secondly was established as an inexpensive tool for in vivo monitoring of physiological and pathological alterations in striatal dopamine transporters using beta-CIT as an specific radionuclear ligand.

  8. Relationships between the catechol substrate binding site and amphetamine, cocaine, and mazindol binding sites in a kinetic model of the striatal transporter of dopamine in vitro.

    Science.gov (United States)

    Wayment, H; Meiergerd, S M; Schenk, J O

    1998-05-01

    Experiments were conducted to determine how (-)-cocaine and S(+)-amphetamine binding sites relate to each other and to the catechol substrate site on the striatal dopamine transporter (sDAT). In controls, m-tyramine and S(+)-amphetamine caused release of dopamine from intracellular stores at concentrations > or = 12-fold those observed to inhibit inwardly directed sDAT activity for dopamine. In preparations from animals pretreated with reserpine, m-tyramine and S(+)-amphetamine caused release of preloaded dopamine at concentrations similar to those that inhibit inwardly directed sDAT activity. S(+)-Amphetamine and m-tyramine inhibited sDAT activity for dopamine by competing for a common binding site with dopamine and each other, suggesting that phenethylamines are substrate analogues at the plasmalemmal sDAT. (-)-Cocaine inhibited sDAT at a site separate from that for substrate analogues. This site is mutually interactive with the substrate site (K(int) = 583 nM). Mazindol competitively inhibited sDAT at the substrate analogue binding site. The results with (-)-cocaine suggest that the (-)-cocaine binding site on sDAT is distinct from that of hydroxyphenethylamine substrates, reinforcing the notion that an antagonist for (-)-cocaine binding may be developed to block (-)-cocaine binding with minimal effects on dopamine transporter activity. However, a strategy of how to antagonize drugs of abuse acting as substrate analogues is still elusive.

  9. Differential up-regulation of striatal dopamine transporter and α-synuclein by the pyrethroid insecticide permethrin

    International Nuclear Information System (INIS)

    Gillette, Jeffrey S.; Bloomquist, Jeffrey R.

    2003-01-01

    The effects of permethrin on striatal dopaminergic biomarkers were assessed in this study. Retired breeder male C57 B1/6 mice were given an ip dose of permethrin (0.1-200 mg/kg) at 7-day intervals, over a 2-week period (Days 0, 7, and 14). Animals were then sacrificed 1 day (t = 1), 14 days (t 14), or 28 days after the last treatment (t = 28). Dopamine transporter (DAT) protein as assayed by Western blotting was increased to 115% in the 0.8 mg/kg group over that of control mice at t = 1 (P 3 H]GBR 12935, used to assay DAT binding, followed the same trend as that for the Western blotting data for 0.8 and 1.5 mg/kg doses of permethrin over the 4 weeks posttreatment. At 200 mg/kg permethrin, DAT protein was unchanged vs controls (t = 1), but had significantly increased by t = 14 and continued to increase at t = 28, suggesting that the reduced dopamine transport at this dose was due to nerve terminal stress and that recovery had occurred. The protein α-synuclein was also significantly induced at the 1.5 mg/kg dose at t = 1; however, unlike DAT up-regulation, this effect had declined to control values by t 14. Maximal induction of α-synuclein protein occurred at a dose of 50 mg/kg permethrin. These data provide evidence that the pyrethroid class of insecticides can modulate the dopaminergic system at low doses, in a persistent manner, which may render neurons more vulnerable to toxicant injury

  10. Further human evidence for striatal dopamine release induced by administration of ∆9-tetrahydrocannabinol (THC): selectivity to limbic striatum.

    NARCIS (Netherlands)

    Bossong, MG; Mehta, Mitul; van Berckel, Bart; Howes, Oliver; Kahn, RS; Stokes, Paul

    2015-01-01

    RATIONALE: Elevated dopamine function is thought to play a key role in both the rewarding effects of addictive drugs and the pathophysiology of schizophrenia. Accumulating epidemiological evidence indicates that cannabis use is a risk factor for the development of schizophrenia. However, human

  11. Adderall produces increased striatal dopamine release and a prolonged time course compared to amphetamine isomers.

    Science.gov (United States)

    Joyce, B Matthew; Glaser, Paul E A; Gerhardt, Greg A

    2007-04-01

    Adderall is currently used for the treatment of Attention-Deficit Hyperactivity Disorder (ADHD) and is composed of a novel mixture of approximately 24% L-amphetamine and 76% D-amphetamine salts. There are, however, no investigations of the pharmacological effects of this combination in vivo. The technique of high-speed chronoamperometry using Nafion-coated single carbon-fiber microelectrodes was used to study amphetamine-evoked dopamine (DA) release produced by Adderall, D-amphetamine, or D,L-amphetamine in the striatum of anesthetized male Fischer 344 (F344) rats. The amphetamine solutions were locally applied from micropipettes by pressure ejection. Local applications of Adderall resulted in significantly greater DA release signal amplitudes with prolonged time course of dopamine release and re-uptake as compared to D-amphetamine and D,L-amphetamine. These data support the hypothesis that the combination of amphetamine enantiomers and salts in Adderall has effects on DA release, which result in increased and prolonged DA release, compared to D- and D,L-amphetamine.

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

    International Nuclear Information System (INIS)

    Kim, S. E.; Cho, S. S.; Choe, Y. S.; Lee, S. Y.; Kang, E.; Kim, B. T.

    2002-01-01

    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 [ 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 [ 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 [ 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 [ 11 C]raclopride PET

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

    International Nuclear Information System (INIS)

    Sang Eun Kim; Yearn Seong Choe; Eunjoo Kang; Dong Soo Lee; June-Key Chung; Myung-Chul Lee; Sang Soo Cho

    2004-01-01

    Purpose: 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 [ 11 C] raclopride PET. Methods: 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 [ 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 V 3 ', calculated as striatal-cerebellar/cerebellar activity ratio, was measured under equilibrium condition, at baseline and during and after the video game. Results: Striatal V 3 ' 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 [ 11 C] raclopride binding was gradually increased and the V 3 ' approached baseline levels. There was a significant correlation between the reduction in striatal V 3 ' and the task performance during the video game. Conclusions: 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 [ 11 C] raclopride PET. (authors)

  14. 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.

  15. Striatal and extrastriatal imaging of dopamine D2receptors in the living human brain with [ 123I[epidepride single-photon emission tomography

    International Nuclear Information System (INIS)

    Kuikka, J.T.; Aakerman, K.K.; Hiltunen, J.; Bergstroem, K.A.; Raesaenen, P.; Vanninen, E.; Halldin, C.; Tiihonen, J.

    1997-01-01

    The iodine-123 labelled ligand benzamide epidepride was evaluated as a probe for in vivo imaging of striatal and extrastriatal dopamine D 2 receptor sites in the human brain. Four healthy males were imaged with a high-resolution single-photon emission tomography scanner. Striatal radioactivity peaked at 3 h after injection. The specific binding in the striatum was 0.91 ±0.03 at 3 h and this ratio steadily increased with time. Extrastriatal radioactivity was highest in the thalamus, in the midbrain and in the temporal cortex, and peaked at 45-60 min after injection of tracer. A smaller amount of radioactivity was found in the parietal, frontal and occipital cortices. Two radioactive metabolites were observed, of which one was more lipophilic than the parent compound. The radiation burden to the patient was 0.035 mSv/MBq (effective dose equivalent). The preliminary results showed that [ 123 I[epidepride can be used for imaging striatal and extrastriatal dopamine D 2 receptor sites in the living human brain. (orig.). With 5 figs., 1 tab

  16. Neurodevelopmental disruption of cortico-striatal function caused by degeneration of habenula neurons.

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    Young-A Lee

    2011-04-01

    Full Text Available The habenula plays an important role on cognitive and affective functions by regulating monoamines transmission such as the dopamine and serotonin, such that its dysfunction is thought to underlie a number of psychiatric conditions. Given that the monoamine systems are highly vulnerable to neurodevelopmental insults, damages in the habenula during early neurodevelopment may cause devastating effects on the wide-spread brain areas targeted by monoamine innervations.Using a battery of behavioral, anatomical, and biochemical assays, we examined the impacts of neonatal damage in the habenula on neurodevelopmental sequelae of the prefrontal cortex (PFC and nucleus accumbens (NAcc and associated behavioral deficits in rodents. Neonatal lesion of the medial and lateral habenula by ibotenic acid produced an assortment of behavioral manifestations consisting of hyper-locomotion, impulsivity, and attention deficit, with hyper-locomotion and impulsivity being observed only in the juvenile period, whereas attention deficit was sustained up until adulthood. Moreover, these behavioral alterations were also improved by amphetamine. Our study further revealed that impulsivity and attention deficit were associated with disruption of PFC volume and dopamine (DA receptor expression, respectively. In contrast, hyper-locomotion was associated with decreased DA transporter expression in the NAcc. We also found that neonatal administration of nicotine into the habenula of neonatal brains produced selective lesion of the medial habenula. Behavioral deficits with neonatal nicotine administration were similar to those caused by ibotenic acid lesion of both medial and lateral habenula during the juvenile period, whereas they were different in adulthood.Because of similarity between behavioral and brain alterations caused by neonatal insults in the habenula and the symptoms and suggested neuropathology in attention deficit/hyperactivity disorder (ADHD, these results

  17. Repeated administration of D-amphetamine induces loss of [{sup 123}I]FP-CIT binding to striatal dopamine transporters in rat brain: a validation study

    Energy Technology Data Exchange (ETDEWEB)

    Booij, Jan [Department of Nuclear Medicine, Academic Medical Center, 1105 AZ Amsterdam (Netherlands)]. E-mail: j.booij@amc.uva.nl; Bruin, Kora de [Department of Nuclear Medicine, Academic Medical Center, 1105 AZ Amsterdam (Netherlands); Gunning, W. Boudewijn [Department of Neurology, Epilepsy Centre Kempenhaeghe, 5590 AB Heeze (Netherlands)

    2006-04-15

    In recent years, several PET and SPECT studies have shown loss of striatal dopamine transporter (DAT) binding in amphetamine (AMPH) users. However, the use of DAT SPECT tracers to detect AMPH-induced changes in DAT binding has not been validated. We therefore examined if repeated administration of D-AMPH or methamphetamine (METH) may induce loss of binding to striatal DATs in rats by using an experimental biodistribution study design and a SPECT tracer for the DAT ([{sup 123}I]FP-CIT). Methods: Groups of male rats (n=10 per group) were treated with D-AMPH (10 mg/kg body weight), METH (10 mg/kg body weight), or saline, twice a day for 5 consecutive days. Five days later, [{sup 123}I]FP-CIT was injected intravenously, and 2 h later, the rats were sacrificed and radioactivity was assayed. Results: In D-AMPH but not METH-treated rats, striatal [{sup 123}I]FP-CIT uptake was significantly lower (approximately 17%) than in the control group. Conclusion: These data show that [{sup 123}I]FP-CIT can be used to detect AMPH-induced changes in DAT binding and may validate the use of DAT radiotracers to study AMPH-induced changes in striatal DAT binding in vivo.

  18. Striatal dopamine ramping may indicate flexible reinforcement learning with forgetting in the cortico-basal ganglia circuits.

    Science.gov (United States)

    Morita, Kenji; Kato, Ayaka

    2014-01-01

    It has been suggested that the midbrain dopamine (DA) neurons, receiving inputs from the cortico-basal ganglia (CBG) circuits and the brainstem, compute reward prediction error (RPE), the difference between reward obtained or expected to be obtained and reward that had been expected to be obtained. These reward expectations are suggested to be stored in the CBG synapses and updated according to RPE through synaptic plasticity, which is induced by released DA. These together constitute the "DA=RPE" hypothesis, which describes the mutual interaction between DA and the CBG circuits and serves as the primary working hypothesis in studying reward learning and value-based decision-making. However, recent work has revealed a new type of DA signal that appears not to represent RPE. Specifically, it has been found in a reward-associated maze task that striatal DA concentration primarily shows a gradual increase toward the goal. We explored whether such ramping DA could be explained by extending the "DA=RPE" hypothesis by taking into account biological properties of the CBG circuits. In particular, we examined effects of possible time-dependent decay of DA-dependent plastic changes of synaptic strengths by incorporating decay of learned values into the RPE-based reinforcement learning model and simulating reward learning tasks. We then found that incorporation of such a decay dramatically changes the model's behavior, causing gradual ramping of RPE. Moreover, we further incorporated magnitude-dependence of the rate of decay, which could potentially be in accord with some past observations, and found that near-sigmoidal ramping of RPE, resembling the observed DA ramping, could then occur. Given that synaptic decay can be useful for flexibly reversing and updating the learned reward associations, especially in case the baseline DA is low and encoding of negative RPE by DA is limited, the observed DA ramping would be indicative of the operation of such flexible reward learning.

  19. The transfection of BDNF to dopamine neurons potentiates the effect of dopamine D3 receptor agonist recovering the striatal innervation, dendritic spines and motor behavior in an aged rat model of Parkinson's disease.

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    Luis F Razgado-Hernandez

    Full Text Available The progressive degeneration of the dopamine neurons of the pars compacta of substantia nigra and the consequent loss of the dopamine innervation of the striatum leads to the impairment of motor behavior in Parkinson's disease. Accordingly, an efficient therapy of the disease should protect and regenerate the dopamine neurons of the substantia nigra and the dopamine innervation of the striatum. Nigral neurons express Brain Derived Neurotropic Factor (BDNF and dopamine D3 receptors, both of which protect the dopamine neurons. The chronic activation of dopamine D3 receptors by their agonists, in addition, restores, in part, the dopamine innervation of the striatum. Here we explored whether the over-expression of BDNF by dopamine neurons potentiates the effect of the activation of D3 receptors restoring nigrostriatal innervation. Twelve-month old Wistar rats were unilaterally injected with 6-hydroxydopamine into the striatum. Five months later, rats were treated with the D3 agonist 7-hydroxy-N,N-di-n-propy1-2-aminotetralin (7-OH-DPAT administered i.p. during 4½ months via osmotic pumps and the BDNF gene transfection into nigral cells using the neurotensin-polyplex nanovector (a non-viral transfection that selectively transfect the dopamine neurons via the high-affinity neurotensin receptor expressed by these neurons. Two months after the withdrawal of 7-OH-DPAT when rats were aged (24 months old, immunohistochemistry assays were made. The over-expression of BDNF in rats receiving the D3 agonist normalized gait and motor coordination; in addition, it eliminated the muscle rigidity produced by the loss of dopamine. The recovery of motor behavior was associated with the recovery of the nigral neurons, the dopamine innervation of the striatum and of the number of dendritic spines of the striatal neurons. Thus, the over-expression of BDNF in dopamine neurons associated with the chronic activation of the D3 receptors appears to be a promising strategy

  20. Ascorbic acid and striatal transport of (/sup 3/H)1-methyl-4-phenylpyridine (MPP/sup +/) and (/sup 3/H)dopamine

    Energy Technology Data Exchange (ETDEWEB)

    Debler, E.A.; Hashim, A.; Lajtha, A.; Sershen, H.

    1988-01-01

    The inhibition of uptake of (/sup 3/H)dopamine and (/sup 3/H)1-methyl-4-phenylpyridine (MPP/sup +/) was examined in mouse striatal synaptosomal preparations. Kinetic analysis indicated that ascorbic acid is a noncompetitive inhibitor of (/sup 3/H)MPP/sup +/ uptake. No inhibition of (/sup 3/H)dopamine uptake is observed. The dopamine uptake blockers, GBR-12909, cocaine, and mazindol strongly inhibit (IC/sub 50/ < 1 ..mu..M) both (/sup 3/H)dopamine and (/sup 3/H)MPP/sup +/ transport. Nicotine, its metabolites, and other tobacco alkaloids are weak inhibitors except 4-phenylpyridine and lobeline, which are moderate inhibitors of both (/sup 3/H)dopamine and (/sup 3/H)MPP/sup +/ uptake. These similarities in potencies are in agreement with the suggestion that (/sup 3/H)MPP/sup +/ and (/sup 3/H) are transported by the same carrier. The differences observed in the alteration of dopaminergic transport and mazindol binding by ascorbic acid suggest that ascorbic acid's effects on (/sup 3/H)MPP/sup +/ transport are related to translocation and/or dissociation processes occurring subsequent to the initial binding event.

  1. Striatal Dopamine Homeostasis is Altered in Mice Following Roux-en-Y Gastric Bypass Surgery

    Science.gov (United States)

    2015-01-01

    Roux-en-Y gastric bypass (RYGB) is an effective treatment for obesity. Importantly, weight loss following RYGB is thought to result in part from changes in brain-mediated regulation of appetite and food intake. Dopamine (DA) within the dorsal striatum plays an important role in feeding behavior; we therefore hypothesized that RYGB alters DA homeostasis in this subcortical region. In the current study, obese RYGB-operated mice consumed significantly less of a high-fat diet, weighed less by the end of the study, and exhibited lower adiposity than obese sham-operated mice. Interestingly, both RYGB and caloric restriction (pair feeding) resulted in elevated DA and reduced norepinephrine (NE) tissue levels compared with ad libitum fed sham animals. Consequently, the ratio of NE to DA, a measure of DA turnover, was significantly reduced in both of these groups. The RYGB mice additionally exhibited a significant increase in phosphorylation of tyrosine hydroxylase at position Ser31, a key regulatory site of DA synthesis. This increase was associated with augmented expression of extracellular-signal-regulated kinases ERK1/2, the kinase targeting Ser31. Additionally, RYGB has been shown in animal models and humans to improve insulin sensitivity and glycemic control. Curiously, we noted a significant increase in the expression of insulin receptor-β in RYGB animals in striatum (a glucosensing brain region) compared to sham ad libitum fed mice. These data demonstrate that RYGB surgery is associated with altered monoamine homeostasis at the level of the dorsal striatum, thus providing a critical foundation for future studies exploring central mechanisms of weight loss in RYGB. PMID:25068716

  2. Reciprocal influences of nigral cells and striatal patch neurons in dissociated co-cultures

    NARCIS (Netherlands)

    Aronica, E.; Costantini, L. C.; Snyder-Keller, A.

    1996-01-01

    Our previous work has shown that the functional efficacy of nigral tissue transplants into dopamine (DA)-depleted rats is increased when embryonic striatal tissue is included (Costantini et al.: Exp Neurol 127:219-231, 1994). To examine further the influence of striatal patch neurons in this regard,

  3. Maternal separation affects dopamine transporter function in the Spontaneously Hypertensive Rat: An in vivo electrochemical study

    Directory of Open Access Journals (Sweden)

    Womersley Jacqueline S

    2011-12-01

    Full Text Available Abstract Background Attention-deficit/hyperactivity disorder (ADHD is a developmental disorder characterised by symptoms of inattention, impulsivity and hyperactivity. The spontaneously hypertensive rat (SHR is a well-characterised model of this disorder and has been shown to exhibit dopamine dysregulation, one of the hypothesised causes of ADHD. Since stress experienced in the early stages of life can have long-lasting effects on behaviour, it was considered that early life stress may alter development of the dopaminergic system and thereby contribute to the behavioural characteristics of SHR. It was hypothesized that maternal separation would alter dopamine regulation by the transporter (DAT in ways that distinguish SHR from control rat strains. Methods SHR and control Wistar-Kyoto (WKY rats were subjected to maternal separation for 3 hours per day from postnatal day 2 to 14. Rats were tested for separation-induced anxiety-like behaviour followed by in vivo chronoamperometry to determine whether changes had occurred in striatal clearance of dopamine by DAT. The rate of disappearance of ejected dopamine was used as a measure of DAT function. Results Consistent with a model for ADHD, SHR were more active than WKY in the open field. SHR entered the inner zone more frequently and covered a significantly greater distance than WKY. Maternal separation increased the time that WKY spent in the closed arms and latency to enter the open arms of the elevated plus maze, consistent with other rat strains. Of note is that, maternal separation failed to produce anxiety-like behaviour in SHR. Analysis of the chronoamperometric data revealed that there was no difference in DAT function in the striatum of non-separated SHR and WKY. Maternal separation decreased the rate of dopamine clearance (k-1 in SHR striatum. Consistent with this observation, the dopamine clearance time (T100 was increased in SHR. These results suggest that the chronic mild stress of

  4. Behavioral and Neurophysiological Correlates of Striatal Dopamine Depletion: A Rodent Model of Parkinson's Disease

    Science.gov (United States)

    Plowman, Emily K.; Kleim, Jeffrey A.

    2011-01-01

    Both limb and cranial motor functions are adversely impacted by Parkinson's disease (PD). While current pharmacological and surgical interventions are effective in alleviating general limb motor symptoms of PD, they have failed to provide significant benefit for cranial motor functions. This suggests that the neuropathologies mediating limb and…

  5. Effect of scatter correction on the compartmental measurement of striatal and extrastriatal dopamine D{sub 2} receptors using [{sup 123}I]epidepride SPET

    Energy Technology Data Exchange (ETDEWEB)

    Fujita, Masahiro; Seneca, Nicholas; Innis, Robert B. [Department of Psychiatry, Yale University School of Medicine and VA Connecticut Healthcare System, West Haven, CT (United States); Molecular Imaging Branch, National Institute of Mental Health, Bethesda, MD (United States); Varrone, Andrea [Department of Psychiatry, Yale University School of Medicine and VA Connecticut Healthcare System, West Haven, CT (United States); Biostructure and Bioimaging Institute, National Research Council, Napoli (Italy); Kim, Kyeong Min; Watabe, Hiroshi; Iida, Hidehiro [Department of Investigative Radiology, National Cardiovascular Center Research Institute, Osaka (Japan); Zoghbi, Sami S. [Department of Psychiatry, Yale University School of Medicine and VA Connecticut Healthcare System, West Haven, CT (United States); Molecular Imaging Branch, National Institute of Mental Health, Bethesda, MD (United States); Department of Radiology, Yale University School of Medicine and VA Connecticut Healthcare System, West Haven, CT (United States); Tipre, Dnyanesh [Molecular Imaging Branch, National Institute of Mental Health, Bethesda, MD (United States); Seibyl, John P. [Institute for Neurodegenerative Disorders, New Haven, CT (United States)

    2004-05-01

    Prior studies with anthropomorphic phantoms and single, static in vivo brain images have demonstrated that scatter correction significantly improves the accuracy of regional quantitation of single-photon emission tomography (SPET) brain images. Since the regional distribution of activity changes following a bolus injection of a typical neuroreceptor ligand, we examined the effect of scatter correction on the compartmental modeling of serial dynamic images of striatal and extrastriatal dopamine D{sub 2} receptors using [{sup 123}I]epidepride. Eight healthy human subjects [age 30{+-}8 (range 22-46) years] participated in a study with a bolus injection of 373{+-}12 (354-389) MBq [{sup 123}I]epidepride and data acquisition over a period of 14 h. A transmission scan was obtained in each study for attenuation and scatter correction. Distribution volumes were calculated by means of compartmental nonlinear least-squares analysis using metabolite-corrected arterial input function and brain data processed with scatter correction using narrow-beam geometry {mu} (SC) and without scatter correction using broad-beam {mu} (NoSC). Effects of SC were markedly different among brain regions. SC increased activities in the putamen and thalamus after 1-1.5 h while it decreased activity during the entire experiment in the temporal cortex and cerebellum. Compared with NoSC, SC significantly increased specific distribution volume in the putamen (58%, P=0.0001) and thalamus (23%, P=0.0297). Compared with NoSC, SC made regional distribution of the specific distribution volume closer to that of [{sup 18}F]fallypride. It is concluded that SC is required for accurate quantification of distribution volumes of receptor ligands in SPET studies. (orig.)

  6. Disruption of the ErbB signaling in adolescence increases striatal dopamine levels and affects learning and hedonic-like behavior in the adult mouse.

    Science.gov (United States)

    Golani, Idit; Tadmor, Hagar; Buonanno, Andres; Kremer, Ilana; Shamir, Alon

    2014-11-01

    The ErbB signaling pathway has been genetically and functionally implicated in schizophrenia. Numerous findings support the dysregulation of Neuregulin (NRG) and epidermal growth factor (EGF) signaling in schizophrenia. However, it is unclear whether alterations of these pathways in the adult brain or during development are involved in the pathophysiology of schizophrenia. Herein we characterized the behavioral profile and molecular changes resulting from pharmacologically blocking the ErbB signaling pathway during a critical period in the development of decision making, planning, judgments, emotions, social cognition and cognitive skills, namely adolescence. We demonstrate that chronic administration of the pan-ErbB kinase inhibitor JNJ-28871063 (JNJ) to adolescent mice elevated striatal dopamine levels and reduced preference for sucrose without affecting locomotor activity and exploratory behavior. In adulthood, adolescent JNJ-treated mice continue to consume less sucrose and needed significantly more correct-response trials to reach the learning criterion during the discrimination phase of the T-maze reversal learning task than their saline-injected controls. In addition, JNJ mice exhibited deficit in reference memory but not in working memory as measured in the radial arm maze. Inhibition of the pathway during adolescence did not affect exploratory behavior and locomotor activity in the open field, social interaction, social memory, and reversal learning in adult mice. Our data suggest that alteration of ErbB signaling during adolescence resulted in changes in the dopaminergic systems that emerge in pathological learning and hedonic behavior in adulthood, and pinpoints the possible role of the pathway in the development of cognitive skills and motivated behavior. Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.

  7. Effects of hypoxic–ischemic brain injury on striatal dopamine transporter in newborn piglets: evaluation of 11C-CFT PET/CT for DAT quantification

    International Nuclear Information System (INIS)

    Zhang Yanfen; Wang Xiaoyu; Cao Li; Guo Qiyong; Wang Xiaoming

    2011-01-01

    Introduction: Alterations of dopamine in striatal presynaptic terminals play an important role in the hypoxic–ischemic (HI) brain injury. Quantification of DAT levels in the presynaptic site using 11 C-N-2-carbomethoxy-3-(4-fluorophenyl)-tropane ( 11 C-CFT) with positron emission tomography (PET) was applied in studies for Parkinson's disease. The current study investigated the changes in striatal DAT following HI brain injury in newborn piglets using 11 C-CFT PET. Methods: Newborn piglets were subjected to occlusion of bilateral common carotid arteries for 30 min and simultaneous peripheral hypoxia. Brain DAT imaging was performed using PET/CT with 11 C-CFT as the probe in each group (including the control group and HI insult groups). Brain tissues were collected for DAT immunohistochemical (IHC) analysis at each time point post the PET/CT procedure. Sham controls had some operation without HI procedure. Results: A few minutes after intravenous injection of 11 C-CFT, radioactive signals for DAT clearly appeared in the cortical area, striatum and cerebellum of newborn piglets of sham control group and HI insult groups. HI brain insult markedly increased striatal DAT at an early period (P 11 C-CFT PET imaging data and IHC DAT staining data were highly correlated (r=0.844, P 11 C-CFT PET/CT imaging data reflected the dynamic changes of DAT in the striatum in vivo.

  8. Modulation by fluoxetine of striatal dopamine release following Δ9-tetrahydrocannabinol: a microdialysis study in conscious rats

    Science.gov (United States)

    Malone, Daniel T; Taylor, David A

    1999-01-01

    The present study was undertaken to investigate the effect of Δ9-tetrahydrocannabinol (Δ9-THC) and possible serotoninergic involvement on the extracellular level of dopamine (DA) in the striatum using microdialysis in conscious, freely-moving rats. A dose-dependent increase in striatal DA release occurred after i.v. administration of 0.5–5 mg kg−1 Δ9-THC when compared with vehicle (n=5–8, P<0.05). Maximum increases, ranging from 42.1±5.4% to 97.4±5.9% (means±s.e.mean) of basal levels occurred 20 min after Δ9-THC. This effect was abolished by pretreatment with the cannabinoid CB1 receptor antagonist, SR 141716 (2.5 mg kg−1 i.p.). Pretreatment with fluoxetine (10 mg kg−1 i.p.) abolished the Δ9-THC-induced DA release. Fluoxetine 10 mg kg−1 i.p. administered 40 min after Δ9-THC had no significant effect on Δ9-THC-induced DA release. However, fluoxetine perfused locally into the striatum by adding it to the microdialysis perfusion fluid (10 μM) 40 min after Δ9-THC significantly potentiated the Δ9-THC-induced DA release (n=6–8, P<0.05). These results suggest that DA release induced by Δ9-THC is modulated by serotoninergic changes induced by fluoxetine, the effect of which depends on the time of its administration relative to that of Δ9-THC. Fluoxetine induces an acute increase in extracellular 5-HT through reuptake inhibition, which can activate autoreceptors which may decrease serotoninergic neuronal activity. This may be the reason fluoxetine pretreatment abolished the Δ9-THC-induced DA release. The potentiation of Δ9-THC-induced DA release by fluoxetine perfusion added 40 min after Δ9-THC may be due to an acute increase in 5-HT produced by reuptake inhibition. PMID:10498830

  9. A Neurocomputational Model of Dopamine and Prefrontal-Striatal Interactions during Multicue Category Learning by Parkinson Patients

    Science.gov (United States)

    Moustafa, Ahmed A.; Gluck, Mark A.

    2011-01-01

    Most existing models of dopamine and learning in Parkinson disease (PD) focus on simulating the role of basal ganglia dopamine in reinforcement learning. Much data argue, however, for a critical role for prefrontal cortex (PFC) dopamine in stimulus selection in attentional learning. Here, we present a new computational model that simulates…

  10. β-asarone and levodopa coadministration increases striatal levels of dopamine and levodopa and improves behavioral competence in Parkinson's rat by enhancing dopa decarboxylase activity.

    Science.gov (United States)

    Huang, Liping; Deng, Minzhen; Zhang, Sheng; Lu, Shiyao; Gui, Xuehong; Fang, Yongqi

    2017-10-01

    Levodopa (L-dopa) is the key component in Parkinson's disease (PD) treatment. Recently, we demonstrated that β-asarone improves the motor behavior of rats with unilateral striatal 6-hydroxydopamine lesion. Striatal level of dopamine (DA) and L-dopa increased after β-asarone and L-dopa co-administered treatment in healthy rat. Since its effects and mechanisms on PD rats are still unclear, we investigated whether coadministration could help treat PD rats. Here, PD rats were randomly divided into seven groups (n=10/group): an untreated group, a Madopar-treated group, a L-dopa-treated group, a β-asarone-treated group, and groups receiving low, medium or high doses of β-asarone respectively plus the same dose of L-dopa. The sham-operated group rats were injected with saline. Treatments were administered to the rats twice per day continuously for 30days. The behavioral tests were assessed. Neurotransmitters, dopa decarboxylase (DDC), tyrosine hydroxylase (TH), catechol-O-methyltransferase (COMT), monoamine oxidase B (MAO-B) and dopamine transporter (DAT) levels were detected. The pathological characteristics of liver and kidney and ultrastructure of dopaminergic neurons were observed. The behavior of PD rats improved significantly after co-administered treatment compared with the untreated group. In addition, our results also showed that co-administered treatment increased L-dopa, DA, DOPAC, HVA and 5-HT levels, enhanced the MAO-B, COMT, TH and DAT levels, reduced creatinine level, decreased the amount of lysosome and mitochondria and showed no liver and kidney toxicity. These findings suggest that co-administered treatment could elevate striatal levels of L-dopa and DA and improve the behavioral abilities in PD rats by regulating the DDC, TH, MAO-B, COMT and DAT levels. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  11. Altered resting-state functional connectivity of striatal-thalamic circuit in bipolar disorder.

    Directory of Open Access Journals (Sweden)

    Shin Teng

    Full Text Available Bipolar disorder is characterized by internally affective fluctuations. The abnormality of inherently mental state can be assessed using resting-state fMRI data without producing task-induced biases. In this study, we hypothesized that the resting-state connectivity related to the frontal, striatal, and thalamic regions, which were associated with mood regulations and cognitive functions, can be altered for bipolar disorder. We used the Pearson's correlation coefficients to estimate functional connectivity followed by the hierarchical modular analysis to categorize the resting-state functional regions of interest (ROIs. The selected functional connectivities associated with the striatal-thalamic circuit and default mode network (DMN were compared between bipolar patients and healthy controls. Significantly decreased connectivity in the striatal-thalamic circuit and between the striatal regions and the middle and posterior cingulate cortex was observed in the bipolar patients. We also observed that the bipolar patients exhibited significantly increased connectivity between the thalamic regions and the parahippocampus. No significant changes of connectivity related to the frontal regions in the DMN were observed. The changed resting-state connectivity related to the striatal-thalamic circuit might be an inherent basis for the altered emotional and cognitive processing in the bipolar patients.

  12. Serotonin 2A receptor regulation of striatal neuropeptide gene expression is selective for tachykinin, but not enkephalin neurons following dopamine depletion.

    Science.gov (United States)

    Basura, G J; Walker, P D

    2001-08-15

    Serotonin (5-HT) 2A receptor-mediated regulation of striatal preprotachykinin (PPT) and preproenkephalin (PPE) mRNAs was studied in adult rodents that had been subjected to near-total dopamine (DA) depletion as neonates. Two months following bilateral 6-hydroxydopamine (6-OHDA) lesion, PPT mRNA levels decreased 59-73% across dorsal subregions of the rostral and caudal striatum while PPE transcripts increased 61-94%. Four hours after a single injection of the serotonin 2A/2C receptor agonist, (+/-)-1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane (DOI; 1 mg/kg), PPT mRNA expression was significantly increased in DA-depleted rats across all dorsal subregions of the rostral and caudal striatum as compared to 6-OHDA-treated animals alone. In the intact rat, DOI did not influence PPT mRNA levels in the rostral striatum, but did raise expression in the caudal striatum where 5-HT2A receptors are prominent. DOI did not regulate PPE mRNA levels in any striatal sub-region of the intact or DA-depleted rat. Prior administration of the 5-HT2A/2C receptor antagonist, ritanserin (1 mg/kg) or the 5-HT2A receptor antagonist, ketanserin (1 mg/kg) completely blocked the DOI-induced increases in striatal PPT mRNA in both lesioned and intact animals. The ability of ketanserin to produce identical results as ritanserin suggests that 5-HT2A receptor-mediated regulation is selectively strengthened within tachykinin neurons of the rostral striatum which are suppressed by DA depletion. The selectivity suggests that 5-HT2A receptor upregulation following DA depletion is capable of regulating tachykinin biosynthesis without influencing enkephalin expression in striatal output neurons.

  13. Decreased striatal dopamine transporter binding assessed with [123I] FP-CIT in first-episode schizophrenic patients with and without short-term antipsychotic-induced parkinsonism.

    Science.gov (United States)

    Mateos, Jose J; Lomeña, Francisco; Parellada, Eduardo; Font, Mireia; Fernandez, Emili; Pavia, Javier; Prats, Alberto; Pons, Francisca; Bernardo, Miquel

    2005-09-01

    Drug-induced parkinsonism (DIP) is one of the main causes of treatment drop-out in schizophrenic patients causing a high incidence of relapse that leads patients to a bad clinical prognosis. The dopaminergic nigrostriatal pathway is involved in the movement control, so the study of the dopamine transporter (DAT) could be of great value to determine its implication in the appearance of DIP. The goal of the study is to determine the striatal DAT binding assessed with [(123)I] FP-CIT SPECT in first-episode neuroleptic-naive schizophrenic in-patients with DIP after short-term antipsychotic treatment. The [(123)I] FP-CIT binding ratios of ten schizophrenic in-patients who developed DIP during the first 4-week period of risperidone treatment (6+/-2 mg/day) were compared with ten schizophrenic in-patients treated with the same doses of risperidone and who do not developed DIP and with ten age-matched healthy subjects. Quantitative analyses of SPECTs were performed using regions of interest located in caudate, putamen and occipital cortex. Parkinsonism was assessed by the Simpson-Angus Scale and the psychopathological status by the Clinical General Impression and Positive and Negative Syndrome Scales. Whole striatal [(123)I] FP-CIT binding ratios were significantly lower in patients with and without DIP than in healthy subjects (p<0.001). This was also observed in whole putamen (p<0.001) and caudate nucleus (p<0.001). Females showed higher whole striatal [(123)I] FP-CIT binding ratios than males (p<0.05). No differences in psychopathological scales were observed between patients with and without DIP. Our first-episode schizophrenic patients with and without DIP after short-term risperidone treatment have a decreased striatal DAT binding assessed with [(123)I] FP-CIT. This alteration could be related to the schizophrenic disease or may be secondary to the antipsychotic treatment.

  14. Effect of Exercise Training on Striatal Dopamine D2/D3 Receptors in Methamphetamine Users during Behavioral Treatment.

    Science.gov (United States)

    Robertson, Chelsea L; Ishibashi, Kenji; Chudzynski, Joy; Mooney, Larissa J; Rawson, Richard A; Dolezal, Brett A; Cooper, Christopher B; Brown, Amira K; Mandelkern, Mark A; London, Edythe D

    2016-05-01

    Methamphetamine use disorder is associated with striatal dopaminergic deficits that have been linked to poor treatment outcomes, identifying these deficits as an important therapeutic target. Exercise attenuates methamphetamine-induced neurochemical damage in the rat brain, and a preliminary observation suggests that exercise increases striatal D2/D3 receptor availability (measured as nondisplaceable binding potential (BPND)) in patients with Parkinson's disease. The goal of this study was to evaluate whether adding an exercise training program to an inpatient behavioral intervention for methamphetamine use disorder reverses deficits in striatal D2/D3 receptors. Participants were adult men and women who met DSM-IV criteria for methamphetamine dependence and were enrolled in a residential facility, where they maintained abstinence from illicit drugs of abuse and received behavioral therapy for their addiction. They were randomized to a group that received 1 h supervised exercise training (n=10) or one that received equal-time health education training (n=9), 3 days/week for 8 weeks. They came to an academic research center for positron emission tomography (PET) using [(18)F]fallypride to determine the effects of the 8-week interventions on striatal D2/D3 receptor BPND. At baseline, striatal D2/D3 BPND did not differ between groups. However, after 8 weeks, participants in the exercise group displayed a significant increase in striatal D2/D3 BPND, whereas those in the education group did not. There were no changes in D2/D3 BPND in extrastriatal regions in either group. These findings suggest that structured exercise training can ameliorate striatal D2/D3 receptor deficits in methamphetamine users, and warrants further evaluation as an adjunctive treatment for stimulant dependence.

  15. The clinical benefit of imaging striatal dopamine transporters with [123I]FP-CIT SPET in differentiating patients with presynaptic parkinsonism from those with other forms of parkinsonism

    International Nuclear Information System (INIS)

    Booij, J.; Speelman, J.DE.; Horstink, M. W.I.M.; Wolters, E.C.

    2001-01-01

    [ 123 I]FP-CIT (N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane) has been developed successfully as a radioligand for single-photon emission tomography (SPET) imaging of dopamine transporters, which are situated in the membrane of dopaminergic neurons. Imaging of these transporters has shown promise as a clinical tool to detect degeneration of the dopaminergic nigrostriatal pathway. Several ''presynaptic parkinsonian'' syndromes, such as Parkinson's disease or multiple system atrophy, are characterised by degeneration of the nigrostriatal pathway. [ 123 I]FP-CIT SPET imaging studies have shown the ability to detect loss of striatal dopamine transporters in such syndromes. However, in clinical practice it is sometimes difficult, but important, to discriminate patients with ''presynaptic parkinsonism'' from those with other forms of parkinsonism not characterised by loss of presynaptic dopaminergic cells (e.g. psychogenic parkinsonism or drug-induced postsynaptic parkinsonism). In these inconclusive cases, it may be of value to confirm or exclude the existence of degeneration of nigrostriatal dopaminergic cells by using imaging techniques such as [ 123 I]FP-CIT SPET. Using [ 123 I]FP-CIT SPET, we have imaged the striatal dopamine transporters in a group of patients with inconclusive forms of parkinsonism, and, moreover, have been able to perform clinical follow-up of these patients 2-4 years after imaging. In 33 inconclusive cases, ratios of specific to non-specific binding were calculated for the caudate nucleus and putamen following [ 123 I]FP-CIT SPET imaging and compared with ratios obtained in healthy controls. In nine of the patients, degeneration of the nigrostriatal pathway was found scintigraphically and in all these cases, presynaptic parkinsonism was confirmed by clinical follow-up. In the other 24 subjects no degeneration was found scintigraphically. Forms of parkinsonism other than the presynaptic were confirmed at follow-up in 19 cases

  16. Aberrant local striatal functional connectivity in attention-deficit/hyperactivity disorder

    NARCIS (Netherlands)

    Rhein, D.T. von; Oldehinkel, M.; Beckmann, C.F.; Oosterlaan, J.; Heslenfeld, D.; Hartman, C.A.; Hoekstra, P.J.; Franke, B.; Cools, R.; Buitelaar, J.K.; Mennes, M.

    2016-01-01

    BACKGROUND: Task-based and resting-state functional Magnetic Resonance Imaging (fMRI) studies report attention-deficit/hyperactivity disorder (ADHD)-related alterations in brain regions implicated in cortico-striatal networks. We assessed whether ADHD is associated with changes in the brain's global

  17. Aberrant local striatal functional connectivity in attention-deficit/hyperactivity disorder

    NARCIS (Netherlands)

    von Rhein, Daniel; Oldehinkel, Marianne; Beckmann, Christian F.; Oosterlaan, Jaap; Heslenfeld, Dirk; Hartman, Catharina A.; Hoekstra, Pieter J.; Franke, Barbara; Cools, Roshan; Buitelaar, Jan K.; Mennes, Maarten

    Background: Task-based and resting-state functional Magnetic Resonance Imaging (fMRI) studies report attention-deficit/hyperactivity disorder (ADHD)-related alterations in brain regions implicated in cortico-striatal networks. We assessed whether ADHD is associated with changes in the brain's global

  18. Varenicline increases in vivo striatal dopamine D2/3 receptor binding: an ultra-high-resolution pinhole [123I]IBZM SPECT study in rats

    International Nuclear Information System (INIS)

    Crunelle, Cleo L.; Wit, Tim C. de; Bruin, Kora de; Ramakers, Ruud M.; Have, Frans van der; Beekman, Freek J.; Brink, Wim van den; Booij, Jan

    2012-01-01

    Introduction: Ex vivo storage phosphor imaging rat studies reported increased brain dopamine D 2/3 receptor (DRD 2/3 ) availability following treatment with varenicline, a nicotinergic drug. However, ex vivo studies can only be performed using cross-sectional designs. Small-animal imaging offers the opportunity to perform serial assessments. We evaluated whether high-resolution pinhole single photon emission computed tomography (SPECT) imaging in rats was able to reproduce previous ex vivo findings. Methods: Rats were imaged for baseline striatal DRD 2/3 availability using ultra-high-resolution pinhole SPECT (U-SPECT-II) and [ 123 I]IBZM as a radiotracer, and randomized to varenicline (n=7; 2 mg/kg) or saline (n=7). Following 2 weeks of treatment, a second scan was acquired. Results: Significantly increased striatal DRD 2/3 availability was found following varenicline treatment compared to saline (time⁎treatment effect): posttreatment difference in binding potential between groups corrected for initial baseline differences was 2.039 (P=.022), indicating a large effect size (d=1.48). Conclusions: Ultra-high-resolution pinhole SPECT can be used to assess varenicline-induced changes in DRD 2/3 availability in small laboratory animals over time. Future small-animal studies should include imaging techniques to enable repeated within-subjects measurements and reduce the amount of animals.

  19. Rats classified as low or high cocaine locomotor responders: A unique model involving striatal dopamine transporters that predicts cocaine addiction-like behaviors

    Science.gov (United States)

    Yamamoto, Dorothy J.; Nelson, Anna M.; Mandt, Bruce H.; Larson, Gaynor A.; Rorabaugh, Jacki M.; Ng, Christopher M.C.; Barcomb, Kelsey M.; Richards, Toni L.; Allen, Richard M.; Zahniser, Nancy R.

    2013-01-01

    Individual differences are a hallmark of drug addiction. Here, we describe a rat model based on differential initial responsiveness to low dose cocaine. Despite similar brain cocaine levels, individual outbred Sprague-Dawley rats exhibit markedly different magnitudes of acute cocaine-induced locomotor activity and, thereby, can be classified as low or high cocaine responders (LCRs or HCRs). LCRs and HCRs differ in drug-induced, but not novelty-associated, hyperactivity. LCRs have higher basal numbers of striatal dopamine transporters (DATs) than HCRs and exhibit marginal cocaine inhibition of in vivo DAT activity and cocaine-induced increases in extracellular DA. Importantly, lower initial cocaine response predicts greater locomotor sensitization, conditioned place preference and greater motivation to self-administer cocaine following low dose acquisition. Further, outbred Long-Evans rats classified as LCRs, versus HCRs, are more sensitive to cocaine’s discriminative stimulus effects. Overall, results to date with the LCR/HCR model underscore the contribution of striatal DATs to individual differences in initial cocaine responsiveness and the value of assessing the influence of initial drug response on subsequent expression of addiction-like behaviors. PMID:23850581

  20. Differential striatal levels of TNF-alpha, NFkappaB p65 subunit and dopamine with chronic typical and atypical neuroleptic treatment: role in orofacial dyskinesia.

    Science.gov (United States)

    Bishnoi, Mahendra; Chopra, Kanwaljit; Kulkarni, Shrinivas K

    2008-08-01

    Long term use of typical neuroleptics such as haloperidol may be limited by unwanted motor side effects like tardive dyskinesia characterized by repetitive involuntary movements, involving the mouth, face and trunk. Atypical neuroleptics, such as clozapine and risperidone are devoid of these side effects. However the precise mechanisms of the neuronal toxicity induced by haloperidol are poorly understood. It is possible that typical and atypical antipsychotic differently affects neuronal survival and death and that these effects considerably contribute to the differences in the development of TD. The aim of the present study is to investigate the role of TNF-alpha and NFkappaB on the toxicity induced by chronic haloperidol administration in an animal model of tardive dyskinesia. Rats were treated for 21 days with: haloperidol (5 mg/kg), clozapine (5 and 10 mg/kg), risperidone (5 mg/kg) or saline. Orofacial dyskinetic movements and total locomotor activity was evaluated. Striatal levels of dopamine were measure by HPLC/ED whereas striatal levels of TNF-alpha and NFkappaB p65 subunit were measured by ELISA technique. Haloperidol increased orofacial dyskinetic movements and total locomotor activity (on day 22) (PClozapine and risperidone also increased the orofacial dyskinetic movements but that significantly less than haloperidol (Pclozapine and risperidone did not. Haloperidol but not clozapine and risperidone significantly increased the levels of TNF-alpha and NFkappaB p65 subunit (Pdyskinesia in rats, an animal model for human tardive dyskinesia.

  1. The effects of donor stage on the survival and function of embryonic striatal grafts in the adult rat brain; II. Correlation between positron emission tomography and reaching behaviour

    Energy Technology Data Exchange (ETDEWEB)

    Dunnett, S.B. [Department of Experimental Psychology and MRC Cambridge Centre for Brain Repair, University of Cambridge, Cambridge (United Kingdom); Brooks, D.J.; Ashworth, S.; Opacka-Juffrey, J.; Myers, R.; Hume, S.P. [PET Methodology Group, Cyclotron Unit, MRC Clinical Science Centre, Hammersmith Hospital, London (United Kingdom); Torres, E.M.; Fricker, R.A. [Department of Experimental Psychology and MRC Cambridge Centre for Brain Repair, University of Cambridge, Cambridge (United Kingdom)

    1997-05-26

    Grafts of embryonic striatal primordia are able to elicit behavioural recovery in rats which have received an excitotoxic lesion to the striatum, and it is believed that the P zones or striatal-like tissue within the transplants play a crucial role in these functional effects. We performed this study to compare the effects of different donor stage of embryonic tissue on both the morphology (see accompanying paper) and function of striatal transplants. Both the medial and lateral ganglionic eminence was dissected from rat embryos of either 10 mm, 15 mm, 19 mm, or 23 mm crown-rump length, and implanted as a cell suspension into adult rats which had received an ibotenic acid lesion 10 days prior to transplantation. After four months the animals were tested on the 'staircase task' of skilled forelimb use. At 10-14 months rats from the groups which had received grafts from 10 mm or 15 mm donor embryos were taken for positron emission tomography scanning in a small diameter postiron emission tomography scanner, using ligands to the dopamine D{sub 1} and D{sub 2} receptors, [{sup 11}C]SCH 23390 and [{sup 11}C]raclopride, respectively. A lesion-alone group was also scanned with the same ligands for comparison. Animals which had received transplants from the 10 mm donors showed a significant recovery with their contralateral paw on the 'staircase test'. No other groups showed recovery on this task. Similarly, the animals with grafts from the youngest donors showed a significant increase in D{sub 1} and D{sub 2} receptor binding when compared to the lesion-alone group. No increase in signal was observed with either ligand in the group which had received grafts from 15 mm donors. Success in paw reaching showed a strong correlation to both the positron emission tomography signal obtained and the P zone volume of the grafts.These results suggest that striatal grafts from younger donors (10 mm CRL) give greater behavioural recovery than grafts preparedfrom

  2. L-type Ca2+ channel blockers promote Ca2+ accumulation when dopamine receptors are activated in striatal neurons.

    Science.gov (United States)

    Eaton, Molly E; Macías, Wendy; Youngs, Rachael M; Rajadhyaksha, Anjali; Dudman, Joshua T; Konradi, Christine

    2004-11-24

    Dopamine (DA) receptor-mediated signal transduction and gene expression play a central role in many brain disorders from schizophrenia to Parkinson's disease to addiction. While trying to evaluate the role of L-type Ca2+ channels in dopamine D1 receptor-mediated phosphorylation of the transcription factor cyclic AMP response element-binding protein (CREB), we found that activation of dopamine D1 receptors alters the properties of L-type Ca2+ channel inhibitors and turns them into facilitators of Ca2+ influx. In D1 receptor-stimulated neurons, L-type Ca2+ channel blockers promote cytosolic Ca2+ accumulation. This leads to the activation of a molecular signal transduction pathway and CREB phosphorylation. In the absence of dopamine receptor stimulation, L-type Ca2+ channel blockers inhibit CREB phosphorylation. The effect of dopamine on L-type Ca2+ channel blockers is dependent on protein kinase A (PKA), suggesting that protein phosphorylation plays a role in this phenomenon. Because of the adverse effect of activated dopamine receptors on L-type Ca2+ channel blocker action, the role of L-type Ca2+ channels in the dopamine D1 receptor signal transduction pathway cannot be assessed with pharmacological tools. However, with antisense technology, we demonstrate that L-type Ca2+ channels contribute to D1 receptor-mediated CREB phosphorylation. We conclude that the D1 receptor signal transduction pathway depends on L-type Ca2+ channels to mediate CREB phosphorylation.

  3. L-type Ca2+ channel blockers promote Ca2+ accumulation when dopamine receptors are activated in striatal neurons

    OpenAIRE

    Eaton, Molly E.; Macías, Wendy; Youngs, Rachael M.; Rajadhyaksha, Anjali; Dudman, Joshua T.; Konradi, Christine

    2004-01-01

    Dopamine (DA) receptor-mediated signal transduction and gene expression play a central role in many brain disorders from schizophrenia to Parkinson’s disease to addiction. While trying to evaluate the role of L-type Ca2+ channels in dopamine D1 receptor-mediated phosphorylation of the transcription factor cyclic AMP response element-binding protein (CREB), we found that activation of dopamine D1 receptors alters the properties of L-type Ca2+ channel inhibitors and turns them into facilitators...

  4. Surface functionalization of polyamide fiber via dopamine polymerization

    Science.gov (United States)

    Kuang, Xiao-Hui; Guan, Jin-Ping; Tang, Ren-Cheng; Chen, Guo-Qiang

    2017-09-01

    The oxidative polymerization of dopamine for the functional surface modification of textile fibers has drawn great attention. In this work, the functionalization of polyamide fiber via dopamine polymerization was studied with the aim of the fabrication of hydrophilic and antistatic surface. The conditions of dopamine application were first discussed in the absence of specific oxidants in terms of the apparent color depth of polyamide fiber. Dopamine concentration, pH and time were found to exert great impact on color depth. The highest color depth was achieved at pH 8.5. In the process of modification, polydopamine was deposited onto the surface of polyamide fiber. The modified polyamide fiber displayed a yellowish brown color with excellent wash and light color fastness, and exhibited good hydrophilic, UV protection and antistatic effects. A disadvantage of the present approach was the slow rate of dopamine polymerization and functionalization.

  5. Cross-hemispheric dopamine projections have functional significance

    Science.gov (United States)

    Fox, Megan E.; Mikhailova, Maria A.; Bass, Caroline E.; Takmakov, Pavel; Gainetdinov, Raul R.; Budygin, Evgeny A.; Wightman, R. Mark

    2016-01-01

    Dopamine signaling occurs on a subsecond timescale, and its dysregulation is implicated in pathologies ranging from drug addiction to Parkinson’s disease. Anatomic evidence suggests that some dopamine neurons have cross-hemispheric projections, but the significance of these projections is unknown. Here we report unprecedented interhemispheric communication in the midbrain dopamine system of awake and anesthetized rats. In the anesthetized rats, optogenetic and electrical stimulation of dopamine cells elicited physiologically relevant dopamine release in the contralateral striatum. Contralateral release differed between the dorsal and ventral striatum owing to differential regulation by D2-like receptors. In the freely moving animals, simultaneous bilateral measurements revealed that dopamine release synchronizes between hemispheres and intact, contralateral projections can release dopamine in the midbrain of 6-hydroxydopamine–lesioned rats. These experiments are the first, to our knowledge, to show cross-hemispheric synchronicity in dopamine signaling and support a functional role for contralateral projections. In addition, our data reveal that psychostimulants, such as amphetamine, promote the coupling of dopamine transients between hemispheres. PMID:27298371

  6. Functional role for cortical-striatal circuitry in modulating alcohol self-administration.

    Science.gov (United States)

    Jaramillo, Anel A; Randall, Patrick A; Stewart, Spencer; Fortino, Brayden; Van Voorhies, Kalynn; Besheer, Joyce

    2018-03-01

    The cortical-striatal brain circuitry is heavily implicated in drug-use. As such, the present study investigated the functional role of cortical-striatal circuitry in modulating alcohol self-administration. Given that a functional role for the nucleus accumbens core (AcbC) in modulating alcohol-reinforced responding has been established, we sought to test the role of cortical brain regions with afferent projections to the AcbC: the medial prefrontal cortex (mPFC) and the insular cortex (IC). Long-Evans rats were trained to self-administer alcohol (15% alcohol (v/v)+2% sucrose (w/v)) during 30 min sessions. To test the functional role of the mPFC or IC, we utilized a chemogenetic technique (hM4D i -Designer Receptors Activation by Designer Drugs) to silence neuronal activity prior to an alcohol self-administration session. Additionally, we chemogenetically silenced mPFC→AcbC or IC→AcbC projections, to investigate the role of cortical-striatal circuitry in modulating alcohol self-administration. Chemogenetically silencing the mPFC decreased alcohol self-administration, while silencing the IC increased alcohol self-administration, an effect absent in mCherry-Controls. Interestingly, silencing mPFC→AcbC projections had no effect on alcohol self-administration. In contrast, silencing IC→AcbC projections decreased alcohol self-administration, in a reinforcer-specific manner as there was no effect in rats trained to self-administer sucrose (0.8%, w/v). Additionally, no change in self-administration was observed in the mCherry-Controls. Together these data demonstrate the complex role of the cortical-striatal circuitry while implicating a role for the insula-striatal circuit in modulating ongoing alcohol self-administration. Copyright © 2017 Elsevier Ltd. All rights reserved.

  7. Occupational exposure to PCBs reduces striatal dopamine transporter densities only in women: A β-CIT imaging study

    Science.gov (United States)

    Seegal, Richard F.; Marek, Kenneth L.; Seibyl, John P.; Jennings, Danna L.; Molho, Eric S.; Higgins, Donald S.; Factor, Stewart A.; Fitzgerald, Edward F.; Hills, Elaine A.; Korrick, Susan A.; Wolff, Mary S.; Haase, Richard F.; Todd, Andrew C.; Parsons, Patrick; McCaffrey, Robert F.

    2010-01-01

    We hypothesize that occupational exposure to PCBs is associated with a reduction in central dopamine (DA) similar to changes previously seen in PCB exposed adult non-human primates. To test that hypothesis we used [123I]β-CIT SPECT imaging to estimate basal ganglia DA transporter density in former capacitor workers. Women, but not men, showed an inverse relationship between lipid-adjusted total serum PCB concentrations and DA transporter densities in the absence of differences in serum PCB concentrations. These sex differences may reflect age-related reductions in the levels of gonadal hormones since these hormones have been shown experimentally to alter response to DA neurotoxicants. These findings may aid in better understanding the roles that sex and age play in modifying central DA function following exposure, not only to PCBs, but also to other DA neurotoxicants as well as further elucidating the role of gonadal hormones in influencing the initiation and/or progression of neurodegenerative disorders. PMID:20096358

  8. Unravelling the differential functions and regulation of striatal neuron sub-populations in motor control, reward and motivational processes

    Directory of Open Access Journals (Sweden)

    Sabrina eEna

    2011-07-01

    Full Text Available The striatum, the major input structure of the basal ganglia, is critically involved in motor control and learning of habits and skills, and is also involved in motivational and reward processes. The dorsal striatum, caudate-putamen, is primarily implicated in motor functions whereas the ventral striatum, the nucleus accumbens, is essential for motivation and drug reinforcement. Severe basal ganglia dysfunction occurs in movement disorders as Parkinson’s and Huntington’s disease, and in psychiatric disorders such as schizophrenia and drug addiction. The striatum is essentially composed of GABAergic medium-sized spiny neurons (MSNs that are output neurons giving rise to the so-called direct and indirect pathways and are targets of the cerebral cortex and mesencephalic dopaminergic neurons. Although the involvement of striatal sub-areas in motor control and motivation has been thoroughly characterized, major issues remained concerning the specific and respective functions of the two MSNs sub-populations, D2R-striatopallidal (dopamine D2 receptor-positive and D1R-striatonigral (dopamine D1 receptor-positive neurons, as well as their specific regulation. Here, we review recent advances that gave new insight in the understanding of the differential roles of striatopallidal and striatonigral neurons in the basal ganglia circuit. We discuss innovative techniques developed in the last decade which allowed a much precise evaluation of molecular pathways implicated in motivational processes and functional roles of striatopallidal and striatonigral neurons in motor control and in the establishment of reward-associated behaviour.

  9. 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.

  10. Diagnostic imaging of dementia with Lewy bodies by susceptibility-weighted imaging of nigrosomes versus striatal dopamine transporter single-photon emission computed tomography: a retrospective observational study

    Energy Technology Data Exchange (ETDEWEB)

    Kamagata, Koji; Sato, Kanako; Suzuki, Michimasa; Hori, Masaaki; Kumamaru, Kanako K.; Aoki, Shigeki [Juntendo University Graduate School of Medicine, Department of Radiology, Bunkyo-ku, Tokyo (Japan); Nakatsuka, Tomoya; Inaoka, Tsutomu; Terada, Hitoshi [Toho University Sakura Medical Center, Department of Radiology, Sakura, Sakura (Japan); Sakakibara, Ryuji; Tsuyusaki, Yohei [Toho University Sakura Medical Center, Department of Neurology, Sakura, Sakura (Japan); Takamura, Tomohiro [University of Yamanashi, Department of Radiology, Chuo-shi, Yamanashi (Japan)

    2017-01-15

    The characteristics of dementia with Lewy bodies (DLB), Alzheimer's disease (AD) and amnestic mild cognitive impairment (a-MCI) overlap but require different treatments; therefore, it is important to differentiate these pathologies. Assessment of dopamine uptake in the striatum using dopamine transporter (DaT) single-photon emission computed tomography (SPECT) is the gold standard for diagnosing DLB; however, this modality is expensive, time consuming and involves radiation exposure. Degeneration of the substantia nigra nigrosome-1, which occurs in DLB, but not in AD/a-MCI, can be identified by 3T susceptibility-weighted imaging (SWI). Therefore, the aim of this retrospective observational study was to compare SWI with DaT-SPECT for differentiation of DLB from AD/a-MCI. SWI data were acquired for patients with clinically diagnosed DLB (n = 29), AD (n = 18), a-MCI (n = 13) and healthy controls (n = 26). Images were analysed for nigrosome-1 degeneration. Diagnostic accuracy was evaluated for DLB, AD and a-MCI compared with striatal dopamine uptake using DaT-SPECT. SWI achieved 90% diagnostic accuracy (93% sensitivity, 87% specificity) for the detection of nigrosome-1 degeneration in DLB and not in AD/a-MCI as compared with 88.3% accuracy (93% sensitivity, 84% specificity) using DaT-SPECT. SWI nigrosome-1 evaluation was useful in differentiating DLB from AD/a-MCI, with high accuracy. This less invasive and less expensive method is a potential alternative to DaT-SPECT for the diagnosis of DLB. (orig.)

  11. Endocannabinoids and striatal function: implications for addiction-related behaviours

    Science.gov (United States)

    Moreira, Fabricio A.; Jupp, Bianca; Belin, David

    2015-01-01

    Since the identification and cloning of the major cannabinoid receptor expressed in the brain almost 25 years ago research has highlighted the potential of drugs that target the endocannabinoid system for treating addiction. The endocannabinoids, anandamide and 2-arachidonoyl glycerol, are lipid-derived metabolites found in abundance in the basal ganglia and other brain areas innervated by the mesocorticolimbic dopamine systems. Cannabinoid CB1 receptor antagonists/inverse agonists reduce reinstatement of responding for cocaine, alcohol and opiates in rodents. However, compounds acting on the endocannabinoid system may have broader application in treating drug addiction by ameliorating associated traits and symptoms such as impulsivity and anxiety that perpetuate drug use and interfere with rehabilitation. As a trait, impulsivity is known to predispose to addiction and facilitate the emergence of addiction to stimulant drugs. In contrast, anxiety and elevated stress responses accompany extended drug use and may underlie the persistence of drug intake in dependent individuals. In this article we integrate and discuss recent findings in rodents showing selective pharmacological modulation of impulsivity and anxiety by cannabinoid agents. We highlight the potential of selective inhibitors of endocannabinoid metabolism, directed at fatty acid amide hydrolase and monoacylglycerol lipase, to reduce anxiety and stress responses, and discuss novel mechanisms underlying the modulation of the endocannabinoid system, including the attenuation of impulsivity, anxiety, and drug reward by selective CB2 receptor agonists. PMID:25369747

  12. Dopamine and the management of attentional resources: genetic markers of striatal D2 dopamine predict individual differences in the attentional blink

    NARCIS (Netherlands)

    Colzato, L.S.; Slagter, H.A.; de Rover, M.; Hommel, B.

    2011-01-01

    The attentional blink (AB)—a deficit in reporting the second of two target stimuli presented in close succession in a rapid sequence of distracters—has been related to processing limitations in working memory. Given that dopamine (DA) plays a crucial role working memory, the present study tested

  13. Beyond Neuronal Activity Markers: Select Immediate Early Genes in Striatal Neuron Subtypes Functionally Mediate Psychostimulant Addiction

    Directory of Open Access Journals (Sweden)

    Ramesh Chandra

    2017-06-01

    Full Text Available Immediate early genes (IEGs were traditionally used as markers of neuronal activity in striatum in response to stimuli including drugs of abuse such as psychostimulants. Early studies using these neuronal activity markers led to important insights in striatal neuron subtype responsiveness to psychostimulants. Such studies have helped identify striatum as a critical brain center for motivational, reinforcement and habitual behaviors in psychostimulant addiction. While the use of IEGs as neuronal activity markers in response to psychostimulants and other stimuli persists today, the functional role and implications of these IEGs has often been neglected. Nonetheless, there is a subset of research that investigates the functional role of IEGs in molecular, cellular and behavioral alterations by psychostimulants through striatal medium spiny neuron (MSN subtypes, the two projection neuron subtypes in striatum. This review article will address and highlight the studies that provide a functional mechanism by which IEGs mediate psychostimulant molecular, cellular and behavioral plasticity through MSN subtypes. Insight into the functional role of IEGs in striatal MSN subtypes could provide improved understanding into addiction and neuropsychiatric diseases affecting striatum, such as affective disorders and compulsive disorders characterized by dysfunctional motivation and habitual behavior.

  14. Timing of caloric intake during weight loss differentially affects striatal dopamine transporter and thalamic serotonin transporter binding

    NARCIS (Netherlands)

    Versteeg, Ruth I.; Schrantee, Anouk; Adriaanse, Sofie M.; Unmehopa, Unga A.; Booij, Jan; Reneman, Liesbeth; Fliers, Eric; la Fleur, Susanne E.; Serlie, Mireille J.

    2017-01-01

    Recent studies have shown that meal timing throughout the day contributes to maintaining or regaining weight after hypocaloric diets. Although brain serotonin and dopamine are well known to be involved in regulating feeding, it is unknown whether meal timing during energy restriction affects these

  15. The dopamine agonist apomorphine differentially affects cognitive performance in alcohol dependent patients and healthy controls.

    NARCIS (Netherlands)

    Schellekens, A.F.A.; Oosterwijck, A.W.A.A.; Ellenbroek, A.A.; Jong, C.A.J. de; Buitelaar, J.K.; Cools, A.R.; Verkes, R.J.

    2009-01-01

    BACKGROUND: Reduced metabolic activity in frontal brain regions, and reduced striatal dopamine receptor densities have been shown in alcohol dependent patients. Little is known on functional changes in the fronto-striatal-thalamic dopaminergic neurocircuitry in these patients. The objective of this

  16. The dopamine agonist apomorphine differentially affects cognitive performance in alcohol dependent patients and healthy controls

    NARCIS (Netherlands)

    Schellekens, A.F.A.; Oosterwijck, A.W.A.A.; Ellenbroek, A.A.; Jong, C.A.J. de; Buitelaar, J.K.; Cools, A.R.; Verkes, R.J.

    2009-01-01

    BACKGROUND: Reduced metabolic activity in frontal brain regions, and reduced striatal dopamine receptor densities have been shown in alcohol dependent patients. Little is known on functional changes in the fronto-striatal-thalamic dopaminergic neurocircuitry in these patients. The objective of this

  17. Western Diet Chow Consumption in Rats Induces Striatal Neuronal Activation While Reducing Dopamine Levels without Affecting Spatial Memory in the Radial Arm Maze.

    Science.gov (United States)

    Nguyen, Jason C D; Ali, Saher F; Kosari, Sepideh; Woodman, Owen L; Spencer, Sarah J; Killcross, A Simon; Jenkins, Trisha A

    2017-01-01

    Rats fed high fat diets have been shown to be impaired in hippocampal-dependent behavioral tasks, such as spatial recognition in the Y-maze and reference memory in the Morris water maze (MWM). It is clear from previous studies, however, that motivation and reward factor into the memory deficits associated with obesity and high-fat diet consumption, and that the prefrontal cortex and striatum and neurotransmitter dopamine play important roles in cognitive performance. In this series of studies we extend our research to investigate the effect of a high fat diet on striatal neurochemistry and performance in the delayed spatial win-shift radial arm maze task, a paradigm highly reliant on dopamine-rich brain regions, such as the striatum after high fat diet consumption. Memory performance, neuronal activation and brain dopaminergic levels were compared in rats fed a "Western" (21% fat, 0.15% cholesterol) chow diet compared to normal diet (6% fat, 0.15% cholesterol)-fed controls. Twelve weeks of dietary manipulation produced an increase in weight in western diet-fed rats, but did not affect learning and performance in the delayed spatial win-shift radial arm maze task. Concurrently, there was an observed decrease in dopamine levels in the striatum and a reduction of dopamine turnover in the hippocampus in western diet-fed rats. In a separate cohort of rats Fos levels were measured after rats had been placed in a novel arena and allowed to explore freely. In normal rats, this exposure to a unique environment did not affect neuronal activation. In contrast, rats fed a western diet were found to have significantly increased Fos expression in the striatum, but not prefrontal cortex or hippocampus. Our study demonstrates that while western diet consumption in rats produces weight gain and brain neuronal and neurotransmitter changes, it did not affect performance in the delayed spatial win-shift paradigm in the radial arm maze. We conclude that modeling the cognitive decline

  18. Creative cognition and dopaminergic modulation of fronto-striatal networks: Integrative review and research agenda.

    Science.gov (United States)

    Boot, Nathalie; Baas, Matthijs; van Gaal, Simon; Cools, Roshan; De Dreu, Carsten K W

    2017-07-01

    Creative cognition is key to human functioning yet the underlying neurobiological mechanisms are sparsely addressed and poorly understood. Here we address the possibility that creative cognition is a function of dopaminergic modulation in fronto-striatal brain circuitries. It is proposed that (i) creative cognition benefits from both flexible and persistent processing, (ii) striatal dopamine and the integrity of the nigrostriatal dopaminergic pathway is associated with flexible processing, while (iii) prefrontal dopamine and the integrity of the mesocortical dopaminergic pathway is associated with persistent processing. We examine this possibility in light of studies linking creative ideation, divergent thinking, and creative problem-solving to polymorphisms in dopamine receptor genes, indirect markers and manipulations of the dopaminergic system, and clinical populations with dysregulated dopaminergic activity. Combined, studies suggest a functional differentiation between striatal and prefrontal dopamine: moderate (but not low or high) levels of striatal dopamine benefit creative cognition by facilitating flexible processes, and moderate (but not low or high) levels of prefrontal dopamine enable persistence-driven creativity. Copyright © 2017 Elsevier Ltd. All rights reserved.

  19. Sex-Dependent Changes in Striatal Dopamine Transport in Preadolescent Rats Exposed Prenatally and/or Postnatally to Methamphetamine

    Czech Academy of Sciences Publication Activity Database

    Šírová, J.; Krištofíková, Z.; Vrajová, M.; Fujakova-Lipski, M.; Řípová, D.; Klaschka, Jan; Šlamberová, R.

    2016-01-01

    Roč. 41, č. 8 (2016), s. 1911-1923 ISSN 0364-3190 Grant - others:GA MŠk(CZ) ED2.1.00/03.0078; GA ČR(CZ) GA14-03708S; Univerzita Karlova(CZ) Prvouk P34; GA UK(CZ) 88315; SVV(CZ) 260277/2016 Institutional support: RVO:67985807 Keywords : methamphetamine * dopamine transporte * sex differences * membrane fluidity Subject RIV: FH - Neurology Impact factor: 2.581, year: 2016

  20. Circadian influences on dopamine circuits of the brain: regulation of striatal rhythms of clock gene expression and implications for psychopathology and disease [version 1; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Michael Verwey

    2016-08-01

    Full Text Available Circadian clock proteins form an autoregulatory feedback loop that is central to the endogenous generation and transmission of daily rhythms in behavior and physiology. Increasingly, circadian rhythms in clock gene expression are being reported in diverse tissues and brain regions that lie outside of the suprachiasmatic nucleus (SCN, the master circadian clock in mammals. For many of these extra-SCN rhythms, however, the region-specific implications are still emerging. In order to gain important insights into the potential behavioral, physiological, and psychological relevance of these daily oscillations, researchers have begun to focus on describing the neurochemical, hormonal, metabolic, and epigenetic contributions to the regulation of these rhythms. This review will highlight important sites and sources of circadian control within dopaminergic and striatal circuitries of the brain and will discuss potential implications for psychopathology and disease. For example, rhythms in clock gene expression in the dorsal striatum are sensitive to changes in dopamine release, which has potential implications for Parkinson’s disease and drug addiction. Rhythms in the ventral striatum and limbic forebrain are sensitive to psychological and physical stressors, which may have implications for major depressive disorder. Collectively, a rich circadian tapestry has emerged that forces us to expand traditional views and to reconsider the psychopathological, behavioral, and physiological importance of these region-specific rhythms in brain areas that are not immediately linked with the regulation of circadian rhythms.

  1. Differential sensitivity to NaCl for inhibitors and substrates that recognize mutually exclusive binding sites on the neuronal transporter of dopamine in rat striatal membranes.

    Science.gov (United States)

    Tidjane Corera, A; Do-Régo, J C; Costentin, J; Bonnet, J J

    2001-03-01

    Addition of NaCl (90--290 mM) to a 10 mM Na(+) medium did not significantly modify B(max) and K(d) values for [3H]mazindol binding to the dopamine neuronal transporter (DAT) studied on rat striatal membranes at 20 degrees C. Addition of NaCl differentially affected the ability of other uptake inhibitors and substrates to block the [3H]mazindol binding. Ratios of 50% inhibiting concentrations calculated for 290 and 90 mM NaCl allowed to distinguish three groups of agents: substrates which were more potent in the presence of 290 mM NaCl (group 1; ratio mazindol, benztropine, nomifensine). However, agents from these three groups recognize mutually exclusive binding sites since in interaction studies the presence of WIN 35,428 (group 2) or mazindol (group 3) increased the 50% inhibiting concentrations of D-amphetamine (group 1) and WIN 35,428 on the [3H]mazindol binding to theoretical values expected for a competition of all of these compounds for the same binding domain on the DAT.

  2. PET/CT imaging of striatal dopamine transporters in a newborn piglet model of hypoxic-ischemic brain injury

    International Nuclear Information System (INIS)

    Zhang Yanfen; Wang Xiaoming; Wang Xiaoyu; Cao Li; Guo Qiyong

    2013-01-01

    Objective: To investigate changes of striatal DAT following hypoxic ischemic (HI) brain injury in newborn piglets using 11 C-N-2-carbomethoxy-3-(4-fluorophenyl)-tropane (CFT) PET/CT, and to evaluate the value of 11 C-CFT PET/CT in brain injury. Methods: Newborn piglets with HI brain injury (n=20) were taken as a model group,and five piglets were used as a control group. Radioligand 11 C-CFT (55.5-74.0 MBq) was injected through the jugular vein, and PET/CT imaging was performed to observe the changes of striatal DAT in newborn piglets. The ST/occipital lobe (OC) ratio was calculated. Model group was divided into 0-6 h, 20-24 h, 44-48 h and 68-72 h sub-groups after HI in accordance with the imaging time. The piglets were sacrificed immediately after 11 C-CFT PET/CT scanning, and then the brains were removed for pathological analysis. Data analysis was performed with one-way analysis of variance and Pearson linear correlation analysis. Results: After intravenous injection of 11 C-CFT, the radioactivity accumulation in cortical, striatum, and cerebellum was shown clearly in the control and model groups. The radioactivity accumulation was lower in the white matter. The radioactivity in cortical and cerebellum exhibited decreased with time, while the striatum was still clear. After HI, the ST/OC activity ratio in the striatum was initially increased, and the ratio of 0-6 h group (1.34 ± 0.04) was statistically significant compared with that of the control group (1.18 ± 0.06; F=4.658, P<0.05), followed by a gradual decrease. ST/OC ratios of other HI subgroups were 1.27 ±0.01, 1.27 ±0.10 and 1.18 ±0.05, respectively. There was a positive correlation between the number of DAT positive neurons ((13 ± 3), (13 ± 4), (8 ±3) and (4 ±4)/high power field) and 11 C-CFT ST/OC activity ratios (r=0.844, P<0.05). Conclusion: 11 C-CFT PET/CT study can accurately reflect the changes of DAT in the striatum, and the amount of DAT is related to the severity of the ischemic insult

  3. Compromised fronto-striatal functioning in HIV: an fMRI investigation of semantic event sequencing.

    Science.gov (United States)

    Melrose, Rebecca J; Tinaz, Sule; Castelo, J Mimi Boer; Courtney, Maureen G; Stern, Chantal E

    2008-04-09

    The human immunodeficiency virus (HIV) damages fronto-striatal regions, and is associated with deficits in executive functioning. We recently developed a semantic event sequencing task based on the Picture Arrangement subtest of the Wechsler Adult Intelligence Scale-III for use with functional magnetic resonance imaging (fMRI) and found recruitment of dorsolateral prefrontal cortex and basal ganglia in healthy participants. To assess the impact of HIV on the functioning of the basal ganglia and prefrontal cortex, we administered this task to 11 HIV+ and 11 Control participants matched for age and education. Neuropsychological evaluation demonstrated that the HIV+ group had mild impairment in memory retrieval and motor functioning, but was not demented. Morphometric measurements suggested no atrophy in basal ganglia regions. The results of the fMRI analysis revealed hypoactivation of the left caudate, left dorsolateral prefrontal cortex, and bilateral ventral prefrontal cortex in the HIV+ group. Functional connectivity analysis demonstrated less functional connectivity between the caudate and prefrontal cortex and basal ganglia regions in the HIV+ group. In contrast, the HIV+ group demonstrated increased activation of right postcentral/supramarginal gyrus, and greater connectivity between the caudate and this same anterior parietal region. The results of this study extend previous investigations by demonstrating compromised function of the caudate and connected prefrontal regions in HIV during cognition. This disruption of fronto-striatal circuitry likely precedes the development of cognitive impairment in HIV.

  4. Plasma functionalized surface of commodity polymers for dopamine detection

    Energy Technology Data Exchange (ETDEWEB)

    Fabregat, Georgina [Departament d’Enginyeria Química, E.T.S. d’Enginyeria Industrial de Barcelona, Universitat Politècnica de Catalunya, Diagonal 647, 08028, Barcelona (Spain); Center for Research in Nano-Engineering, Universitat Politècnica de Catalunya, Campus Sud, Edifici C’, C/Pasqual i Vila s/n, Barcelona, E-08028 (Spain); Osorio, Joaquin [Departament d’Enginyeria Química, E.T.S. d’Enginyeria Industrial de Barcelona, Universitat Politècnica de Catalunya, Diagonal 647, 08028, Barcelona (Spain); Castedo, Alejandra [Center for Research in Nano-Engineering, Universitat Politècnica de Catalunya, Campus Sud, Edifici C’, C/Pasqual i Vila s/n, Barcelona, E-08028 (Spain); Institut de Tècniques Energètiques, E.T.S. d’Enginyeria Industrial de Barcelona, Universitat Politècnica de Catalunya, Diagonal 647, 08028, Barcelona (Spain); Armelin, Elaine [Departament d’Enginyeria Química, E.T.S. d’Enginyeria Industrial de Barcelona, Universitat Politècnica de Catalunya, Diagonal 647, 08028, Barcelona (Spain); Center for Research in Nano-Engineering, Universitat Politècnica de Catalunya, Campus Sud, Edifici C’, C/Pasqual i Vila s/n, Barcelona, E-08028 (Spain); and others

    2017-03-31

    Highlights: • Electrochemically inert polymers become electroactive after plasma functionalization. • Selective dopamine detection has been achieved functionalizing polymers with plasma. • Plasma-functionalized polymers are sensitive dopamine detectors. • XPS analyses reflect the transformation of inert polymers into electrosensors. - Abstract: We have fabricated potentially generalizable sensors based on polymeric-modified electrodes for the electrochemical detection of dopamine. Sensitive and selective sensors have been successfully obtained by applying a cold-plasma treatment during 1–2 min not only to conducting polymers but also to electrochemically inert polymers, such as polyethylene, polypropylene, polyvinylpyrrolidone, polycaprolactone and polystyrene. The effects of the plasma in the electrode surface activation, which is an essential requirement for the dopamine detection when inert polymers are used, have been investigated using X-ray photoelectron spectroscopy. Results indicate that exposure of polymer-modified electrodes to cold-plasma produces the formation of a large variety of reactive species adsorbed on the electrode surface, which catalyse the dopamine oxidation. With this technology, which is based on the application of a very simple physical functionalization, we have defined a paradox-based paradigm for the fabrication of electrochemical sensors by using inert and cheap plastics.

  5. Transcriptional profiling of striatal neurons in response to single or concurrent activation of dopamine D2, adenosine A(2A) and metabotropic glutamate type 5 receptors: focus on beta-synuclein expression.

    Science.gov (United States)

    Canela, Laia; Selga, Elisabet; García-Martínez, Juan Manuel; Amaral, Olavo B; Fernández-Dueñas, Víctor; Alberch, Jordi; Canela, Enric I; Franco, Rafael; Noé, Véronique; Lluís, Carme; Ciudad, Carlos J; Ciruela, Francisco

    2012-10-25

    G protein-coupled receptor oligomerization is a concept which is changing the understanding of classical pharmacology. Both, oligomerization and functional interaction between adenosine A(2A,) dopamine D(2) and metabotropic glutamate type 5 receptors have been demonstrated in the striatum. However, the transcriptional consequences of receptors co-activation are still unexplored. We aim here to determine the changes in gene expression of striatal primary cultured neurons upon isolated or simultaneous receptor activation. Interestingly, we found that 95 genes of the total analyzed (15,866 transcripts and variants) changed their expression in response to simultaneous stimulation of all three receptors. Among these genes, we focused on the β-synuclein (β-Syn) gene (SCNB). Quantitative PCR verified the magnitude and direction of change in expression of SCNB. Since β-Syn belongs to the homologous synuclein family and may be considered a natural regulator of α-synuclein (α-Syn), it has been proposed that β-Syn might act protectively against α-Syn neuropathology. Copyright © 2012 Elsevier B.V. All rights reserved.

  6. Dopamine release in dissociable striatal subregions predicts the different effects of oral methylphenidate on reversal learning and spatial working memory.

    Science.gov (United States)

    Clatworthy, Philip L; Lewis, Simon J G; Brichard, Laurent; Hong, Young T; Izquierdo, David; Clark, Luke; Cools, Roshan; Aigbirhio, Franklin I; Baron, Jean-Claude; Fryer, Timothy D; Robbins, Trevor W

    2009-04-15

    Previous data suggest that methylphenidate can have variable effects on different cognitive tasks both within and between individuals. This is thought to be underpinned by inverted U-shaped relationships between cognitive performance and dopaminergic activity in relatively separate fronto-striatal circuits and reflected by individual differences in trait impulsivity. Direct evidence for this is currently lacking. In this study, we demonstrate for the first time that therapeutic doses of oral methylphenidate administered to young healthy subjects result in different sized changes in D(2)/D(3) receptor availability in different regions of the human striatum and that the change in receptor availability within an individual subregion predicts cognitive performance on a particular task. Methylphenidate produced significantly different effects on reversal learning and spatial working memory tasks within individuals. Performance on the reversal learning task was predicted by the drug-induced change in D(2)/D(3) receptor availability in postcommissural caudate, measured using [(11)C]-raclopride radioligand PET imaging, whereas performance on the spatial working memory task was predicted by changes in receptor availability in the ventral striatum. Reversal learning performance was also predicted by subjects' trait impulsivity, such that the most impulsive individuals benefited more from methylphenidate, consistent with this drug's beneficial effects on cognition in attention deficit hyperactivity disorder.

  7. Adenosine A2A receptors and A2A receptor heteromers as key players in striatal function

    Directory of Open Access Journals (Sweden)

    Sergi eFerre

    2011-06-01

    Full Text Available A very significant density of adenosine adenosine A2A receptors (A2ARs is present in the striatum, where they are preferentially localized postsynaptically in striatopallidal medium spiny neurons (MSNs. In this localization A2ARs establish reciprocal antagonistic interactions with dopamine D2 receptors (D2Rs. In one type of interaction, A2AR and D2R are forming heteromers and, by means of an allosteric interaction, A2AR counteracts D2R-mediated inhibitory modulation of the effects of NMDA receptor stimulation in the striato-pallidal neuron. This interaction is probably mostly responsible for the locomotor depressant and activating effects of A2AR agonist and antagonists, respectively. The second type of interaction involves A2AR and D2R that do not form heteromers and takes place at the level of adenylyl-cyclase (AC. Due to a strong tonic effect of endogenous dopamine on striatal D2R, this interaction keeps A2AR from signaling through AC. However, under conditions of dopamine depletion or with blockade of D2R, A2AR-mediated AC activation is unleashed with an increased gene expression and activity of the striato-pallidal neuron and with a consequent motor depression. This interaction is probably the main mechanism responsible for the locomotor depression induced by D2R antagonists. Finally, striatal A2ARs are also localized presynaptically, in cortico-striatal glutamatergic terminals that contact the striato-nigral MSN. These presynaptic A2ARs heteromerize with A1 receptors (A1Rs and their activation facilitates glutamate release. These three different types of A2ARs can be pharmacologically dissected by their ability to bind ligands with different affinity and can therefore provide selective targets for drug development in different basal ganglia disorders.

  8. Fluorodopa is a Promising Fluorine-19 MRI Probe for Evaluating Striatal Dopaminergic Function in a Rat Model of Parkinson's Disease.

    Science.gov (United States)

    Yanagisawa, Daijiro; Oda, Keisuke; Inden, Masatoshi; Morikawa, Shigehiro; Inubushi, Toshiro; Taniguchi, Takashi; Hijioka, Masanori; Kitamura, Yoshihisa; Tooyama, Ikuo

    2017-07-01

    Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra projecting to the striatum. It has been estimated that approximately 80% of the striatal dopamine and 50% of nigral dopaminergic neurons are lost before the onset of typical motor symptoms, indicating that early diagnosis of PD using noninvasive imaging is feasible. Fluorine-19 ( 19 F) magnetic resonance imaging (MRI) represents a highly sensitive, easily available, low-background, and cost-effective approach to evaluate dopaminergic function using non-radioactive fluorine-containing dopaminergic agents. The aim of this study was to find a potent 19 F MRI probe to evaluate dopaminergic presynaptic function in the striatum. To select candidates for 19 F MRI probes, we investigated the following eight non-radioactive fluorine-containing dopaminergic agents: fluorodopa (F-DOPA), F-tyrosine, haloperidol, GBR13069 duhydrochloride, GBR12909 duhydrochloride, 3-bis-(4-fluorophenyl) methoxytropane hydrochloride, flupenthixol, and fenfluramine. In 19 F nuclear magnetic resonance measurements, F-tyrosine and F-DOPA displayed a relatively higher signal-to-noise ratio value in brain homogenates than in others. F-DOPA, but not F-tyrosine, induced the rotational behavior in a 6-hydroxydopamine (6-OHDA)-induced hemiparkinsonian rat model. In addition, a significantly high amount of F-DOPA accumulated in the ipsilateral striatum of hemiparkinsonian rats after the injection. We performed 19 F MRI in PC12 cells and isolated rat brain using a 7T MR scanner. Our findings suggest that F-DOPA is a promising 19 F MRI probe for evaluating dopaminergic presynaptic function in the striatum of hemiparkinsonian rats. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  9. Presence and function of dopamine transporter (DAT in stallion sperm: dopamine modulates sperm motility and acrosomal integrity.

    Directory of Open Access Journals (Sweden)

    Javier A Urra

    Full Text Available Dopamine is a catecholamine with multiple physiological functions, playing a key role in nervous system; however its participation in reproductive processes and sperm physiology is controversial. High dopamine concentrations have been reported in different portions of the feminine and masculine reproductive tract, although the role fulfilled by this catecholamine in reproductive physiology is as yet unknown. We have previously shown that dopamine type 2 receptor is functional in boar sperm, suggesting that dopamine acts as a physiological modulator of sperm viability, capacitation and motility. In the present study, using immunodetection methods, we revealed the presence of several proteins important for the dopamine uptake and signalling in mammalian sperm, specifically monoamine transporters as dopamine (DAT, serotonin (SERT and norepinephrine (NET transporters in equine sperm. We also demonstrated for the first time in equine sperm a functional dopamine transporter using 4-[4-(Dimethylaminostyryl]-N-methylpyridinium iodide (ASP(+, as substrate. In addition, we also showed that dopamine (1 mM treatment in vitro, does not affect sperm viability but decreases total and progressive sperm motility. This effect is reversed by blocking the dopamine transporter with the selective inhibitor vanoxerine (GBR12909 and non-selective inhibitors of dopamine reuptake such as nomifensine and bupropion. The effect of dopamine in sperm physiology was evaluated and we demonstrated that acrosome integrity and thyrosine phosphorylation in equine sperm is significantly reduced at high concentrations of this catecholamine. In summary, our results revealed the presence of monoamine transporter DAT, NET and SERT in equine sperm, and that the dopamine uptake by DAT can regulate sperm function, specifically acrosomal integrity and sperm motility.

  10. Predicting treatment response in schizophrenia: The role of striatal and frontal dopamine D2/D3 receptor binding potential

    DEFF Research Database (Denmark)

    Nørbak, Henrik; Wulff, Sanne; Nielsen, Mette Ødegaard

    included 25 patients. The ligand [123I]epidepride was used for quantification of extrastriatal dopamine D2/D3 receptors. Patients were randomised to twelve weeks of treatment with either risperidone or zuclopenthixol. Results: In the IBZMcohort the mean PANSS total score was 79 at baseline and 65 at follow...... group (Rho=-0,417 P=0,060). In the EPIcohort the mean PANSS total score was 70 at baseline and 48 at follow up. In the frontal cortex we found a positive correlation (Rho=0.56 P=0.003) between BP and change in positive symptom score for the whole group as well as in the subgroup treated with risperidone...

  11. Variability in Dopamine Genes Dissociates Model-Based and Model-Free Reinforcement Learning.

    Science.gov (United States)

    Doll, Bradley B; Bath, Kevin G; Daw, Nathaniel D; Frank, Michael J

    2016-01-27

    Considerable evidence suggests that multiple learning systems can drive behavior. Choice can proceed reflexively from previous actions and their associated outcomes, as captured by "model-free" learning algorithms, or flexibly from prospective consideration of outcomes that might occur, as captured by "model-based" learning algorithms. However, differential contributions of dopamine to these systems are poorly understood. Dopamine is widely thought to support model-free learning by modulating plasticity in striatum. Model-based learning may also be affected by these striatal effects, or by other dopaminergic effects elsewhere, notably on prefrontal working memory function. Indeed, prominent demonstrations linking striatal dopamine to putatively model-free learning did not rule out model-based effects, whereas other studies have reported dopaminergic modulation of verifiably model-based learning, but without distinguishing a prefrontal versus striatal locus. To clarify the relationships between dopamine, neural systems, and learning strategies, we combine a genetic association approach in humans with two well-studied reinforcement learning tasks: one isolating model-based from model-free behavior and the other sensitive to key aspects of striatal plasticity. Prefrontal function was indexed by a polymorphism in the COMT gene, differences of which reflect dopamine levels in the prefrontal cortex. This polymorphism has been associated with differences in prefrontal activity and working memory. Striatal function was indexed by a gene coding for DARPP-32, which is densely expressed in the striatum where it is necessary for synaptic plasticity. We found evidence for our hypothesis that variations in prefrontal dopamine relate to model-based learning, whereas variations in striatal dopamine function relate to model-free learning. Decisions can stem reflexively from their previously associated outcomes or flexibly from deliberative consideration of potential choice outcomes

  12. Serotonin agonists reduce dopamine synthesis in the striatum only when the impulse flow of nigro-striatal neurons is intact.

    Science.gov (United States)

    Spampinato, U; Esposito, E; Samanin, R

    1985-09-01

    The effects of 5-methoxy-N, N-dimethyltryptamine (5-MeO-DMT) and m-chlorophenylpiperazine (CPP), two 5-hydroxytryptamine (5-HT, serotonin) agonists, on the accumulation of 3,4-dihydroxyphenylalanine (DOPA] were studied in the striatum of rats treated with gamma-butyrolactone (GBL). Unlike 2 mg/kg i.p. apomorphine, neither 5 mg/kg i.p. 5-MeO-DMT nor 2.5 mg/kg i.p. CPP significantly reduced the GBL-induced increase in DOPA accumulation in the striatum. 5-MeO-DMT and CPP significantly reduced DOPA accumulation in animals that had received the aromatic amino acid decarboxylase inhibitor Ro 4-4602 but not GBL. 5-HT (10 micrograms in 0.5 microliter) injected in the substantia nigra, pars compacta, like GBL, significantly increased Ro 4-4602-induced accumulation of DOPA in the striatum. The data indicate that 5-HT agonists can reduce 3,4-dihydroxyphenylethylamine (DA, dopamine) synthesis in the striatum of rats only when the impulse flow of DA neurons is intact. An indirect effect through mechanisms controlling DA synthesis in the striatum, for instance cholinergic and GABA-ergic neurons, is suggested.

  13. Mazindol and amphetamine as inhibitors of the uptake and releasers of 3H-dopamine by rat striatal synaptosomes.

    Science.gov (United States)

    Carruba, M O; Picotti, G B; Zambotti, F; Mantegazza, P

    1977-05-01

    The effects of mazindol, amphetamine and fenfluramine on uptake and release of 3H-DA by synaptosomes were studied in different systems. In in vitro incubations of 3H-DA with synaptosomes isolated from the caudate nucleus of the rat, mazindol inhibited the uptake of the radioactivity more potently than did amphetamine. When the synaptosomes were isolated from the caudate nuclei of rats treated in vivo with either mazindol or amphetamine, the uptake of 3H-DA during in vitro incuation was lower with synaptosomes of amphetamine-treated rats than with those of mazindol-treated rats. When synaptosomes of untreated rats were prelabelled with 3H-DA and incubated in the presence of amphetamine or of mazindol, amphetamine caused a greater release of radioactivity than did mazindol. Fenfluramine was without activity in all these systems. In spite of the quantitative differences, both amphetamine and mazindol appear to have similar effects on uptake and release of dopamine, and this may account for their analogous pharmacological profile.

  14. Striatal and extrastriatal dopamine D2 receptor occupancy by a novel antipsychotic, blonanserin: a PET study with [11C]raclopride and [11C]FLB 457 in schizophrenia.

    Science.gov (United States)

    Tateno, Amane; Arakawa, Ryosuke; Okumura, Masaki; Fukuta, Hajime; Honjo, Kazuyoshi; Ishihara, Keiichi; Nakamura, Hiroshi; Kumita, Shin-ichiro; Okubo, Yoshiro

    2013-04-01

    Blonanserin is a novel antipsychotic with high affinities for dopamine D(2) and 5-HT(2A) receptors, and it was recently approved for the treatment of schizophrenia in Japan and Korea. Although double-blind clinical trials have demonstrated that blonanserin has equal efficacy to risperidone, and with a better profile especially with respect to prolactin elevation, its profile of in vivo receptor binding has not been investigated in patients with schizophrenia. Using positron emission tomography (PET), we measured striatal and extrastriatal dopamine D(2) receptor occupancy by blonanserin in 15 patients with schizophrenia treated with fixed doses of blonanserin (ie, 8, 16, and 24 mg/d) for at least 4 weeks before PET scans, and in 15 healthy volunteers. Two PET scans, 1 with [(11)C]raclopride for the striatum and 1 with [(11)C]FLB 457 for the temporal cortex and pituitary, were performed on the same day. Striatal dopamine D(2) receptor occupancy by blonanserin was 60.8% (3.0%) [mean (SD)] at 8 mg, 73.4% (4.9%) at 16 mg, and 79.7% (2.3%) at 24 mg. The brain/plasma concentration ratio calculated from D(2) receptor occupancy in the temporal cortex and pituitary was 3.38, indicating good blood-brain barrier permeability. This was the first study to show clinical daily dose amounts of blonanserin occupying dopamine D(2) receptors in patients with schizophrenia. The clinical implications obtained in this study were the optimal therapeutic dose range of 12.9 to 22.1 mg/d of blonanserin required for 70% to 80% dopamine D(2) receptor occupancy in the striatum, and the good blood-brain barrier permeability that suggested a relatively lower risk of hyperprolactinemia.

  15. Perineuronal nets play a role in regulating striatal function in the mouse.

    Directory of Open Access Journals (Sweden)

    Hyunchul Lee

    Full Text Available The striatum is the primary input nucleus of the basal ganglia, a collection of nuclei that play important roles in motor control and associative learning. We have previously reported that perineuronal nets (PNNs, aggregations of chondroitin-sulfate proteoglycans (CSPGs, form in the matrix compartment of the mouse striatum during the second postnatal week. This period overlaps with important developmental changes, including the attainment of an adult-like gait. Here, we investigate the identity of the cells encapsulated by PNNs, characterize their topographical distribution and determine their function by assessing the impact of enzymatic digestion of PNNs on two striatum-dependent behaviors: ambulation and goal-directed spatial learning. We show PNNs are more numerous caudally, and that a substantial fraction (41% of these structures surrounds parvalbumin positive (PV+ interneurons, while approximately 51% of PV+ cells are ensheathed by PNNs. The colocalization of these structures is greatest in dorsal, lateral and caudal regions of the striatum. Bilateral digestion of striatal PNNs led to an increase in both the width and variability of hind limb gait. Intriguingly, this also resulted in an improvement in the acquisition rate of the Morris water maze. Together, these data show that PNNs are associated with specific elements of striatal circuits and play a key role in regulating the function of this important structure in the mouse.

  16. Perineuronal nets play a role in regulating striatal function in the mouse.

    Science.gov (United States)

    Lee, Hyunchul; Leamey, Catherine A; Sawatari, Atomu

    2012-01-01

    The striatum is the primary input nucleus of the basal ganglia, a collection of nuclei that play important roles in motor control and associative learning. We have previously reported that perineuronal nets (PNNs), aggregations of chondroitin-sulfate proteoglycans (CSPGs), form in the matrix compartment of the mouse striatum during the second postnatal week. This period overlaps with important developmental changes, including the attainment of an adult-like gait. Here, we investigate the identity of the cells encapsulated by PNNs, characterize their topographical distribution and determine their function by assessing the impact of enzymatic digestion of PNNs on two striatum-dependent behaviors: ambulation and goal-directed spatial learning. We show PNNs are more numerous caudally, and that a substantial fraction (41%) of these structures surrounds parvalbumin positive (PV+) interneurons, while approximately 51% of PV+ cells are ensheathed by PNNs. The colocalization of these structures is greatest in dorsal, lateral and caudal regions of the striatum. Bilateral digestion of striatal PNNs led to an increase in both the width and variability of hind limb gait. Intriguingly, this also resulted in an improvement in the acquisition rate of the Morris water maze. Together, these data show that PNNs are associated with specific elements of striatal circuits and play a key role in regulating the function of this important structure in the mouse.

  17. Optogenetic approaches to evaluate striatal function in animal models of Parkinson disease.

    Science.gov (United States)

    Parker, Krystal L; Kim, Youngcho; Alberico, Stephanie L; Emmons, Eric B; Narayanan, Nandakumar S

    2016-03-01

    Optogenetics refers to the ability to control cells that have been genetically modified to express light-sensitive ion channels. The introduction of optogenetic approaches has facilitated the dissection of neural circuits. Optogenetics allows for the precise stimulation and inhibition of specific sets of neurons and their projections with fine temporal specificity. These techniques are ideally suited to investigating neural circuitry underlying motor and cognitive dysfunction in animal models of human disease. Here, we focus on how optogenetics has been used over the last decade to probe striatal circuits that are involved in Parkinson disease, a neurodegenerative condition involving motor and cognitive abnormalities resulting from degeneration of midbrain dopaminergic neurons. The precise mechanisms underlying the striatal contribution to both cognitive and motor dysfunction in Parkinson disease are unknown. Although optogenetic approaches are somewhat removed from clinical use, insight from these studies can help identify novel therapeutic targets and may inspire new treatments for Parkinson disease. Elucidating how neuronal and behavioral functions are influenced and potentially rescued by optogenetic manipulation in animal models could prove to be translatable to humans. These insights can be used to guide future brain-stimulation approaches for motor and cognitive abnormalities in Parkinson disease and other neuropsychiatric diseases.

  18. Essential Control of the Function of the Striatopallidal Neuron by Pre-coupled Complexes of Adenosine A2A-Dopamine D2 Receptor Heterotetramers and Adenylyl Cyclase

    Directory of Open Access Journals (Sweden)

    Sergi Ferré

    2018-04-01

    Full Text Available The central adenosine system and adenosine receptors play a fundamental role in the modulation of dopaminergic neurotransmission. This is mostly achieved by the strategic co-localization of different adenosine and dopamine receptor subtypes in the two populations of striatal efferent neurons, striatonigral and striatopallidal, that give rise to the direct and indirect striatal efferent pathways, respectively. With optogenetic techniques it has been possible to dissect a differential role of the direct and indirect pathways in mediating “Go” responses upon exposure to reward-related stimuli and “NoGo” responses upon exposure to non-rewarded or aversive-related stimuli, respectively, which depends on their different connecting output structures and their differential expression of dopamine and adenosine receptor subtypes. The striatopallidal neuron selectively expresses dopamine D2 receptors (D2R and adenosine A2A receptors (A2AR, and numerous experiments using multiple genetic and pharmacological in vitro, in situ and in vivo approaches, demonstrate they can form A2AR-D2R heteromers. It was initially assumed that different pharmacological interactions between dopamine and adenosine receptor ligands indicated the existence of different subpopulations of A2AR and D2R in the striatopallidal neuron. However, as elaborated in the present essay, most evidence now indicates that all interactions can be explained with a predominant population of striatal A2AR-D2R heteromers forming complexes with adenylyl cyclase subtype 5 (AC5. The A2AR-D2R heteromer has a tetrameric structure, with two homodimers, which allows not only multiple allosteric interactions between different orthosteric ligands, agonists, and antagonists, but also the canonical Gs-Gi antagonistic interaction at the level of AC5. We present a model of the function of the A2AR-D2R heterotetramer-AC5 complex, which acts as an integrative device of adenosine and dopamine signals that

  19. 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

    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

  20. PET evidence for a role for striatal dopamine in the attentional blink: functional implications

    NARCIS (Netherlands)

    Slagter, H.A.; Tomer, R.; Christian, B.T.; Fox, A.S.; Colzato, L.S.; King, C.R.; Murali, D.; Davidson, R.J.

    2012-01-01

    Our outside world changes continuously, for example, when driving through traffic. An important question is how our brain deals with this constant barrage of rapidly changing sensory input and flexibly selects only newly goal-relevant information for further capacity-limited processing in working

  1. Simultaneous 99mTc and 123I dual-isotope brain striatal phantom single photon emission computed tomography: validation of 99mTc-TRODAT-1 and 123I-IBZM simultaneous dopamine system brain imaging.

    Science.gov (United States)

    Kao, Pan-Fu; Wey, Shiaw-Pyng; Yang, An-Shoei

    2009-11-01

    [2[[2-[[[3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3,2,1]-oct-2-yl]-methyl](2-mercaptoethyl)-amino]ethyl]amino]ethanethiolato(3-)-N2,N2',S2,S2]oxo-[1R-exo-exo)])-[99mTc]-technetium (99mTc-TRODAT-1) and 123I-iodobenzamide (123I-IBZM) are radiotracers for brain dopamine pre- and postsynaptic neuron imaging. The purpose of this study was to evaluate imaging parameters and crossed energy interference using simultaneous single photon emission computed tomography (SPECT) 99mTc and 123I data acquisition. A five-compartment brain striatal phantom was filled with 99mTc and/or 123I radioactive solutions with different striatal-to-background ratios, ranging from 3:1 to 9:1. SPECT data were acquired with energy window settings of 15% for the centered window at 140 keV for 99mTc and a 10% asymmetric window at 159 keV for 123I. The experiments were carried out using either individual (99mTc or 123I only) or both radionuclides. The striatal-to-background ratios and energy crossed interference between 99mTc and 123I were calculated. The phantom SPECT images demonstrated that the energy crossed interferences from 123I to 99mTc, and vice versa, were 22 +/- 12.4% and 0.4 +/- 1.0%, respectively. A net interference of 7.1 +/- 4.0% for the counts in the 15% centered 99mTc window can be expected from 123I and a net interference of 1.6 +/- 3.3% for the counts in the 10% asymmetric 123I window was derived from 99mTc. The correlation of striatal-to-background ratios between single isotope and simultaneous dual-isotope was excellent (R2 = 0.99). The imaging parameters used in this simultaneous dualisotope SPECT imaging could be used in future clinical practice for imaging patients with movement disorders by using 99mTc-TRODAT-1 and 123I-IBZM. The striatal-to-background ratios were not affected by the crossed interference between 99mTc and 123I.

  2. Simultaneous 99mTC and 123I Dual-Isotope Brain Striatal Phantom Single Photon Emission Computed Tomography: Validation of 99mTC-Trodat-1 and 123I-IBZM Simultaneous Dopamine System Brain Imaging

    Directory of Open Access Journals (Sweden)

    Pan-Fu Kao

    2009-11-01

    Full Text Available [2[[2-[[[3-(4-chlorophenyl-8-methyl-8-azabicyclo[3,2,1]-oct-2-yl]-methyl](2-mercaptoethylamino]ethyl]amino]ethanethiolato(3--N2,N2′,S2,S2]oxo-[1R-exo-exo]-[99mTc]-technetium (99mTc-TRODAT-1 and 123I-iodobenzamide (123I-IBZM are radiotracers for brain dopamine preand postsynaptic neuron imaging. The purpose of this study was to evaluate imaging parameters and crossed energy interference using simultaneous single photon emission computed tomography (SPECT 99mTc and 123I data acquisition. A five-compartment brain striatal phantom was filled with 99mTc and/or 123I radioactive solutions with different striatal-to-background ratios, ranging from 3:1 to 9:1. SPECT data were acquired with energy window settings of 15% for the centered window at 140 keV for 99mTc and a 10% asymmetric window at 159 keV for 123I. The experiments were carried out using either individual (99mTc or 123I only or both radionuclides. The striatal-to-background ratios and energy crossed interference between 99mTc and 123I were calculated. The phantom SPECT images demonstrated that the energy crossed interferences from 123I to 99mTc, and vice versa, were 22 ± 12.4% and 0.4 ± 1.0%, respectively. A net interference of 7.1 ± 4.0% for the counts in the 15% centered 99mTc window can be expected from 123I and a net interference of 1.6 ± 3.3% for the counts in the 10% asymmetric 123I window was derived from 99mTc. The correlation of striatal-to-background ratios between single isotope and simultaneous dual-isotope was excellent (R2 = 0.99. The imaging parameters used in this simultaneous dual-isotope SPECT imaging could be used in future clinical practice for imaging patients with movement disorders by using 99mTc-TRODAT-1 and 123I-IBZM. The striatal-to-background ratios were not affected by the crossed interference between 99mTc and 123I.

  3. Transfer functions for protein signal transduction: application to a model of striatal neural plasticity.

    Science.gov (United States)

    Scheler, Gabriele

    2013-01-01

    We present a novel formulation for biochemical reaction networks in the context of protein signal transduction. The model consists of input-output transfer functions, which are derived from differential equations, using stable equilibria. We select a set of "source" species, which are interpreted as input signals. Signals are transmitted to all other species in the system (the "target" species) with a specific delay and with a specific transmission strength. The delay is computed as the maximal reaction time until a stable equilibrium for the target species is reached, in the context of all other reactions in the system. The transmission strength is the concentration change of the target species. The computed input-output transfer functions can be stored in a matrix, fitted with parameters, and even recalled to build dynamical models on the basis of state changes. By separating the temporal and the magnitudinal domain we can greatly simplify the computational model, circumventing typical problems of complex dynamical systems. The transfer function transformation of biochemical reaction systems can be applied to mass-action kinetic models of signal transduction. The paper shows that this approach yields significant novel insights while remaining a fully testable and executable dynamical model for signal transduction. In particular we can deconstruct the complex system into local transfer functions between individual species. As an example, we examine modularity and signal integration using a published model of striatal neural plasticity. The modularizations that emerge correspond to a known biological distinction between calcium-dependent and cAMP-dependent pathways. Remarkably, we found that overall interconnectedness depends on the magnitude of inputs, with higher connectivity at low input concentrations and significant modularization at moderate to high input concentrations. This general result, which directly follows from the properties of individual transfer

  4. Transfer functions for protein signal transduction: application to a model of striatal neural plasticity.

    Directory of Open Access Journals (Sweden)

    Gabriele Scheler

    Full Text Available We present a novel formulation for biochemical reaction networks in the context of protein signal transduction. The model consists of input-output transfer functions, which are derived from differential equations, using stable equilibria. We select a set of "source" species, which are interpreted as input signals. Signals are transmitted to all other species in the system (the "target" species with a specific delay and with a specific transmission strength. The delay is computed as the maximal reaction time until a stable equilibrium for the target species is reached, in the context of all other reactions in the system. The transmission strength is the concentration change of the target species. The computed input-output transfer functions can be stored in a matrix, fitted with parameters, and even recalled to build dynamical models on the basis of state changes. By separating the temporal and the magnitudinal domain we can greatly simplify the computational model, circumventing typical problems of complex dynamical systems. The transfer function transformation of biochemical reaction systems can be applied to mass-action kinetic models of signal transduction. The paper shows that this approach yields significant novel insights while remaining a fully testable and executable dynamical model for signal transduction. In particular we can deconstruct the complex system into local transfer functions between individual species. As an example, we examine modularity and signal integration using a published model of striatal neural plasticity. The modularizations that emerge correspond to a known biological distinction between calcium-dependent and cAMP-dependent pathways. Remarkably, we found that overall interconnectedness depends on the magnitude of inputs, with higher connectivity at low input concentrations and significant modularization at moderate to high input concentrations. This general result, which directly follows from the properties of

  5. Chronic alcohol intake abolishes the relationship between dopamine synthesis capacity and learning signals in the ventral striatum

    DEFF Research Database (Denmark)

    Deserno, Lorenz; Beck, Anne; Huys, Quentin J. M.

    2015-01-01

    -drug-related stimuli towards drug-related stimuli. Such ‘hijacked’ dopamine signals may impair flexible learning from non-drug-related rewards, and thus promote craving for the drug of abuse. Here, we used functional magnetic resonance imaging to measure ventral striatal activation by reward prediction errors (RPEs......Drugs of abuse elicit dopamine release in the ventral striatum, possibly biasing dopamine-driven reinforcement learning towards drug-related reward at the expense of non-drug-related reward. Indeed, in alcohol-dependent patients, reactivity in dopaminergic target areas is shifted from non......) during a probabilistic reversal learning task in recently detoxified alcohol-dependent patients and healthy controls (N = 27). All participants also underwent 6-[18F]fluoro-DOPA positron emission tomography to assess ventral striatal dopamine synthesis capacity. Neither ventral striatal activation...

  6. Dopamine systems adaptation during acquisition and consolidation of a skill

    Directory of Open Access Journals (Sweden)

    Wolfgang H Sommer

    2014-11-01

    Full Text Available The striatum plays a key role in motor learning. Striatal function depends strongly on dopaminergic neurotransmission, but little is known about neuroadaptions of the dopamine system during striatal learning. Using an established task that allows differentiation between acquisition and consolidation of motor learning, we here investigate D1 and D2-like receptor binding and transcriptional levels after initial and long-term training of mice. We found profound reduction in D1 binding within the dorsomedial striatum (DMS after the first training session on the accelerated rotarod and a progressive reduction in D2-like binding within the dorsolateral striatum (DLS after extended training. Given that similar phase- and region-specific striatal neuroadaptations have been found also during learning of complex procedural tasks including habit formation and automatic responding, the here observed neurochemical alterations are important for our understanding of neuropsychiatric disorders that show a dysbalance in the function of striatal circuits, such as in addictive behaviours.

  7. Study on dopamine D{sub 2} binding capacity in vascular parkinsonism

    Energy Technology Data Exchange (ETDEWEB)

    Terashi, Hiroo; Nagata, Ken; Hirata, Yutaka; Hatazawa, Jun [Research Inst. for Brain and Blood Vessels, Akita (Japan); Utsumi, Hiroya [Tokyo Medical Coll. (Japan)

    2001-10-01

    To investigate whether the striatal dopamine receptor function is involved in the development of vascular parkinsonism (VP), a positron emission tomography (PET) study was conducted on 9 patients with VP by using [{sup 11}C] N-methylspiperone as the tracer. The rate of binding availability in the striatal dopamine D{sub 2} receptor (k{sub 3}) was determined semiquantitatively, and the values were compared to the predicted normal values based on the results from 7 normal volunteers. Of 9 patients with VP, the normalized D{sub 2} receptor binding [%k{sub 3}] was more than 90% in 5 patients, 89 to 87% in 3, and 75% in one. These values showed no evident correlation with the Hoehn and Yahr stage. The laterality of the striatal %k{sub 3} did not correspond to that of the parkinsonism. Thus, the striatal dopamine D{sub 2} receptor binding was not severely impaired and did not correlate with the neurological status in patients with VP. This may indicate that striatal dopamine D{sub 2} receptor function is not primarily associated with the development of the parkinsonism in VP. (author)

  8. Endogenous versus exogenous lithium clearance for evaluation of dopamine-induced changes in renal tubular function

    DEFF Research Database (Denmark)

    Olsen, Niels Vidiendal; Fogh-Andersen, N; Strandgaard, S

    1996-01-01

    1. The present randomized, double-blind cross-over study compared endogenous and exogenous lithium clearance (CLi) for estimation of the effect of dopamine on tubular sodium reabsorption. Twelve normal, salt-repleted male subjects were investigated on three different occasions with either placebo...... that the two methods are interchangeable for estimation of dopamine-induced changes in tubular function....

  9. Dopamine transporter-dependent and -independent striatal binding of the benztropine analog JHW 007, a cocaine antagonist with low abuse liability

    Science.gov (United States)

    The benztropine analog JHW 007 displays high affinity for the dopamine transporter (DAT), but unlike typical DAT ligands, has relatively low abuse liability and blocks effects of cocaine,including its self-administration. To determine sites responsible for the cocaine-antagonist effects of JHW 007, ...

  10. Dysregulation of striatal projection neurons in Parkinson's disease.

    Science.gov (United States)

    Beck, Goichi; Singh, Arun; Papa, Stella M

    2018-03-01

    The loss of nigrostriatal dopamine (DA) is the primary cause of motor dysfunction in Parkinson's disease (PD), but the underlying striatal mechanisms remain unclear. In spite of abundant literature portraying structural, biochemical and plasticity changes of striatal projection neurons (SPNs), in the past there has been a data vacuum from the natural human disease and its close model in non-human primates. Recently, single-cell recordings in advanced parkinsonian primates have generated new insights into the altered function of SPNs. Currently, there are also human data that provide direct evidence of profoundly dysregulated SPN activity in PD. Here, we review primate recordings that are impacting our understanding of the striatal dysfunction after DA loss, particularly through the analysis of physiologic correlates of parkinsonian motor behaviors. In contrast to recordings in rodents, data obtained in primates and patients demonstrate similar major abnormalities of the spontaneous SPN firing in the alert parkinsonian state. Furthermore, these studies also show altered SPN responses to DA replacement in the advanced parkinsonian state. Clearly, there is yet much to learn about the striatal discharges in PD, but studies using primate models are contributing unique information to advance our understanding of pathophysiologic mechanisms.

  11. Functional Connectome Analysis of Dopamine Neuron Glutamatergic Connections in Forebrain Regions.

    Science.gov (United States)

    Mingote, Susana; Chuhma, Nao; Kusnoor, Sheila V; Field, Bianca; Deutch, Ariel Y; Rayport, Stephen

    2015-12-09

    In the ventral tegmental area (VTA), a subpopulation of dopamine neurons express vesicular glutamate transporter 2 and make glutamatergic connections to nucleus accumbens (NAc) and olfactory tubercle (OT) neurons. However, their glutamatergic connections across the forebrain have not been explored systematically. To visualize dopamine neuron forebrain projections and to enable photostimulation of their axons independent of transmitter status, we virally transfected VTA neurons with channelrhodopsin-2 fused to enhanced yellow fluorescent protein (ChR2-EYFP) and used DAT(IREScre) mice to restrict expression to dopamine neurons. ChR2-EYFP-expressing neurons almost invariably stained for tyrosine hydroxylase, identifying them as dopaminergic. Dopamine neuron axons visualized by ChR2-EYFP fluorescence projected most densely to the striatum, moderately to the amygdala and entorhinal cortex (ERC), sparsely to prefrontal and cingulate cortices, and rarely to the hippocampus. Guided by ChR2-EYFP fluorescence, we recorded systematically from putative principal neurons in target areas and determined the incidence and strength of glutamatergic connections by activating all dopamine neuron terminals impinging on recorded neurons with wide-field photostimulation. This revealed strong glutamatergic connections in the NAc, OT, and ERC; moderate strength connections in the central amygdala; and weak connections in the cingulate cortex. No glutamatergic connections were found in the dorsal striatum, hippocampus, basolateral amygdala, or prefrontal cortex. These results indicate that VTA dopamine neurons elicit widespread, but regionally distinct, glutamatergic signals in the forebrain and begin to define the dopamine neuron excitatory functional connectome. Dopamine neurons are important for the control of motivated behavior and are involved in the pathophysiology of several major neuropsychiatric disorders. Recent studies have shown that some ventral midbrain dopamine neurons are

  12. Parsing Heterogeneous Striatal Activity

    Directory of Open Access Journals (Sweden)

    Kae Nakamura

    2017-05-01

    Full Text Available The striatum is an input channel of the basal ganglia and is well known to be involved in reward-based decision making and learning. At the macroscopic level, the striatum has been postulated to contain parallel functional modules, each of which includes neurons that perform similar computations to support selection of appropriate actions for different task contexts. At the single-neuron level, however, recent studies in monkeys and rodents have revealed heterogeneity in neuronal activity even within restricted modules of the striatum. Looking for generality in the complex striatal activity patterns, here we briefly survey several types of striatal activity, focusing on their usefulness for mediating behaviors. In particular, we focus on two types of behavioral tasks: reward-based tasks that use salient sensory cues and manipulate outcomes associated with the cues; and perceptual decision tasks that manipulate the quality of noisy sensory cues and associate all correct decisions with the same outcome. Guided by previous insights on the modular organization and general selection-related functions of the basal ganglia, we relate striatal activity patterns on these tasks to two types of computations: implementation of selection and evaluation. We suggest that a parsing with the selection/evaluation categories encourages a focus on the functional commonalities revealed by studies with different animal models and behavioral tasks, instead of a focus on aspects of striatal activity that may be specific to a particular task setting. We then highlight several questions in the selection-evaluation framework for future explorations.

  13. D1 dopamine receptor signaling is modulated by the R7 RGS protein EAT-16 and the R7 binding protein RSBP-1 in Caenoerhabditis elegans motor neurons.

    Directory of Open Access Journals (Sweden)

    Khursheed A Wani

    Full Text Available Dopamine signaling modulates voluntary movement and reward-driven behaviors by acting through G protein-coupled receptors in striatal neurons, and defects in dopamine signaling underlie Parkinson's disease and drug addiction. Despite the importance of understanding how dopamine modifies the activity of striatal neurons to control basal ganglia output, the molecular mechanisms that control dopamine signaling remain largely unclear. Dopamine signaling also controls locomotion behavior in Caenorhabditis elegans. To better understand how dopamine acts in the brain we performed a large-scale dsRNA interference screen in C. elegans for genes required for endogenous dopamine signaling and identified six genes (eat-16, rsbp-1, unc-43, flp-1, grk-1, and cat-1 required for dopamine-mediated behavior. We then used a combination of mutant analysis and cell-specific transgenic rescue experiments to investigate the functional interaction between the proteins encoded by two of these genes, eat-16 and rsbp-1, within single cell types and to examine their role in the modulation of dopamine receptor signaling. We found that EAT-16 and RSBP-1 act together to modulate dopamine signaling and that while they are coexpressed with both D1-like and D2-like dopamine receptors, they do not modulate D2 receptor signaling. Instead, EAT-16 and RSBP-1 act together to selectively inhibit D1 dopamine receptor signaling in cholinergic motor neurons to modulate locomotion behavior.

  14. D1 Dopamine Receptor Signaling Is Modulated by the R7 RGS Protein EAT-16 and the R7 Binding Protein RSBP-1 in Caenoerhabditis elegans Motor Neurons

    Science.gov (United States)

    Wani, Khursheed A.; Catanese, Mary; Normantowicz, Robyn; Herd, Muriel; Maher, Kathryn N.; Chase, Daniel L.

    2012-01-01

    Dopamine signaling modulates voluntary movement and reward-driven behaviors by acting through G protein-coupled receptors in striatal neurons, and defects in dopamine signaling underlie Parkinson's disease and drug addiction. Despite the importance of understanding how dopamine modifies the activity of striatal neurons to control basal ganglia output, the molecular mechanisms that control dopamine signaling remain largely unclear. Dopamine signaling also controls locomotion behavior in Caenorhabditis elegans. To better understand how dopamine acts in the brain we performed a large-scale dsRNA interference screen in C. elegans for genes required for endogenous dopamine signaling and identified six genes (eat-16, rsbp-1, unc-43, flp-1, grk-1, and cat-1) required for dopamine-mediated behavior. We then used a combination of mutant analysis and cell-specific transgenic rescue experiments to investigate the functional interaction between the proteins encoded by two of these genes, eat-16 and rsbp-1, within single cell types and to examine their role in the modulation of dopamine receptor signaling. We found that EAT-16 and RSBP-1 act together to modulate dopamine signaling and that while they are coexpressed with both D1-like and D2-like dopamine receptors, they do not modulate D2 receptor signaling. Instead, EAT-16 and RSBP-1 act together to selectively inhibit D1 dopamine receptor signaling in cholinergic motor neurons to modulate locomotion behavior. PMID:22629462

  15. Evaluation of striatal dopamine transporter density using ({sup 123}I)-{beta}-CIT SPECT in schizophrenic patients treated with olanzapine: pilot study

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Chul Eung; Moon, Hey Won; Choe, Won Sick; Kim, Chang Ho; Chi, Dae Yoon [Inha Univ., Incheon (Korea, Republic of)

    2002-08-01

    This pilot study was performed to understand the pharmacological effect of olanzapine, an atypical antipsychotic agent, on dopamine transporter in schizophrenic patients. Six patients (3 male, 3 female) with schizophrenia, who had not taken any psychotropic drugs for at least four weeks, were studied. Nuclear imaging using ({sup 123}I)-{beta}-CIT SPECT was obtained before and after 4-week treatment with olanzapine. Analysis of ROI on the striatum, caudate nucleus, and putamen was performed. Post-treatment uptake was significantly increased in all the ROIs compared with pre-treatment uptake. This preliminary study with the small number of schizophrenic patients suggested an increase in uptake of dopamine transporter in the striatum, caudate nucleus, and putamen after 4-week treatment with olanzapine, which warrants a large-scaled controlled study to confirm the current findings.

  16. The effects of surgical and chemical lesions on striatal [3H]threo-(+-)-methylphenidate binding: correlation with [3H]dopamine uptake

    International Nuclear Information System (INIS)

    Janowsky, A.; Berger, P.; Long, R.; Paul, S.M.; Schweri, M.M.; Skolnick, P.

    1985-01-01

    The specific binding of [ 3 H]threo-(+-)-methylphenidate to membranes prepared from rat striatum was significantly reduced following either surgical lesions of the medial forebrain bundle or intracerebroventricular administration of 6-hydroxydopamine. The decrease in the density of [ 3 H]threo-(+-)-methylphenidate binding sites in striatum following chemical or surgical denervation was highly correlated with the decrease in [ 3 H]dopamine uptake. In contrast, intracerebroventricular administration of 5,7-dihydroxytryptamine, AF64A, or chronic parenteral administration of reserpine did not alter either the number or apparent affinity of [ 3 H]threo-(+-)-methylphenidate binding sites. These data suggest that the specific binding sites for [ 3 H]threo-(+-)-methylphenidate in striatum are localized to dopaminergic nerve terminals, and may be associated with the dopamine transport complex. (orig.)

  17. α2A- and α2C-Adrenoceptors as Potential Targets for Dopamine and Dopamine Receptor Ligands.

    Science.gov (United States)

    Sánchez-Soto, Marta; Casadó-Anguera, Verònica; Yano, Hideaki; Bender, Brian Joseph; Cai, Ning-Sheng; Moreno, Estefanía; Canela, Enric I; Cortés, Antoni; Meiler, Jens; Casadó, Vicent; Ferré, Sergi

    2018-03-18

    The poor norepinephrine innervation and high density of Gi/o-coupled α 2A - and α 2C -adrenoceptors in the striatum and the dense striatal dopamine innervation have prompted the possibility that dopamine could be an effective adrenoceptor ligand. Nevertheless, the reported adrenoceptor agonistic properties of dopamine are still inconclusive. In this study, we analyzed the binding of norepinephrine, dopamine, and several compounds reported as selective dopamine D 2 -like receptor ligands, such as the D 3 receptor agonist 7-OH-PIPAT and the D 4 receptor agonist RO-105824, to α 2 -adrenoceptors in cortical and striatal tissue, which express α 2A -adrenoceptors and both α 2A - and α 2C -adrenoceptors, respectively. The affinity of dopamine for α 2 -adrenoceptors was found to be similar to that for D 1 -like and D 2 -like receptors. Moreover, the exogenous dopamine receptor ligands also showed high affinity for α 2A - and α 2C -adrenoceptors. Their ability to activate Gi/o proteins through α 2A - and α 2C -adrenoceptors was also analyzed in transfected cells with bioluminescent resonance energy transfer techniques. The relative ligand potencies and efficacies were dependent on the Gi/o protein subtype. Furthermore, dopamine binding to α 2 -adrenoceptors was functional, inducing changes in dynamic mass redistribution, adenylyl cyclase activity, and ERK1/2 phosphorylation. Binding events were further studied with computer modeling of ligand docking. Docking of dopamine at α 2A - and α 2C -adrenoceptors was nearly identical to its binding to the crystallized D 3 receptor. Therefore, we provide conclusive evidence that α 2A - and α 2C -adrenoceptors are functional receptors for norepinephrine, dopamine, and other previously assumed selective D 2 -like receptor ligands, which calls for revisiting previous studies with those ligands.

  18. Levodopa administration modulates striatal processing of punishment-associated items in healthy participants.

    Science.gov (United States)

    Wittmann, Bianca C; D'Esposito, Mark

    2015-01-01

    Appetitive and aversive processes share a number of features such as their relevance for action and learning. On a neural level, reward and its predictors are associated with increased firing of dopaminergic neurons, whereas punishment processing has been linked to the serotonergic system and to decreases in dopamine transmission. Recent data indicate, however, that the dopaminergic system also responds to aversive stimuli and associated actions. In this pharmacological functional magnetic resonance imaging study, we investigated the contribution of the dopaminergic system to reward and punishment processing in humans. Two groups of participants received either placebo or the dopamine precursor levodopa and were scanned during alternating reward and punishment anticipation blocks. Levodopa administration increased striatal activations for cues presented in punishment blocks. In an interaction with individual personality scores, levodopa also enhanced striatal activation for punishment-predictive compared with neutral cues in participants scoring higher on the novelty-seeking dimension. These data support recent indications that dopamine contributes to punishment processing and suggest that the novelty-seeking trait is a measure of susceptibility to drug effects on motivation. These findings are also consistent with the possibility of an inverted U-shaped response function of dopamine in the striatum, suggesting an optimal level of dopamine release for motivational processing.

  19. Dopamine-dependent changes in the functional connectivity between basal ganglia and cerebral cortex in humans

    NARCIS (Netherlands)

    Williams, D; Tijssen, M; van Bruggen, G; Bosch, A; Insola, A; Di Lazzaro, V; Mazzone, P; Oliviero, A; Quartarone, A; Speelman, H; Brown, P

    2002-01-01

    We test the hypothesis that interaction between the human basal ganglia and cerebral cortex involves activity in multiple functional circuits characterized by their frequency of oscillation, phase characteristics, dopamine dependency and topography. To this end we took recordings from

  20. In vivo effects of olanzapine on striatal dopamine D[sub 2]/D[sub 3] receptor binding in schizophrenic patients: an iodine-123 iodobenzamide single-photon emission tomography study

    Energy Technology Data Exchange (ETDEWEB)

    Dresel, S.; Rossmueller, B.; Hahn, K.; Tatsch, K. (Department of Nuclear Medicine, University of Munich (Germany)); Mager, T.; Meisenzahl, E.; Moeller, H.J. (Department of Psychiatry, University of Munich (Germany))

    1999-08-01

    Olanzapine is a new atypical antipsychotic agent that belongs to the same chemical class as clozapine. The pharmacological efficacy of olanzapine (in contrast to that of risperidone) has been shown to be comparable to that of clozapine, but olanzapine has the advantage of producing a less pronounced bone marrow depressing effect than clozapine. The specific aims of this study were (a) to assess dopamine D[sub 2]/D[sub 3] receptor availability in patients treated with olanzapine by means of iodine-123 iodobenzamide [[sup 123]I]IBZM single-photon emission tomography (SPET), (b) to compare the results with findings of [[sup 123]I]IBZM SPET in patients under treatment with risperidone and (c) to correlate the results with the occurrance of extrapyramidal side-effects (EPMS). Brain SPET scans were performed in 20 schizophrenic patients (DSM III R) at 2 h after i.v. administration of 185 MBq [[sup 123]I]IBZM. Images were acquired using a triple-head gamma camera (Picker Prism 3000 XP). For semiquantitative evaluation of D[sub 2]/D[sub 3] receptor binding, transverse slices corrected for attenuation were used to calculate specific uptake values [STR-BKG]/BKG (STR=striatum; BKG=background). The mean daily dose of olanzapine ranged from 0.05 to 0.6 mg/kg body weight. The dopamine D[sub 2]/D[sub 3] receptor binding was reduced in all patients treated with olanzapine. Specific IBZM binding [STR-BKG]/BKG ranged from 0.13 to 0.61 (normal controls >0.95). The decreased D[sub 2]/D[sub 3] receptor availability revealed an exponential dose-response relationship (r=-0.85, P<0.001). The slope of the curve was similar to that of risperidone and considerably higher than that of clozapine as compared with the results of a previously published study. EPMS were observed in only one patient, presenting with the lowest D[sub 2]/D[sub 3] availability. The frequency of EPMS induced by olanzapine (5%) was considerably lower than the frequency under risperidone treatment (40%). Our findings

  1. In vivo effects of olanzapine on striatal dopamine D{sub 2}/D{sub 3} receptor binding in schizophrenic patients: an iodine-123 iodobenzamide single-photon emission tomography study

    Energy Technology Data Exchange (ETDEWEB)

    Dresel, S.; Rossmueller, B.; Hahn, K.; Tatsch, K. [Department of Nuclear Medicine, University of Munich (Germany); Mager, T.; Meisenzahl, E.; Moeller, H.J. [Department of Psychiatry, University of Munich (Germany)

    1999-08-01

    Olanzapine is a new atypical antipsychotic agent that belongs to the same chemical class as clozapine. The pharmacological efficacy of olanzapine (in contrast to that of risperidone) has been shown to be comparable to that of clozapine, but olanzapine has the advantage of producing a less pronounced bone marrow depressing effect than clozapine. The specific aims of this study were (a) to assess dopamine D{sub 2}/D{sub 3} receptor availability in patients treated with olanzapine by means of iodine-123 iodobenzamide [{sup 123}I]IBZM single-photon emission tomography (SPET), (b) to compare the results with findings of [{sup 123}I]IBZM SPET in patients under treatment with risperidone and (c) to correlate the results with the occurrance of extrapyramidal side-effects (EPMS). Brain SPET scans were performed in 20 schizophrenic patients (DSM III R) at 2 h after i.v. administration of 185 MBq [{sup 123}I]IBZM. Images were acquired using a triple-head gamma camera (Picker Prism 3000 XP). For semiquantitative evaluation of D{sub 2}/D{sub 3} receptor binding, transverse slices corrected for attenuation were used to calculate specific uptake values [STR-BKG]/BKG (STR=striatum; BKG=background). The mean daily dose of olanzapine ranged from 0.05 to 0.6 mg/kg body weight. The dopamine D{sub 2}/D{sub 3} receptor binding was reduced in all patients treated with olanzapine. Specific IBZM binding [STR-BKG]/BKG ranged from 0.13 to 0.61 (normal controls >0.95). The decreased D{sub 2}/D{sub 3} receptor availability revealed an exponential dose-response relationship (r=-0.85, P<0.001). The slope of the curve was similar to that of risperidone and considerably higher than that of clozapine as compared with the results of a previously published study. EPMS were observed in only one patient, presenting with the lowest D{sub 2}/D{sub 3} availability. The frequency of EPMS induced by olanzapine (5%) was considerably lower than the frequency under risperidone treatment (40%). Our findings

  2. Surface functionalization of dopamine coated iron oxide nanoparticles for various surface functionalities

    Energy Technology Data Exchange (ETDEWEB)

    Sherwood, Jennifer; Xu, Yaolin; Lovas, Kira [Chemical and Biological Engineering, The University of Alabama, Tuscaloosa , AL 35487 (United States); Qin, Ying [Alabama Innovation and Mentoring of Entrepreneurs, The University of Alabama, Tuscaloosa, AL 35487 (United States); Bao, Yuping, E-mail: ybao@eng.ua.edu [Chemical and Biological Engineering, The University of Alabama, Tuscaloosa , AL 35487 (United States)

    2017-04-01

    We present effective conjugation of four small molecules (glutathione, cysteine, lysine, and Tris(hydroxymethyl)aminomethane) onto dopamine-coated iron oxide nanoparticles. Conjugation of these molecules could improve the surface functionality of nanoparticles for more neutral surface charge at physiological pH and potentially reduce non-specific adsorption of proteins to nanoparticles surfaces. The success of conjugation was evaluated with dynamic light scattering by measuring the surface charge changes and Fourier transform infrared spectroscopy for surface chemistry analysis. The stability of dopamine-coated nanoparticles and the ability of conjugated nanoparticles to reduce the formation of protein corona were evaluated by measuring the size and charge of the nanoparticles in biological medium. This facile conjugation method opens up possibilities for attaching various surface functionalities onto iron oxide nanoparticle surfaces for biomedical applications.

  3. Surface functionalization of dopamine coated iron oxide nanoparticles for various surface functionalities

    International Nuclear Information System (INIS)

    Sherwood, Jennifer; Xu, Yaolin; Lovas, Kira; Qin, Ying; Bao, Yuping

    2017-01-01

    We present effective conjugation of four small molecules (glutathione, cysteine, lysine, and Tris(hydroxymethyl)aminomethane) onto dopamine-coated iron oxide nanoparticles. Conjugation of these molecules could improve the surface functionality of nanoparticles for more neutral surface charge at physiological pH and potentially reduce non-specific adsorption of proteins to nanoparticles surfaces. The success of conjugation was evaluated with dynamic light scattering by measuring the surface charge changes and Fourier transform infrared spectroscopy for surface chemistry analysis. The stability of dopamine-coated nanoparticles and the ability of conjugated nanoparticles to reduce the formation of protein corona were evaluated by measuring the size and charge of the nanoparticles in biological medium. This facile conjugation method opens up possibilities for attaching various surface functionalities onto iron oxide nanoparticle surfaces for biomedical applications.

  4. Is Dopamine an Iatrogenic Disruptor of Thyroid and Cortisol Function in the Extremely Premature Infant?

    Directory of Open Access Journals (Sweden)

    Sze M. Ng

    2014-01-01

    Full Text Available Background. Dopamine is frequently used as an inotropic and vasoactive agent in neonatal intensive care units. Recent studies have reported that treatment with dopamine is associated with hypothyroxinaemia of prematurity. Objectives. The aim of this study was to determine if dopamine treatment in extremely premature infants altered thyroid and cortisol function. Methods. We prospectively measured plasma cortisol, TSH, free T4, total T4, and free triiodothyronine concentrations in babies born below 28 weeks’ gestation within 5 days of birth, who were either treated with dopamine (D+ or who did not receive any dopamine (D− within 12 hours of birth. Clinical Risk Index for Babies scores, lowest mean arterial pressure and highest plasma lactate concentrations in the first 12 hours, were recorded. Results. There were 78 babies included in the study (43 males. Mean gestational age was 25 weeks and 3 days (SD 1.3 weeks. Univariate analyses showed significant differences in cortisol and thyroid function between D+ and D−. Multivariable analyses showed that dopamine, gestation, and CRIB were independent factors affecting FT4 concentrations. No independent factors were shown to affect cortisol or TSH concentrations. Conclusion. Dopamine administration appeared to affect FT4 concentrations but not cortisol concentrations. The mechanisms are unclear but the effect does not appear to be related to hypotension or tissue underperfusion.

  5. Pyrethroid pesticide-induced alterations in dopamine transporter function

    International Nuclear Information System (INIS)

    Elwan, Mohamed A.; Richardson, Jason R.; Guillot, Thomas S.; Caudle, W. Michael; Miller, Gary W.

    2006-01-01

    Parkinson's disease (PD) is a progressive neurodegenerative disease affecting the nigrostriatal dopaminergic pathway. Several epidemiological studies have demonstrated an association between pesticide exposure and the incidence of PD. Studies from our laboratory and others have demonstrated that certain pesticides increase levels of the dopamine transporter (DAT), an integral component of dopaminergic neurotransmission and a gateway for dopaminergic neurotoxins. Here, we report that repeated exposure (3 injections over 2 weeks) of mice to two commonly used pyrethroid pesticides, deltamethrin (3 mg/kg) and permethrin (0.8 mg/kg), increases DAT-mediated dopamine uptake by 31 and 28%, respectively. Using cells stably expressing DAT, we determined that exposure (10 min) to deltamethrin and permethrin (1 nM-100 μM) had no effect on DAT-mediated dopamine uptake. Extending exposures to both pesticides for 30 min (10 μM) or 24 h (1, 5, and 10 μM) resulted in significant decrease in dopamine uptake. This reduction was not the result of competitive inhibition, loss of DAT protein, or cytotoxicity. However, there was an increase in DNA fragmentation, an index of apoptosis, in cells exhibiting reduced uptake at 30 min and 24 h. These data suggest that up-regulation of DAT by in vivo pyrethroid exposure is an indirect effect and that longer-term exposure of cells results in apoptosis. Since DAT can greatly affect the vulnerability of dopamine neurons to neurotoxicants, up-regulation of DAT by deltamethrin and permethrin may increase the susceptibility of dopamine neurons to toxic insult, which may provide insight into the association between pesticide exposure and PD

  6. Altered resting state cortico-striatal connectivity in mild to moderate stage Parkinson’s disease

    Directory of Open Access Journals (Sweden)

    Youngbin Kwak

    2010-09-01

    Full Text Available Parkinson’s disease (PD is a progressive neurodegenerative disorder that is characterized by dopamine depletion in the striatum. One consistent pathophysiological hallmark of PD is an increase in spontaneous oscillatory activity in the basal ganglia thalamocortical networks. We evaluated these effects using resting state functional connectivity MRI (fcMRI in mild to moderate stage Parkinson’s patients on and off L-DOPA and age-matched controls using six different striatal seed regions. We observed an overall increase in the strength of cortico-striatal functional connectivity in PD patients off L-DOPA compared to controls. This enhanced connectivity was down-regulated by L-DOPA as shown by an overall decrease in connectivity strength, particularly within motor cortical regions. We also performed a frequency content analysis of the BOLD signal time course extracted from the six striatal seed regions. PD off L-DOPA exhibited increased power in the frequency band 0.02 – 0.05 Hz compared to controls and to PD on L-DOPA. The L-DOPA associated decrease in the power of this frequency range modulated the L-DOPA associated decrease in connectivity strength between striatal seeds and the thalamus. In addition, the L-DOPA associated decrease in power in this frequency band also correlated with the L-DOPA associated improvement in cognitive performance. Our results demonstrate that PD and L-DOPA modulate striatal resting state BOLD signal oscillations and corticostriatal network coherence.

  7. The Role of Genes, Stress, and Dopamine in the Development of Schizophrenia.

    Science.gov (United States)

    Howes, Oliver D; McCutcheon, Robert; Owen, Michael J; Murray, Robin M

    2017-01-01

    The dopamine hypothesis is the longest standing pathoetiologic theory of schizophrenia. Because it was initially based on indirect evidence and findings in patients with established schizophrenia, it was unclear what role dopamine played in the onset of the disorder. However, recent studies in people at risk of schizophrenia have found elevated striatal dopamine synthesis capacity and increased dopamine release to stress. Furthermore, striatal dopamine changes have been linked to altered cortical function during cognitive tasks, in line with preclinical evidence that a circuit involving cortical projections to the striatum and midbrain may underlie the striatal dopamine changes. Other studies have shown that a number of environmental risk factors for schizophrenia, such as social isolation and childhood trauma, also affect presynaptic dopaminergic function. Advances in preclinical work and genetics have begun to unravel the molecular architecture linking dopamine, psychosis, and psychosocial stress. Included among the many genes associated with risk of schizophrenia are the gene encoding the dopamine D 2 receptor and those involved in the upstream regulation of dopaminergic synthesis, through glutamatergic and gamma-aminobutyric acidergic pathways. A number of these pathways are also linked to the stress response. We review these new lines of evidence and present a model of how genes and environmental factors may sensitize the dopamine system so that it is vulnerable to acute stress, leading to progressive dysregulation and the onset of psychosis. Finally, we consider the implications for rational drug development, in particular regionally selective dopaminergic modulation, and the potential of genetic factors to stratify patients. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  8. Key modulatory role of presynaptic adenosine A2A receptors in cortical neurotransmission to the striatal direct pathway.

    Science.gov (United States)

    Quiroz, César; Luján, Rafael; Uchigashima, Motokazu; Simoes, Ana Patrícia; Lerner, Talia N; Borycz, Janusz; Kachroo, Anil; Canas, Paula M; Orru, Marco; Schwarzschild, Michael A; Rosin, Diane L; Kreitzer, Anatol C; Cunha, Rodrigo A; Watanabe, Masahiko; Ferré, Sergi

    2009-11-18

    Basal ganglia processing results from a balanced activation of direct and indirect striatal efferent pathways, which are controlled by dopamine D1 and D2 receptors, respectively. Adenosine A2A receptors are considered novel antiparkinsonian targets, based on their selective postsynaptic localization in the indirect pathway, where they modulate D2 receptor function. The present study provides evidence for the existence of an additional, functionally significant, segregation of A2A receptors at the presynaptic level. Using integrated anatomical, electrophysiological, and biochemical approaches, we demonstrate that presynaptic A2A receptors are preferentially localized in cortical glutamatergic terminals that contact striatal neurons of the direct pathway, where they exert a selective modulation of corticostriatal neurotransmission. Presynaptic striatal A2A receptors could provide a new target for the treatment of neuropsychiatric disorders.

  9. Key Modulatory Role of Presynaptic Adenosine A2A Receptors in Cortical Neurotransmission to the Striatal Direct Pathway

    Directory of Open Access Journals (Sweden)

    César Quiroz

    2009-01-01

    Full Text Available Basal ganglia processing results from a balanced activation of direct and indirect striatal efferent pathways, which are controlled by dopamine D1 and D2 receptors, respectively. Adenosine A2A receptors are considered novel antiparkinsonian targets, based on their selective postsynaptic localization in the indirect pathway, where they modulate D2 receptor function. The present study provides evidence for the existence of an additional, functionally significant, segregation of A2A receptors at the presynaptic level. Using integrated anatomical, electrophysiological, and biochemical approaches, we demonstrate that presynaptic A2A receptors are preferentially localized in cortical glutamatergic terminals that contact striatal neurons of the direct pathway, where they exert a selective modulation of corticostriatal neurotransmission. Presynaptic striatal A2A receptors could provide a new target for the treatment of neuropsychiatric disorders.

  10. Continuous cerebroventricular administration of dopamine: A new treatment for severe dyskinesia in Parkinson's disease?

    Science.gov (United States)

    Laloux, C; Gouel, F; Lachaud, C; Timmerman, K; Do Van, B; Jonneaux, A; Petrault, M; Garcon, G; Rouaix, N; Moreau, C; Bordet, R; Duce, J A; Devedjian, J C; Devos, D

    2017-07-01

    In Parkinson's disease (PD) depletion of dopamine in the nigro-striatal pathway is a main pathological hallmark that requires continuous and focal restoration. Current predominant treatment with intermittent oral administration of its precursor, Levodopa (l-dopa), remains the gold standard but pharmacological drawbacks trigger motor fluctuations and dyskinesia. Continuous intracerebroventricular (i.c.v.) administration of dopamine previously failed as a therapy because of an inability to resolve the accelerated dopamine oxidation and tachyphylaxia. We aim to overcome prior challenges by demonstrating treatment feasibility and efficacy of continuous i.c.v. of dopamine close to the striatum. Dopamine prepared either anaerobically (A-dopamine) or aerobically (O-dopamine) in the presence or absence of a conservator (sodium metabisulfite, SMBS) was assessed upon acute MPTP and chronic 6-OHDA lesioning and compared to peripheral l-dopa treatment. A-dopamine restored motor function and induced a dose dependent increase of nigro-striatal tyrosine hydroxylase positive neurons in mice after 7days of MPTP insult that was not evident with either O-dopamine or l-dopa. In the 6-OHDA rat model, continuous circadian i.c.v. injection of A-dopamine over 30days also improved motor activity without occurrence of tachyphylaxia. This safety profile was highly favorable as A-dopamine did not induce dyskinesia or behavioral sensitization as observed with peripheral l-dopa treatment. Indicative of a new therapeutic strategy for patients suffering from l-dopa related complications with dyskinesia, continuous i.c.v. of A-dopamine has greater efficacy in mediating motor impairment over a large therapeutic index without inducing dyskinesia and tachyphylaxia. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  11. Impaired dual tasking in Parkinson's disease is associated with reduced focusing of cortico-striatal activity.

    Science.gov (United States)

    Nieuwhof, Freek; Bloem, Bastiaan R; Reelick, Miriam F; Aarts, Esther; Maidan, Inbal; Mirelman, Anat; Hausdorff, Jeffrey M; Toni, Ivan; Helmich, Rick C

    2017-05-01

    See Bell et al. (doi:10.1093/awx063) for a scientific commentary on this article. Impaired dual tasking, namely the inability to concurrently perform a cognitive and a motor task (e.g. 'stops walking while talking'), is a largely unexplained and frequent symptom of Parkinson's disease. Here we consider two circuit-level accounts of how striatal dopamine depletion might lead to impaired dual tasking in patients with Parkinson's disease. First, the loss of segregation between striatal territories induced by dopamine depletion may lead to dysfunctional overlaps between the motor and cognitive processes usually implemented in parallel cortico-striatal circuits. Second, the known dorso-posterior to ventro-anterior gradient of dopamine depletion in patients with Parkinson's disease may cause a funnelling of motor and cognitive processes into the relatively spared ventro-anterior putamen, causing a neural bottleneck. Using functional magnetic resonance imaging, we measured brain activity in 19 patients with Parkinson's disease and 26 control subjects during performance of a motor task (auditory-cued ankle movements), a cognitive task (implementing a switch-stay rule), and both tasks simultaneously (dual task). The distribution of task-related activity respected the known segregation between motor and cognitive territories of the putamen in both groups, with motor-related responses in the dorso-posterior putamen and task switch-related responses in the ventro-anterior putamen. During dual task performance, patients made more motor and cognitive errors than control subjects. They recruited a striatal territory (ventro-posterior putamen) not engaged during either the cognitive or the motor task, nor used by controls. Relatively higher ventro-posterior putamen activity in controls was associated with worse dual task performance. These observations suggest that dual task impairments in Parkinson's disease are related to reduced spatial focusing of striatal activity. This

  12. Dopamine denervation does not alter in vivo 3H-spiperone binding in rat striatum: implications for external imaging of dopamine receptors in Parkinson's disease

    International Nuclear Information System (INIS)

    Bennett, J.P. Jr.; Wooten, G.F.

    1986-01-01

    Striatal particulate preparations, both from rats with lesion-induced striatal dopamine (DA) loss and from some striatal dopamine (DA) loss and from some patients with Parkinson's disease, exhibit increased 3 H-neuroleptic binding, which is interpreted to be the mechanism of denervation-induced behavioral supersensitivity to dopaminergic compounds. After intravenous 3 H-spiperone ( 3 H-SP) administration to rats with unilateral nigral lesions, we found no differences in accumulation of total or particulate-bound 3 H-SP in dopamine-denervated compared with intact striata. 3 H-SP in vivo binds to less than 10% of striatal sites labeled by 3 H-SP incubated with striatal particulate preparations in vitro. Quantitative autoradiography of 3 H-SP binding to striatal sections in vitro also failed to reveal any effects of dopamine denervation. 3 H-SP bound to striatal sites in vivo dissociates more slowly than that bound to striatal particulate preparations labeled in vitro. Striatal binding properties of 3 H-SP administered in vivo are quite different from the same kinetic binding parameters estimated in vitro using crude membrane preparations of striatum. In addition, striatal binding of in vivo-administered 3H-SP is not affected by prior lesion of the substantia nigra, which results in profound ipsilateral striatal dopamine depletion. Thus, behavioral supersensitivity to dopaminergic compounds may not be associated with altered striatal binding properties for dopamine receptor ligands in vivo

  13. Alterations in dopamine system function across the estrous cycle of the MAM rodent model of schizophrenia.

    Science.gov (United States)

    Perez, Stephanie M; Chen, Li; Lodge, Daniel J

    2014-09-01

    Clinical studies have reported differences in the incidence and severity of schizophrenia symptoms between male and female schizophrenia patients. Unfortunately, the cause of these differences is not currently known due, in part, to the fact that preclinical studies largely focus on male subjects. Dopamine neuron activity has been previously demonstrated to change across the estrous cycle, and may therefore be of relevance, as aberrant dopamine signaling is thought to underlie the positive symptoms of schizophrenia. Here we examine dopamine neuron activity across the estrous cycle in the MAM rodent model of schizophrenia. We demonstrate that the elevation in dopamine neuron activity, consistently observed in male MAM-treated rats, is most prominent during estrus and attenuated in met-estrus. Furthermore, this appears to be mediated, in part, by progesterone in the ventral hippocampus, as increases in dopamine neuron population activity (observed in estrus) were normalized by the intra-hippocampal administration of the progesterone receptor antagonist, mifepristone (but not the estrogen receptor antagonists, fulvestrant). Taken together, these data suggest that changes in dopamine system function occur across the estrous cycle in MAM-treated rats and may contribute to the differences in symptomatology between male and female schizophrenia patients. Copyright © 2014 Elsevier Ltd. All rights reserved.

  14. Altered Functional Connectivity of Fronto-Cingulo-Striatal Circuits during Error Monitoring in Adolescents with a History of Childhood Abuse

    Science.gov (United States)

    Hart, Heledd; Lim, Lena; Mehta, Mitul A.; Curtis, Charles; Xu, Xiaohui; Breen, Gerome; Simmons, Andrew; Mirza, Kah; Rubia, Katya

    2018-01-01

    Childhood maltreatment is associated with error hypersensitivity. We examined the effect of childhood abuse and abuse-by-gene (5-HTTLPR, MAOA) interaction on functional brain connectivity during error processing in medication/drug-free adolescents. Functional connectivity was compared, using generalized psychophysiological interaction (gPPI) analysis of functional magnetic resonance imaging (fMRI) data, between 22 age- and gender-matched medication-naïve and substance abuse-free adolescents exposed to severe childhood abuse and 27 healthy controls, while they performed an individually adjusted tracking stop-signal task, designed to elicit 50% inhibition failures. During inhibition failures, abused participants relative to healthy controls exhibited reduced connectivity between right and left putamen, bilateral caudate and anterior cingulate cortex (ACC), and between right supplementary motor area (SMA) and right inferior and dorsolateral prefrontal cortex. Abuse-related connectivity abnormalities were associated with longer abuse duration. No group differences in connectivity were observed for successful inhibition. The findings suggest that childhood abuse is associated with decreased functional connectivity in fronto-cingulo-striatal networks during error processing. Furthermore that the severity of connectivity abnormalities increases with abuse duration. Reduced connectivity of error detection networks in maltreated individuals may be linked to constant monitoring of errors in order to avoid mistakes which, in abusive contexts, are often associated with harsh punishment. PMID:29434543

  15. Dopamine transporter polymorphism modulates oculomotor function and DAT1 mRNA expression in schizophrenia.

    Science.gov (United States)

    Wonodi, Ikwunga; Hong, L Elliot; Stine, O Colin; Mitchell, Braxton D; Elliott, Amie; Roberts, Rosalinda C; Conley, Robert R; McMahon, Robert P; Thaker, Gunvant K

    2009-03-05

    Smooth pursuit eye movement (SPEM) deficit is an established schizophrenia endophenotype with a similar neurocognitive construct to working memory. Frontal eye field (FEF) neurons controlling SPEM maintain firing when visual sensory information is removed, and their firing rates directly correlate with SPEM velocity. We previously demonstrated a paradoxical association between a functional polymorphism of dopamine signaling (COMT gene) and SPEM. Recent evidence implicates the dopamine transporter gene (DAT1) in modulating cortical dopamine and associated neurocognitive functions. We hypothesized that DAT1 10/10 genotype, which reduces dopamine transporter expression and increases extracellular dopamine, would affect SPEM. We examined the effects of DAT1 genotype on: Clinical diagnosis in the study sample (n = 418; 190 with schizophrenia), SPEM measures in a subgroup with completed oculomotor measures (n = 200; 87 schizophrenia), and DAT1 gene expression in FEF tissue obtained from postmortem brain samples (n = 32; 16 schizophrenia). DAT1 genotype was not associated with schizophrenia. DAT1 10/10 genotype was associated with better SPEM in healthy controls, intermediate SPEM in unaffected first-degree relatives of schizophrenia subjects, and worse SPEM in schizophrenia subjects. In the gene expression study, DAT1 10/10 genotype was associated with significantly reduced DAT1 mRNA transcript in FEF tissue from healthy control donors (P < 0.05), but higher expression in schizophrenia donors. Findings suggest regulatory effects of another gene(s) or etiological factor in schizophrenia, which modulate DAT1 gene function. 2008 Wiley-Liss, Inc.

  16. Neuroglial plasticity at striatal glutamatergic synapses in Parkinson's disease

    Directory of Open Access Journals (Sweden)

    Rosa M Villalba

    2011-08-01

    Full Text Available Striatal dopamine denervation is the pathological hallmark of Parkinson’s disease (PD. Another major pathological change described in animal models and PD patients is a significant reduction in the density of dendritic spines on medium spiny striatal projection neurons. Simultaneously, the ultrastructural features of the neuronal synaptic elements at the remaining corticostriatal and thalamostriatal glutamatergic axo-spinous synapses undergo complex ultrastructural remodeling consistent with increased synaptic activity (Villalba et al., 2011. The concept of tripartite synapses (TS was introduced a decade ago, according to which astrocytes process and exchange information with neuronal synaptic elements at glutamatergic synapses (Araque et al., 1999a. Although there has been compelling evidence that astrocytes are integral functional elements of tripartite glutamatergic synaptic complexes in the cerebral cortex and hippocampus, their exact functional role, degree of plasticity and preponderance in other CNS regions remain poorly understood. In this review, we discuss our recent findings showing that neuronal elements at cortical and thalamic glutamatergic synapses undergo significant plastic changes in the striatum of MPTP-treated parkinsonian monkeys. We also present new ultrastructural data that demonstrate a significant expansion of the astrocytic coverage of striatal TS synapses in the parkinsonian state, providing further evidence for ultrastructural compensatory changes that affect both neuronal and glial elements at TS. Together with our limited understanding of the mechanisms by which astrocytes respond to changes in neuronal activity and extracellular transmitter homeostasis, the role of both neuronal and glial components of excitatory synapses must be considered, if one hopes to take advantage of glia-neuronal communication knowledge to better understand the pathophysiology of striatal processing in parkinsonism, and develop new PD

  17. Delta-9-tetrahydrocannabinol-induced dopamine release as a function of psychosis risk: 18F-fallypride positron emission tomography study.

    Directory of Open Access Journals (Sweden)

    Rebecca Kuepper

    Full Text Available Cannabis use is associated with psychosis, particularly in those with expression of, or vulnerability for, psychotic illness. The biological underpinnings of these differential associations, however, remain largely unknown. We used Positron Emission Tomography and (18F-fallypride to test the hypothesis that genetic risk for psychosis is expressed by differential induction of dopamine release by Δ(9-THC (delta-9-tetrahydrocannabinol, the main psychoactive ingredient of cannabis. In a single dynamic PET scanning session, striatal dopamine release after pulmonary administration of Δ(9-THC was measured in 9 healthy cannabis users (average risk psychotic disorder, 8 patients with psychotic disorder (high risk psychotic disorder and 7 un-related first-degree relatives (intermediate risk psychotic disorder. PET data were analyzed applying the linear extension of the simplified reference region model (LSRRM, which accounts for time-dependent changes in (18F-fallypride displacement. Voxel-based statistical maps, representing specific D2/3 binding changes, were computed to localize areas with increased ligand displacement after Δ(9-THC administration, reflecting dopamine release. While Δ(9-THC was not associated with dopamine release in the control group, significant ligand displacement induced by Δ(9-THC in striatal subregions, indicative of dopamine release, was detected in both patients and relatives. This was most pronounced in caudate nucleus. This is the first study to demonstrate differential sensitivity to Δ(9-THC in terms of increased endogenous dopamine release in individuals at risk for psychosis.

  18. Renal hemodynamics, tubular function, and response to low-dose dopamine during acute hypoxia in humans

    DEFF Research Database (Denmark)

    Olsen, Niels Vidiendal; Hansen, J M; Kanstrup, I L

    1993-01-01

    Renal function was investigated in eight normal subjects before and during infusion of dopamine (3 micrograms.kg-1 x min-1) at sea level (SL) and at high altitude (HA, 4,350 m). Lithium clearance (CLi) was used as an index of proximal tubular outflow. HA significantly increased arterial pressure...... unaltered, suggesting that natriuresis in both environments was secondary to an increased outflow from the proximal tubules. The absence of a diuretic response to dopamine at HA seemed to be caused by an effect on distal tubular function....

  19. Striatal functional connectivity changes following specific balance training in elderly people: MRI results of a randomized controlled pilot study.

    Science.gov (United States)

    Magon, Stefano; Donath, Lars; Gaetano, Laura; Thoeni, Alain; Radue, Ernst-Wilhelm; Faude, Oliver; Sprenger, Till

    2016-09-01

    Practice-induced effects of specific balance training on brain structure and activity in elderly people are largely unknown. In the present study, we investigated morphological and functional brain changes following slacking training (balancing over nylon ribbons) in a group of elderly people. Twenty-eight healthy volunteers were recruited and randomly assigned to the intervention (mean age: 62.3±5.4years) or control group (mean age: 61.8±5.3years). The intervention group completed six-weeks of slackline training. Brain morphological changes were investigated using voxel-based morphometry and functional connectivity changes were computed via independent component analysis and seed-based analyses. All analyses were applied to the whole sample and to a subgroup of participants who improved in slackline performance. The repeated measures analysis of variance showed a significant interaction effect between groups and sessions. Specifically, the Tukey post-hoc analysis revealed a significantly improved slackline standing performance after training for the left leg stance time (pre: 4.5±3.6s vs. 26.0±30.0s, pslackline performance showed a decrease of connectivity between the striatum and other brain areas during the training period. These preliminary results suggest that improved balance performance with slackline training goes along with an increased efficiency of the striatal network. Copyright © 2016 Elsevier B.V. All rights reserved.

  20. Drug induced increases in CNS dopamine alter monocyte, macrophage and T cell functions: implications for HAND

    Science.gov (United States)

    Gaskill, Peter J.; Calderon, Tina M.; Coley, Jacqueline S.; Berman, Joan W.

    2013-01-01

    Central nervous system (CNS) complications resulting from HIV infection remain a major public health problem as individuals live longer due to the success of combined antiretroviral therapy (cART). As many as 70% of HIV infected people have HIV associated neurocognitive disorders (HAND). Many HIV infected individuals abuse drugs, such as cocaine, heroin or methamphetamine, that may be important cofactors in the development of HIV CNS disease. Despite different mechanisms of action, all drugs of abuse increase extracellular dopamine in the CNS. The effects of dopamine on HIV neuropathogenesis are not well understood, and drug induced increases in CNS dopamine may be a common mechanism by which different types of drugs of abuse impact the development of HAND. Monocytes and macrophages are central to HIV infection of the CNS and to HAND. While T cells have not been shown to be a major factor in HIV-associated neuropathogenesis, studies indicate that T cells may play a larger role in the development of HAND in HIV infected drug abusers. Drug induced increases in CNS dopamine may dysregulate functions of, or increase HIV infection in, monocytes, macrophages and T cells in the brain. Thus, characterizing the effects of dopamine on these cells is important for understanding the mechanisms that mediate the development of HAND in drug abusers. PMID:23456305

  1. Reduced striatal D2 receptor binding in myoclonus-dystonia

    International Nuclear Information System (INIS)

    Beukers, R.J.; Weisscher, N.; Tijssen, M.A.J.; Booij, J.; Zijlstra, F.; Amelsvoort, T.A.M.J. van

    2009-01-01

    To study striatal dopamine D 2 receptor availability in DYT11 mutation carriers of the autosomal dominantly inherited disorder myoclonus-dystonia (M-D). Fifteen DYT11 mutation carriers (11 clinically affected) and 15 age- and sex-matched controls were studied using 123 I-IBZM SPECT. Specific striatal binding ratios were calculated using standard templates for striatum and occipital areas. Multivariate analysis with corrections for ageing and smoking showed significantly lower specific striatal to occipital IBZM uptake ratios (SORs) both in the left and right striatum in clinically affected patients and also in all DYT11 mutation carriers compared to control subjects. Our findings are consistent with the theory of reduced dopamine D 2 receptor (D2R) availability in dystonia, although the possibility of increased endogenous dopamine, and consequently, competitive D2R occupancy cannot be ruled out. (orig.)

  2. Differential effects of a selective dopamine D1-like receptor agonist on motor activity and c-fos expression in the frontal-striatal circuitry of SHR and Wistar-Kyoto rats.

    Science.gov (United States)

    Diaz Heijtz, Rochellys; Castellanos, F Xavier

    2006-05-26

    Molecular genetic studies suggest the dopamine D1 receptor (D1R) may be implicated in attention-deficit/hyperactivity disorder (ADHD). As little is known about the potential motor role of D1R in ADHD, animal models may provide important insights into this issue. We investigated the effects of a full and selective D1R agonist, SKF-81297 (0.3, 3 and 10 mg/kg), on motor behaviour and expression of the plasticity-associated gene, c-fos, in habituated young adult male Spontaneously Hypertensive Rats (SHR), the most commonly used animal model of ADHD, and Wistar-Kyoto (WKY; the strain from which SHR were derived). SHR rats were more behaviourally active than WKY rats after injection with vehicle. The 0.3 mg/kg dose of SKF-81297 increased motor behaviour (locomotion, sifting, rearing, and sniffing) in both SHR and WKY rats. Total grooming was also stimulated, but only in WKY rats. The same dose increased c-fos mRNA expression in the piriform cortex of both strains. The 3 mg/kg dose increased sifting and sniffing in both strains. Locomotion was also stimulated towards the end of the testing period. The intermediate dose decreased total rearing in both strains, and produced a significant increase in c-fos mRNA in the striatum, nucleus accumbens, olfactory tuberculum, and in the cingulate, agranular insular and piriform cortices. The 10 mg/kg dose of SKF-81297 produced a biphasic effect on locomotion, which was characterized by an initial decrease followed by later stimulation. The latter stimulatory effect was more pronounced in SHR than in WKY rats when compared to their respective vehicle-injected groups. The 10 mg/kg dose also stimulated sifting and sniffing in both strains. Both the 3 and 10 mg/kg doses had no effect on total grooming. The 10 mg/kg dose induced significantly higher levels of c-fos mRNA expression in the nucleus accumbens and adjacent cortical regions (but not striatum) of SHR when compared to WKY rats. The present results suggest a potential alteration

  3. Anhedonia, Reduced Cocaine Reward, and Dopamine Dysfunction in a Rat Model of Posttraumatic Stress Disorder.

    Science.gov (United States)

    Enman, Nicole M; Arthur, Kayti; Ward, Sara J; Perrine, Shane A; Unterwald, Ellen M

    2015-12-15

    Posttraumatic stress disorder (PTSD) co-occurs with substance use disorders at high rates, but the neurobiological basis of this relationship is largely unknown. PTSD and drug addiction each involve dysregulation of brain reward circuitry; therefore, the identification of pathology of the mesolimbic dopamine system may aid in understanding their functional relationship. Dopamine reward dysfunction also may be relevant to the mechanisms underlying the PTSD symptoms of anhedonia and emotional numbing. Single-prolonged stress (SPS) was used as a rat model of PTSD, and a series of behavioral and neuropharmacologic assays were applied to assess the impact of SPS on reward, cocaine intake, and components of the striatal dopamine system. Exposure to SPS increased anhedonia-like behaviors and decreased the rewarding properties of cocaine compared with control handling. Altered cocaine intake during extended access self-administration sessions was observed in rats exposed to SPS, further suggesting a difference in the reinforcing properties of cocaine following severe stress. SPS reduced tissue content of dopamine and its metabolites in the striatum, as well as altered striatal dopamine transporter and D2, but not D1, receptor densities. These results support a role for altered dopaminergic transmission in reduced reward function in PTSD. Pathology of the dopamine system and the degradation of reward processes may contribute to PTSD symptomology and have implications for co-occurring psychiatric disorders such as substance abuse or depression. Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  4. Dysfunction and dysconnection in cortical-striatal networks during sustained attention: Genetic risk for schizophrenia or bipolar disorder and its impact on brain network function

    Directory of Open Access Journals (Sweden)

    Vaibhav A. Diwadkar

    2014-05-01

    Full Text Available Abnormalities in the brain’s attention network may represent early identifiable neurobiological impairments in individuals at increased risk for schizophrenia or bipolar disorder. Here we provide evidence of dysfunctional regional and network function in adolescents at higher genetic risk for schizophrenia or bipolar disorder (henceforth HGR. During fMRI, participants engaged in a sustained attention task with variable demands. The task alternated between attention (120 s, visual control (passive viewing; 120 s and rest (20 s epochs. Low and high demand attention conditions were created using the rapid presentation of 2- or 3-digit numbers. Subjects were required to detect repeated presentation of numbers. We demonstrate that the recruitment of cortical and striatal regions are disordered in HGR: Relative to typical controls (TC, HGR showed lower recruitment of the dorsal prefrontal cortex, but higher recruitment of the superior parietal cortex. This imbalance was more dramatic in the basal ganglia. There, a group by task demand interaction was observed, such that increased attention demand led to increased engagement in TC, but disengagement in HGR. These activation studies were complemented by network analyses using Dynamic Causal Modeling. Competing model architectures were assessed across a network of cortical-striatal regions, distinguished at a second level using random effects Bayesian model selection. In the winning architecture, HGR were characterized by significant reductions in coupling across both frontal-striatal and frontal-parietal pathways. The effective connectivity analyses indicate emergent network dysconnection, consistent with findings in patients with schizophrenia. Emergent patterns of regional dysfunction and disconnection in cortical-striatal pathways may provide functional biological signatures in the adolescent risk state for psychiatric illness.

  5. Human Dopamine Receptors Interaction Network (DRIN): a systems biology perspective on topology, stability and functionality of the network.

    Science.gov (United States)

    Podder, Avijit; Jatana, Nidhi; Latha, N

    2014-09-21

    Dopamine receptors (DR) are one of the major neurotransmitter receptors present in human brain. Malfunctioning of these receptors is well established to trigger many neurological and psychiatric disorders. Taking into consideration that proteins function collectively in a network for most of the biological processes, the present study is aimed to depict the interactions between all dopamine receptors following a systems biology approach. To capture comprehensive interactions of candidate proteins associated with human dopamine receptors, we performed a protein-protein interaction network (PPIN) analysis of all five receptors and their protein partners by mapping them into human interactome and constructed a human Dopamine Receptors Interaction Network (DRIN). We explored the topology of dopamine receptors as molecular network, revealing their characteristics and the role of central network elements. More to the point, a sub-network analysis was done to determine major functional clusters in human DRIN that govern key neurological pathways. Besides, interacting proteins in a pathway were characterized and prioritized based on their affinity for utmost drug molecules. The vulnerability of different networks to the dysfunction of diverse combination of components was estimated under random and direct attack scenarios. To the best of our knowledge, the current study is unique to put all five dopamine receptors together in a common interaction network and to understand the functionality of interacting proteins collectively. Our study pinpointed distinctive topological and functional properties of human dopamine receptors that have helped in identifying potential therapeutic drug targets in the dopamine interaction network. Copyright © 2014 Elsevier Ltd. All rights reserved.

  6. Distinct roles for direct and indirect pathway striatal neurons in reinforcement.

    Science.gov (United States)

    Kravitz, Alexxai V; Tye, Lynne D; Kreitzer, Anatol C

    2012-06-01

    Dopamine signaling is implicated in reinforcement learning, but the neural substrates targeted by dopamine are poorly understood. We bypassed dopamine signaling itself and tested how optogenetic activation of dopamine D1 or D2 receptor–expressing striatal projection neurons influenced reinforcement learning in mice. Stimulating D1 receptor–expressing neurons induced persistent reinforcement, whereas stimulating D2 receptor–expressing neurons induced transient punishment, indicating that activation of these circuits is sufficient to modify the probability of performing future actions.

  7. Functional circuit mapping of striatal output nuclei using simultaneous deep brain stimulation and fMRI.

    Science.gov (United States)

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

    2017-02-01

    The substantia nigra pars reticulata (SNr) and external globus pallidus (GPe) constitute the two major output targets of the rodent striatum. Both the SNr and GPe converge upon thalamic relay nuclei (directly or indirectly, respectively), and are traditionally modeled as functionally antagonistic relay inputs. However, recent anatomical and functional studies have identified unanticipated circuit connectivity in both the SNr and GPe, demonstrating their potential as far more than relay nuclei. In the present study, we employed simultaneous deep brain stimulation and functional magnetic resonance imaging (DBS-fMRI) with cerebral blood volume (CBV) measurements to functionally and unbiasedly map the circuit- and network level connectivity of the SNr and GPe. Sprague-Dawley rats were implanted with a custom-made MR-compatible stimulating electrode in the right SNr (n=6) or GPe (n=7). SNr- and GPe-DBS, conducted across a wide range of stimulation frequencies, revealed a number of surprising evoked responses, including unexpected CBV decreases within the striatum during DBS at either target, as well as GPe-DBS-evoked positive modulation of frontal cortex. Functional connectivity MRI revealed global modulation of neural networks during DBS at either target, sensitive to stimulation frequency and readily reversed following cessation of stimulation. This work thus contributes to a growing literature demonstrating extensive and unanticipated functional connectivity among basal ganglia nuclei. Copyright © 2016 Elsevier Inc. All rights reserved.

  8. Beyond the Dopamine Receptor: Regulation and Roles of Serine/Threonine Protein Phosphatases

    Directory of Open Access Journals (Sweden)

    Sven I Walaas

    2011-08-01

    Full Text Available Dopamine plays an important modulatory role in the central nervous system, helping to control critical aspects of motor function and reward learning. Alteration in normal dopaminergic neurotransmission underlies multiple neurological diseases including schizophrenia, Huntington's disease and Parkinson's disease. Modulation of dopamine-regulated signaling pathways is also important in the addictive actions of most drugs of abuse. Our studies over the last 30 years have focused on the molecular actions of dopamine acting on medium spiny neurons, the predominant neurons of the neostriatum. Striatum-enriched phosphoproteins, particularly DARPP-32, RCS (Regulator of Calmodulin Signaling and ARPP-16, mediate pleiotropic actions of dopamine. Notably, each of these proteins, either directly or indirectly, regulates the activity of one of the three major subclasses of serine/threonine protein phosphatases, PP1, PP2B and PP2A, respectively. For example, phosphorylation of DARPP-32 at Thr34 by protein kinase A results in potent inhibition of PP1, leading to potentiation of dopaminergic signaling at multiple steps from the dopamine receptor to the nucleus. The discovery of DARPP-32 and its emergence as a critical molecular integrator of striatal signaling will be discussed, as will more recent studies that highlight novel roles for RCS and ARPP-16 in dopamine-regulated striatal signaling pathways.

  9. GDNF control of the glutamatergic cortico-striatal pathway requires tonic activation of adenosine A2A Receptors

    Science.gov (United States)

    Gomes, Catarina A.R.V.; Simões, Patrícia F.; Canas, Paula M.; Quiroz, César; Sebastião, Ana M.; Ferré, Sergi; Cunha, Rodrigo A.; Ribeiro, Joaquim A.

    2009-01-01

    Glial cell line-derived neurotrophic factor (GDNF) affords neuroprotection in Parkinson’s disease in accordance with its ability to bolster nigrostriatal innervation. We previously found that GDNF facilitates dopamine release in a manner dependent on adenosine A2A receptor activation. Since motor dysfunction also involves modifications of striatal glutamatergic innervation, we now tested if GDNF and its receptor system, Ret (rearranged during transfection) and GFRα1 (GDNF family receptor alpha 1) controlled the cortico-striatal glutamatergic pathway in an A2A receptor-dependent manner. GDNF (10 ng/ml) enhanced (by ≈13%) glutamate release from rat striatal nerve endings, an effect potentiated (up to ≈ 30%) by the A2A receptor agonist CGS 21680 (10 nM) and prevented by the A2A receptor antagonist, SCH 58261 (50 nM). Triple immunocytochemical studies revealed that Ret and GFRα1 were located in 50% of rat striatal glutamatergic terminals (immunopositive for vesicular glutamate transporters-1/2), where they were found to be co-located with A2A receptors. Activation of the glutamatergic system upon in vivo electrical stimulation of the rat cortico-striatal input induced striatal Ret phosphoprylation that was prevented by pre-treatment with the A2A receptor antagonist, MSX-3 (3 mg/kg). The results provide the first functional and morphological evidence that GDNF controls cortico-striatal glutamatergic pathways in a manner largely dependent on the co-activation of adenosine A2A receptors. PMID:19141075

  10. Cannabidiol is a partial agonist at dopamine D2High receptors, predicting its antipsychotic clinical dose.

    Science.gov (United States)

    Seeman, P

    2016-10-18

    Although all current antipsychotics act by interfering with the action of dopamine at dopamine D2 receptors, two recent reports showed that 800 to 1000 mg of cannabidiol per day alleviated the signs and symptoms of schizophrenia, although cannabidiol is not known to act on dopamine receptors. Because these recent clinical findings may indicate an important exception to the general rule that all antipsychotics interfere with dopamine at dopamine D2 receptors, the present study examined whether cannabidiol acted directly on D2 receptors, using tritiated domperidone to label rat brain striatal D2 receptors. It was found that cannabidiol inhibited the binding of radio-domperidone with dissociation constants of 11 nm at dopamine D2High receptors and 2800 nm at dopamine D2Low receptors, in the same biphasic manner as a dopamine partial agonist antipsychotic drug such as aripiprazole. The clinical doses of cannabidiol are sufficient to occupy the functional D2High sites. it is concluded that the dopamine partial agonist action of cannabidiol may account for its clinical antipsychotic effects.

  11. Selective augmentation of striatal functional connectivity following NMDA receptor antagonism: implications for psychosis.

    Science.gov (United States)

    Dandash, Orwa; Harrison, Ben J; Adapa, Ram; Gaillard, Raphael; Giorlando, Francesco; Wood, Stephen J; Fletcher, Paul C; Fornito, Alex

    2015-02-01

    The psychotomimetic effect of the N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine is thought to arise from a functional modulation of the brain's fronto-striato-thalamic (FST) circuits. Animal models suggest a pronounced effect on ventral 'limbic' FST systems, although recent work in patients with psychosis and high-risk individuals suggests specific alterations of dorsal 'associative' FST circuits. Here, we used functional magnetic resonance imaging to investigate the effects of a subanesthetic dose of ketamine on measures of functional connectivity as indexed by the temporal coherence of spontaneous neural activity in both dorsal and ventral FST circuits, as well as their symptom correlates. We adopted a placebo-controlled, double-blind, randomized, repeated-measures design in which 19 healthy participants received either an intravenous saline infusion or a racemic mixture of ketamine (100 ng/ml) separated by at least 1 week. Compared with placebo, ketamine increased functional connectivity between the dorsal caudate and both the thalamus and midbrain bilaterally. Ketamine additionally increased functional connectivity of the ventral striatum/nucleus accumbens and ventromedial prefrontal cortex. Both connectivity increases significantly correlated with the psychosis-like and dissociative symptoms under ketamine. Importantly, dorsal caudate connectivity with the ventrolateral thalamus and subthalamic nucleus showed inverse correlation with ketamine-induced symptomatology, pointing to a possible resilience role to disturbances in FST circuits. Although consistent with the role of FST in mediating psychosis, these findings contrast with previous research in clinical samples by suggesting that acute NMDAR antagonism may lead to psychosis-like experiences via a mechanism that is distinct from that implicated in frank psychotic illness.

  12. Dopamine Treatment and Cognitive Functioning in Individuals with Parkinson’s Disease: The “Cognitive Flexibility” Hypothesis Seems to Work

    Directory of Open Access Journals (Sweden)

    Alberto Costa

    2014-01-01

    Full Text Available Background. Previous data suggest that (i dopamine modulates the ability to implement nonroutine schemata and update operations (flexibility processes and that (ii dopamine-related improvement may be related to baseline dopamine levels in target pathways (inverted U-shaped hypothesis. Objective. To investigate above hypotheses in individuals with Parkinson's disease (PD. Methods. Twenty PD patients were administered tasks varying as to flexibility load in two treatment conditions: (i “off” condition, about 18 hours after dopamine dose and (ii “on” condition, after dopamine administration. PD patients were separated into two groups: low performers (i.e., performance on Digit Span Backward below the sample mean and high performers (i.e., performance above the mean. Twenty healthy individuals performed the tasks in two sessions without taking drugs. Results. Passing from the “off” to the “on” state, only low performer PD patients significantly improved their performance on high-flexibility measures (interference condition of the Stroop test; P<0.05; no significant effect was found on low-flexibility tasks. Conclusions. These findings document that high-flexibility processes are sensitive to dopamine neuromodulation in the early phases of PD. This is in line with the hypothesis that striatal dopamine pathways, affected early by PD, are precociously implicated in the expression of cognitive disorders in these individuals.

  13. Decreased dopamine activity predicts relapse in methamphetamine abusers

    International Nuclear Information System (INIS)

    Wang, G.J.; Smith, L.; Volkow, N.D.; Telang, F.; Logan, J.; Tomasi, D.; Wong, C.T.; Hoffman, W.; Jayne, M.; Alia-Klein, N.; Thanos, P.; Fowler, J.S.

    2011-01-01

    Studies in methamphetamine (METH) abusers showed that the decreases in brain dopamine (DA) function might recover with protracted detoxification. However, the extent to which striatal DA function in METH predicts recovery has not been evaluated. Here we assessed whether striatal DA activity in METH abusers is associated with clinical outcomes. Brain DA D2 receptor (D2R) availability was measured with positron emission tomography and ( 11 C)raclopride in 16 METH abusers, both after placebo and after challenge with 60 mg oral methylphenidate (MPH) (to measure DA release) to assess whether it predicted clinical outcomes. For this purpose, METH abusers were tested within 6 months of last METH use and then followed up for 9 months of abstinence. In parallel, 15 healthy controls were tested. METH abusers had lower D2R availability in caudate than in controls. Both METH abusers and controls showed decreased striatal D2R availability after MPH and these decreases were smaller in METH than in controls in left putamen. The six METH abusers who relapsed during the follow-up period had lower D2R availability in dorsal striatum than in controls, and had no D2R changes after MPH challenge. The 10 METH abusers who completed detoxification did not differ from controls neither in striatal D2R availability nor in MPH-induced striatal DA changes. These results provide preliminary evidence that low striatal DA function in METH abusers is associated with a greater likelihood of relapse during treatment. Detection of the extent of DA dysfunction may be helpful in predicting therapeutic outcomes.

  14. Decreased dopamine activity predicts relapse in methamphetamine abusers

    Energy Technology Data Exchange (ETDEWEB)

    Wang G. J.; Wang, G.-J.; Smith, L.; Volkow, N.D.; Telang, F.; Logan, J.; Tomasi, D.; Wong, C.T.; Hoffman, W.; Jayne, M.; Alia-Klein, N.; Thanos, P.; Fowler, J.S.

    2011-01-20

    Studies in methamphetamine (METH) abusers showed that the decreases in brain dopamine (DA) function might recover with protracted detoxification. However, the extent to which striatal DA function in METH predicts recovery has not been evaluated. Here we assessed whether striatal DA activity in METH abusers is associated with clinical outcomes. Brain DA D2 receptor (D2R) availability was measured with positron emission tomography and [{sup 11}C]raclopride in 16 METH abusers, both after placebo and after challenge with 60 mg oral methylphenidate (MPH) (to measure DA release) to assess whether it predicted clinical outcomes. For this purpose, METH abusers were tested within 6 months of last METH use and then followed up for 9 months of abstinence. In parallel, 15 healthy controls were tested. METH abusers had lower D2R availability in caudate than in controls. Both METH abusers and controls showed decreased striatal D2R availability after MPH and these decreases were smaller in METH than in controls in left putamen. The six METH abusers who relapsed during the follow-up period had lower D2R availability in dorsal striatum than in controls, and had no D2R changes after MPH challenge. The 10 METH abusers who completed detoxification did not differ from controls neither in striatal D2R availability nor in MPH-induced striatal DA changes. These results provide preliminary evidence that low striatal DA function in METH abusers is associated with a greater likelihood of relapse during treatment. Detection of the extent of DA dysfunction may be helpful in predicting therapeutic outcomes.

  15. Striatal [123I]β-CIT SPECT and prefrontal cognitive functions in Parkinson's disease

    International Nuclear Information System (INIS)

    Mueller, U.; Waechter, T.; Barthel, H.; Reuter, M.; Cramon, D.Y. von

    2000-01-01

    Twenty non-demented patients with idiopathic Parkinson's disease (PD) underwent single photon emission computed tomography (SPECT) with [ 123 I]β-CIT to further investigate the contribution of nigrostriatal dysfunction to cognitive and motor deficits. Compared to matched controls PD patients showed normal verbal intelligence, short-term memory and phasic alertness. There were significant (p 123 I]β-CIT SPECT. These results support the view that the striatum is part of a neuronal network that is mediating prefrontal cognitive functions. (author)

  16. Endocannabinoid modulation of dopamine neurotransmission.

    Science.gov (United States)

    Covey, Dan P; Mateo, Yolanda; Sulzer, David; Cheer, Joseph F; Lovinger, David M

    2017-09-15

    Dopamine (DA) is a major catecholamine neurotransmitter in the mammalian brain that controls neural circuits involved in the cognitive, emotional, and motor aspects of goal-directed behavior. Accordingly, perturbations in DA neurotransmission play a central role in several neuropsychiatric disorders. Somewhat surprisingly given its prominent role in numerous behaviors, DA is released by a relatively small number of densely packed neurons originating in the midbrain. The dopaminergic midbrain innervates numerous brain regions where extracellular DA release and receptor binding promote short- and long-term changes in postsynaptic neuron function. Striatal forebrain nuclei receive the greatest proportion of DA projections and are a predominant hub at which DA influences behavior. A number of excitatory, inhibitory, and modulatory inputs orchestrate DA neurotransmission by controlling DA cell body firing patterns, terminal release, and effects on postsynaptic sites in the striatum. The endocannabinoid (eCB) system serves as an important filter of afferent input that acts locally at midbrain and terminal regions to shape how incoming information is conveyed onto DA neurons and to output targets. In this review, we aim to highlight existing knowledge regarding how eCB signaling controls DA neuron function through modifications in synaptic strength at midbrain and striatal sites, and to raise outstanding questions on this topic. This article is part of the Special Issue entitled "A New Dawn in Cannabinoid Neurobiology". Copyright © 2017 Elsevier Ltd. All rights reserved.

  17. Preserving cortico-striatal function: Deep brain stimulation in Huntington's disease

    Directory of Open Access Journals (Sweden)

    Sean J Nagel

    2015-03-01

    Full Text Available Huntington’s disease (HD is an incurable neurodegenerative disease characterized by the triad of chorea, cognitive dysfunction and psychiatric disturbances. Since the discovery of the HD gene, the pathogenesis has been outlined, but to date a cure has not been found. Disease modifying therapies are needed desperately to improve function, alleviate suffering, and provide hope for symptomatic patients. Deep brain stimulation (DBS, a proven therapy for managing the symptoms of some neurodegenerative movement disorders, including Parkinson’s disease, has been reported as a palliative treatment in select cases of HD with debilitating chorea with variable success. New insights into the mechanism of action of DBS suggest it may have the potential to circumvent other manifestations of HD including cognitive deterioration. Furthermore, because DBS is already widely used, reversible, and has a risk profile that is relatively low, new studies can be initiated. In this article we contend that new clinical trials be considered to test the effects of DBS for HD

  18. Advances in the understanding of early Huntington's disease using the functional imaging techniques of PET and SPET

    International Nuclear Information System (INIS)

    Andrews, T.C.; Brooks, D.J.

    1998-01-01

    The functional imaging techniques of positron emission tomography (PET) and single photon emission tomography (SPET) have been used to study regional brain function in Huntington's disease (HD) in vivo. Reduced striatal glucose metabolism and dopamine receptor binding are evident in all symptomatic HD patients and in ∼50% of asymptomatic adult mutation carriers. These characteristics correlate with clinical measures of disease severity. Reduced cortical glucose metabolism and dopamine receptor binding, together with reduced striatal and cortical opioid receptor binding, have also been demonstrated in symptomatic patients with HD. Repeat PET measures of striatal function have been used to monitor the progression of this disease objectively. In the future, functional imaging will provide a valuable way of assessing the efficacy of both fetal striatal cell implants and putative neuroprotective agents, such as nerve growth factors. (Copyright (c) 1998 Elsevier Science B.V., Amsterdam. All rights reserved.)

  19. Up-regulation of striatal adenosine A2A receptors with iron deficiency in rats. Effects on locomotion and cortico-striatal neurotransmission

    Science.gov (United States)

    Quiroz, César; Pearson, Virginia; Gulyani, Seema; Allen, Richard; Earley, Christopher; Ferré, Sergi

    2010-01-01

    Brain iron deficiency leads to altered dopaminergic function in experimental animals, which can provide a mechanistic explanation for iron deficiency-related human sensory-motor disorders, such as Restless Legs Syndrome (RLS). However, mechanisms linking both conditions have not been determined. Considering the strong modulation exerted by adenosine on dopamine signaling, one connection could involve changes in adenosine receptor expression or function. In the striatum, presynaptic A2A receptors are localized in glutamatergic terminals contacting GABAergic dynorphinergic neurons and their function can be analyzed by the ability of A2A receptor antagonists to block the motor output induced by cortical electrical stimulation. Postsynaptic A2A receptors are localized in the dendritic field of GABAergic enkephalinergic neurons and their function can be analyzed by studying the ability of A2A receptor antagonists to produce locomotor activity and to counteract striatal ERK1/2 phosphorylation induced by cortical electrical stimulation. Increased density of striatal A2A receptors was found in rats fed during three weeks with an iron-deficient diet during the post-weaning period. In iron-deficient rats, the selective A2A receptor antagonist MSX-3, at doses of 1 and 3 mg/kg, was more effective at blocking motor output induced by cortical electrical stimulation (presynaptic A2A receptor-mediated effect) and at enhancing locomotor activation and blocking striatal ERK phosphorylation induced by cortical electrical stimulation (postsynaptic A2A receptor-mediated effects). These results indicate that brain iron deficiency induces a functional up-regulation of both striatal pre- and postsynaptic A2A receptor, which could be involved in sensory-motor disorders associated with iron deficiency such as RLS. PMID:20385128

  20. Up-regulation of striatal adenosine A(2A) receptors with iron deficiency in rats: effects on locomotion and cortico-striatal neurotransmission.

    Science.gov (United States)

    Quiroz, César; Pearson, Virginia; Gulyani, Seema; Allen, Richard; Earley, Christopher; Ferré, Sergi

    2010-07-01

    Brain iron deficiency leads to altered dopaminergic function in experimental animals, which can provide a mechanistic explanation for iron deficiency-related human sensory-motor disorders, such as Restless Legs Syndrome (RLS). However, mechanisms linking both conditions have not been determined. Considering the strong modulation exerted by adenosine on dopamine signaling, one connection could involve changes in adenosine receptor expression or function. In the striatum, presynaptic A(2A) receptors are localized in glutamatergic terminals contacting GABAergic dynorphinergic neurons and their function can be analyzed by the ability of A(2A) receptor antagonists to block the motor output induced by cortical electrical stimulation. Postsynaptic A(2A) receptors are localized in the dendritic field of GABAergic enkephalinergic neurons and their function can be analyzed by studying the ability of A(2A) receptor antagonists to produce locomotor activity and to counteract striatal ERK1/2 phosphorylation induced by cortical electrical stimulation. Increased density of striatal A(2A) receptors was found in rats fed during 3 weeks with an iron-deficient diet during the post-weaning period. In iron-deficient rats, the selective A(2A) receptor antagonist MSX-3, at doses of 1 and 3 mg/kg, was more effective at blocking motor output induced by cortical electrical stimulation (presynaptic A(2A) receptor-mediated effect) and at enhancing locomotor activation and blocking striatal ERK phosphorylation induced by cortical electrical stimulation (postsynaptic A(2A) receptor-mediated effects). These results indicate that brain iron deficiency induces a functional up-regulation of both striatal pre- and postsynaptic A(2A) receptor, which could be involved in sensory-motor disorders associated with iron deficiency such as RLS. Copyright 2010. Published by Elsevier Inc.

  1. Effects of Methylphenidate on Resting-State Functional Connectivity of the Mesocorticolimbic Dopamine Pathways in Cocaine Addiction

    Energy Technology Data Exchange (ETDEWEB)

    Konova, Anna B.; Moeller, Scott J.; Tomasi, Dardo; Volkow, Nora D.; Goldstein, Rita Z.

    2013-08-01

    Cocaine addiction is associated with altered resting-state functional connectivity among regions of the mesocorticolimbic dopamine pathways. Methylphenidate hydrochloride, an indirect dopamine agonist, normalizes task-related regional brain activity and associated behavior in cocaine users; however, the neural systems–level effects of methylphenidate in this population have not yet been described. To use resting-state functional magnetic resonance imaging to examine changes in mesocorticolimbic connectivity with methylphenidate and how connectivity of affected pathways relates to severity of cocaine addiction.

  2. At-risk for pathological gambling: imaging neural reward processing under chronic dopamine agonists.

    Science.gov (United States)

    Abler, Birgit; Hahlbrock, Roman; Unrath, Alexander; Grön, Georg; Kassubek, Jan

    2009-09-01

    Treatment with dopamine receptor agonists has been associated with impulse control disorders and pathological gambling (PG) secondary to medication in previously unaffected patients with Parkinson's disease or restless legs syndrome (RLS). In a within-subjects design, we investigated the underlying neurobiology in RLS patients using functional magnetic resonance imaging. We scanned 12 female RLS patients without a history of PG. All patients were scanned twice: once whilst taking their regular medication with low dose dopamine receptor agonists and once after a washout phase interval. They performed an established gambling game task involving expectation and receipt or omission of monetary rewards at different levels of probabilities. Upon expectation of rewards, reliable ventral striatal activation was detected only when patients were on, but not when patients were off medication. Upon receipt or omission of rewards, the observed ventral striatal signal under medication differed markedly from its predicted pattern which by contrast was apparent when patients were off medication. Orbitofrontal activation was not affected by medication. Chronic dopamine receptor agonist medication changed the neural signalling of reward expectation predisposing the dopaminergic reward system to mediate an increased appetitive drive. Even without manifest PG, chronic medication with dopamine receptor agonists led to markedly changed neural processing of negative consequences probably mediating dysfunctional learning of contingencies. Intact orbitofrontal functioning, potentially moderating impulse control, may explain why none of the patients actually developed PG. Our results support the notion of a general medication effect in patients under dopamine receptor agonists in terms of a sensitization towards impulse control disorders.

  3. Dopamine D2/3 receptor availability and amphetamine-induced dopamine release in obesity

    NARCIS (Netherlands)

    van de Giessen, Elsmarieke; Celik, Funda; Schweitzer, Dave H.; van den Brink, Wim; Booij, Jan

    2014-01-01

    The neurotransmitter dopamine is important in the regulation of food intake. It is hypothesised that obese people experience less reward from food due to lower striatal dopamine release, which consequently leads to overeating. This study is the first to assess whether obese subjects have blunted

  4. Functionalization of a Membrane Sublayer Using Reverse Filtration of Enzymes and Dopamine Coating

    DEFF Research Database (Denmark)

    Luo, Jianquan; Meyer, Anne S.; Mateiu, Ramona Valentina

    2014-01-01

    , and the resulting enzyme-loaded sublayer was covered with a dopamine coating. After membrane reversal, the virgin membrane skin layer was facing the feed and the enzymes were entrapped by a polydopamine network in the membrane sublayer. Thus, the membrane sublayer was functionalized as a catalytically active layer....... The effects of the original membrane properties (i.e., materials, pore size, and structure), enzyme type (i.e., laccase and alcohol dehydrogenase), and coating conditions (i.e., time and pH) on the resulting biocatalytic membrane permeability, enzyme loading, and activity were investigated. Using a RC10 k......Da membrane with sponge-like sublayer to immobilize laccase with dopamine coating, the trade-off between permeability and enzyme loading was broken, and enzyme loading reached 44.5% without any permeability loss. After 85 days of storage and reuse 14 times, more than 80% of the immobilized laccase activity...

  5. PCBs Alter Dopamine Mediated Function in Aging Workers

    Science.gov (United States)

    2007-01-01

    assessment of toxicant - induced deficits in neuropsychological function, measurement of serum PCB concentrations, non-invasive determination of bone...likelihood of exposure to PCBs, lead, mercury , and pesticides, using a four point scale. Each job has also been classified using Standard Industrial and... Diuretics Anti-depressants Beta blockers Diabetes meds Acetaminophen Potassium supplement Gastro-intestinals Ace inhibitors Hyperlipoproteinemia meds

  6. Unseen scars: Cocaine patients with prior trauma evidence heightened resting state functional connectivity (RSFC) between the amygdala and limbic-striatal regions.

    Science.gov (United States)

    Gawrysiak, Michael J; Jagannathan, Kanchana; Regier, Paul; Suh, Jesse J; Kampman, Kyle; Vickery, Timothy; Childress, Anna Rose

    2017-11-01

    Substance use disorder (SUD) patients with a history of trauma exhibit poorer treatment outcome, greater functional impairment and higher risk for relapse. Endorsement of prior trauma has, in several SUD populations, been linked to abnormal functional connectivity (FC) during task-based studies. We examined amygdala FC in the resting state (RS), testing for differences between cocaine patients with and without prior trauma. Patients with cocaine use disorder (CUD; n=34) were stabilized in an inpatient setting prior to a BOLD fMRI scan. Responses to Addiction Severity Index and the Mini-International Neuropsychiatric Interview were used to characterize the No-Trauma (n=16) and Trauma (n=18) groups. Seed-based RSFC was conducted using the right and left amygdala as regions of interest. Examination of amygdala RSFC was restricted to an a priori anatomical mask that incorporated nodes of the limbic-striatal motivational network. RSFC was compared for the Trauma versus No-Trauma groups. The Trauma group evidenced greater connectivity between the amygdala and the a priori limbic-striatal mask. Peaks within the statistically significant limbic-striatal mask included the amygdala, putamen, pallidum, caudate, thalamus, insula, hippocampus/parahippocampus, and brain stem. Results suggest that cocaine patients with prior trauma (versus without) have heightened communication within nodes of the motivational network, even at rest. To our knowledge, this is the first fMRI study to examine amygdala RSFC among those with CUD and trauma history. Heightened RSFC intralimbic connectivity for the Trauma group may reflect a relapse-relevant brain vulnerability and a novel treatment target for this clinically-challenging population. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Prolonged high fat diet reduces dopamine reuptake without altering DAT gene expression.

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    Jackson J Cone

    Full Text Available The development of diet-induced obesity (DIO can potently alter multiple aspects of dopamine signaling, including dopamine transporter (DAT expression and dopamine reuptake. However, the time-course of diet-induced changes in DAT expression and function and whether such changes are dependent upon the development of DIO remains unresolved. Here, we fed rats a high (HFD or low (LFD fat diet for 2 or 6 weeks. Following diet exposure, rats were anesthetized with urethane and striatal DAT function was assessed by electrically stimulating the dopamine cell bodies in the ventral tegmental area (VTA and recording resultant changes in dopamine concentration in the ventral striatum using fast-scan cyclic voltammetry. We also quantified the effect of HFD on membrane associated DAT in striatal cell fractions from a separate group of rats following exposure to the same diet protocol. Notably, none of our treatment groups differed in body weight. We found a deficit in the rate of dopamine reuptake in HFD rats relative to LFD rats after 6 but not 2 weeks of diet exposure. Additionally, the increase in evoked dopamine following a pharmacological challenge of cocaine was significantly attenuated in HFD relative to LFD rats. Western blot analysis revealed that there was no effect of diet on total DAT protein. However, 6 weeks of HFD exposure significantly reduced the 50 kDa DAT isoform in a synaptosomal membrane-associated fraction, but not in a fraction associated with recycling endosomes. Our data provide further evidence for diet-induced alterations in dopamine reuptake independent of changes in DAT production and demonstrates that such changes can manifest without the development of DIO.

  8. Serotonin 5-HT2A but not 5-HT2C receptor antagonism reduces hyperlocomotor activity induced in dopamine-depleted rats by striatal administration of the D1 agonist SKF 82958.

    Science.gov (United States)

    Bishop, Christopher; Daut, Gregory S; Walker, Paul D

    2005-09-01

    While recent work has indicated that D1 receptor agonist-induced hyperlocomotion in DA-depleted rats is reduced by striatal 5-HT2 receptor antagonism, the 5-HT receptor(s) subtypes mediating these effects are not yet known. In the present study, we examined the influence(s) of striatal 5-HT2A and 5-HT2C receptors on locomotor behavior induced by D1 agonism in neonatal DA-depleted rats. On postnatal day 3, male Sprague-Dawley rats (n=68) were treated with either vehicle or 6-hydroxydopamine (6-OHDA; 60 microg) which produced >98% DA depletion. Sixty days later, all rats were fitted with bilateral striatal cannulae. A subset of control and 6-OHDA-lesioned rats (n=20) was tested for locomotor responses to striatal infusion of the D1 agonist SKF 82958 (0, 0.1, 1.0, 10 microg/side). The remaining rats (n=48) were tested for locomotor responses to intrastriatal SKF 82958 (2.0 microg/side) alone or in combination with the 5-HT2A- or 5-HT2C-preferring antagonists M100907 or RS102221 (0.1 or 1.0 microg/side), respectively. Intrastriatal SKF 82958 dose-dependently increased measures of motor activity within DA-depleted rats. This hyperlocomotor activity was suppressed by co-infusion of M100907, but not RS102221. These results indicate that DA depletion strengthens striatal 5-HT2A/D1 receptor interactions and suggest that 5-HT2A receptor antagonists may prove useful in reducing D1-related movements.

  9. Deficient dopamine D2 receptor function causes renal inflammation independently of high blood pressure.

    Directory of Open Access Journals (Sweden)

    Yanrong Zhang

    Full Text Available Renal dopamine receptors participate in the regulation of blood pressure. Genetic factors, including polymorphisms of the dopamine D(2 receptor gene (DRD2 are associated with essential hypertension, but the mechanisms of their contribution are incompletely understood. Mice lacking Drd2 (D(2-/- have elevated blood pressure, increased renal expression of inflammatory factors, and renal injury. We tested the hypothesis that decreased dopamine D(2 receptor (D(2R function increases vulnerability to renal inflammation independently of blood pressure, is an immediate cause of renal injury, and contributes to the subsequent development of hypertension. In D(2-/- mice, treatment with apocynin normalized blood pressure and decreased oxidative stress, but did not affect the expression of inflammatory factors. In mouse RPTCs Drd2 silencing increased the expression of TNFα and MCP-1, while treatment with a D(2R agonist abolished the angiotensin II-induced increase in TNF-α and MCP-1. In uni-nephrectomized wild-type mice, selective Drd2 silencing by subcapsular infusion of Drd2 siRNA into the remaining kidney produced the same increase in renal cytokines/chemokines that occurs after Drd2 deletion, increased the expression of markers of renal injury, and increased blood pressure. Moreover, in mice with two intact kidneys, short-term Drd2 silencing in one kidney, leaving the other kidney undisturbed, induced inflammatory factors and markers of renal injury in the treated kidney without increasing blood pressure. Our results demonstrate that the impact of decreased D(2R function on renal inflammation is a primary effect, not necessarily associated with enhanced oxidant activity, or blood pressure; renal damage is the cause, not the result, of hypertension. Deficient renal D(2R function may be of clinical relevance since common polymorphisms of the human DRD2 gene result in decreased D(2R expression and function.

  10. Deficient dopamine D2 receptor function causes renal inflammation independently of high blood pressure.

    Science.gov (United States)

    Zhang, Yanrong; Cuevas, Santiago; Asico, Laureano D; Escano, Crisanto; Yang, Yu; Pascua, Annabelle M; Wang, Xiaoyan; Jones, John E; Grandy, David; Eisner, Gilbert; Jose, Pedro A; Armando, Ines

    2012-01-01

    Renal dopamine receptors participate in the regulation of blood pressure. Genetic factors, including polymorphisms of the dopamine D(2) receptor gene (DRD2) are associated with essential hypertension, but the mechanisms of their contribution are incompletely understood. Mice lacking Drd2 (D(2)-/-) have elevated blood pressure, increased renal expression of inflammatory factors, and renal injury. We tested the hypothesis that decreased dopamine D(2) receptor (D(2)R) function increases vulnerability to renal inflammation independently of blood pressure, is an immediate cause of renal injury, and contributes to the subsequent development of hypertension. In D(2)-/- mice, treatment with apocynin normalized blood pressure and decreased oxidative stress, but did not affect the expression of inflammatory factors. In mouse RPTCs Drd2 silencing increased the expression of TNFα and MCP-1, while treatment with a D(2)R agonist abolished the angiotensin II-induced increase in TNF-α and MCP-1. In uni-nephrectomized wild-type mice, selective Drd2 silencing by subcapsular infusion of Drd2 siRNA into the remaining kidney produced the same increase in renal cytokines/chemokines that occurs after Drd2 deletion, increased the expression of markers of renal injury, and increased blood pressure. Moreover, in mice with two intact kidneys, short-term Drd2 silencing in one kidney, leaving the other kidney undisturbed, induced inflammatory factors and markers of renal injury in the treated kidney without increasing blood pressure. Our results demonstrate that the impact of decreased D(2)R function on renal inflammation is a primary effect, not necessarily associated with enhanced oxidant activity, or blood pressure; renal damage is the cause, not the result, of hypertension. Deficient renal D(2)R function may be of clinical relevance since common polymorphisms of the human DRD2 gene result in decreased D(2)R expression and function.

  11. Stronger Dopamine D1 Receptor-Mediated Neurotransmission in Dyskinesia.

    Science.gov (United States)

    Farré, Daniel; Muñoz, Ana; Moreno, Estefanía; Reyes-Resina, Irene; Canet-Pons, Júlia; Dopeso-Reyes, Iria G; Rico, Alberto J; Lluís, Carme; Mallol, Josefa; Navarro, Gemma; Canela, Enric I; Cortés, Antonio; Labandeira-García, José L; Casadó, Vicent; Lanciego, José L; Franco, Rafael

    2015-12-01

    Radioligand binding assays to rat striatal dopamine D1 receptors showed that brain lateralization of the dopaminergic system were not due to changes in expression but in agonist affinity. D1 receptor-mediated striatal imbalance resulted from a significantly higher agonist affinity in the left striatum. D1 receptors heteromerize with dopamine D3 receptors, which are considered therapeutic targets for dyskinesia in parkinsonian patients. Expression of both D3 and D1-D3 receptor heteromers were increased in samples from 6-hydroxy-dopamine-hemilesioned rats rendered dyskinetic by treatment with 3, 4-dihydroxyphenyl-L-alanine (L-DOPA). Similar findings were obtained using striatal samples from primates. Radioligand binding studies in the presence of a D3 agonist led in dyskinetic, but not in lesioned or L-DOPA-treated rats, to a higher dopamine sensitivity. Upon D3-receptor activation, the affinity of agonists for binding to the right striatal D1 receptor increased. Excess dopamine coming from L-DOPA medication likely activates D3 receptors thus making right and left striatal D1 receptors equally responsive to dopamine. These results show that dyskinesia occurs concurrently with a right/left striatal balance in D1 receptor-mediated neurotransmission.

  12. Thinking and doing: the effects of dopamine and oxytocin genes and executive function on mothering behaviours.

    Science.gov (United States)

    Tombeau Cost, K; Unternaehrer, E; Plamondon, A; Steiner, M; Meaney, M; Atkinson, L; Kennedy, J L; Fleming, A S

    2017-02-01

    Animal and human studies suggest that initial expression of maternal behaviour depends on oxytocin and dopamine systems. However, the mechanism by which these systems affect parenting behaviours and the timing of these effects are not well understood. This article explores the role of mothers' executive function in mediating the relation between oxytocin and dopamine gene variants and maternal responsiveness at 48 months post-partum. Participants (n = 157) were mothers recruited in the Maternal Adversity, Vulnerability and Neurodevelopment Study, which assesses longitudinally two cohorts of mothers and children in Canada. We examined single nucleotide polymorphisms (SNPs) related to the dopamine and oxytocin systems (DRD1 rs686, DRD1 rs265976, OXTR rs237885 and OXTR rs2254298), assessed mothers' decision-making at 48 months using the Cambridge Neurological Automated Testing Battery (CANTAB) and evaluated maternal responsiveness from videotaped interactions during the Etch-A-Sketch co-operation task. Mediation analyses showed that OXTR rs2254298 A-carriers had an indirect effect on positive parenting which was mediated by mothers' performance on decision-making task (estimate = 0.115, P effects on physically controlling parenting, also mediated through enhanced performance on decision-making (estimate = -0.059, P  0.05). While oxytocin has previously been associated with only the early onset of maternal behaviour, we show that an OXTR polymorphism is involved in maternal behaviour at 48 months post-partum through mothers' executive function. This research highlights the importance of the oxytocin system to maternal parenting beyond infancy. © 2016 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

  13. A Subpopulation of Neuronal M4 Muscarinic Acetylcholine Receptors Plays a Critical Role in Modulating Dopamine-Dependent Behaviors

    OpenAIRE

    Jeon, Jongrye; Dencker, Ditte; Wortwein, Gitta; Woldbye, David P. D.; Cui, Yinghong; Davis, Albert A.; Levey, Allan I.; Schütz, Günther; Sager, Thomas; Mørk, Arne; Li, Cuiling; Deng, Chu-Xia; Fink-Jensen, Anders; Wess, Jürgen

    2010-01-01

    Acetylcholine (ACh) regulates many key functions of the CNS by activating cell surface receptors referred to as muscarinic ACh receptors (M1–M5 mAChRs). Like other mAChR subtypes, the M4 mAChR is widely expressed in different regions of the forebrain. Interestingly, M4 mAChRs are coexpressed with D1 dopamine receptors in a specific subset of striatal projection neurons. To investigate the physiological relevance of this M4 mAChR subpopulation in modulating dopamine-dependent behaviors, we use...

  14. Activating Developmental Reserve Capacity Via Cognitive Training or Non-invasive Brain Stimulation: Potentials for Promoting Fronto-Parietal and Hippocampal-Striatal Network Functions in Old Age.

    Science.gov (United States)

    Passow, Susanne; Thurm, Franka; Li, Shu-Chen

    2017-01-01

    Existing neurocomputational and empirical data link deficient neuromodulation of the fronto-parietal and hippocampal-striatal circuitries with aging-related increase in processing noise and declines in various cognitive functions. Specifically, the theory of aging neuronal gain control postulates that aging-related suboptimal neuromodulation may attenuate neuronal gain control, which yields computational consequences on reducing the signal-to-noise-ratio of synaptic signal transmission and hampering information processing within and between cortical networks. Intervention methods such as cognitive training and non-invasive brain stimulation, e.g., transcranial direct current stimulation (tDCS), have been considered as means to buffer cognitive functions or delay cognitive decline in old age. However, to date the reported effect sizes of immediate training gains and maintenance effects of a variety of cognitive trainings are small to moderate at best; moreover, training-related transfer effects to non-trained but closely related (i.e., near-transfer) or other (i.e., far-transfer) cognitive functions are inconsistent or lacking. Similarly, although applying different tDCS protocols to reduce aging-related cognitive impairments by inducing temporary changes in cortical excitability seem somewhat promising, evidence of effects on short- and long-term plasticity is still equivocal. In this article, we will review and critically discuss existing findings of cognitive training- and stimulation-related behavioral and neural plasticity effects in the context of cognitive aging, focusing specifically on working memory and episodic memory functions, which are subserved by the fronto-parietal and hippocampal-striatal networks, respectively. Furthermore, in line with the theory of aging neuronal gain control we will highlight that developing age-specific brain stimulation protocols and the concurrent applications of tDCS during cognitive training may potentially facilitate

  15. DISC1 and striatal volume: a potential risk phenotype for mental illness

    Directory of Open Access Journals (Sweden)

    M. Mallar eChakravarty

    2012-06-01

    Full Text Available Disrupted-in-schizophrenia 1 was originally discovered in a large Scottish family with abnormally high rates of severe mental illness, including schizophrenia, bipolar disorder, and depression. An accumulating body of evidence from genetic, postmortem, and animal data supports a role for DISC1 in different forms of mental illness. DISC1 may play an important role in determining structure and function of several brain regions. One brain region of particular importance for several mental disorders is the striatum, and DISC1 mutant mice have demonstrated an increase in dopamine (D2 receptors in this structure. However, association between DISC1 functional polymorphisms and striatal structure have not been examined in humans to our knowledge. We, therefore hypothesized that there would be a relationship between human striatal volume and DISC1 genotype, specifically in the Leu607Phe (rs6675281 and Ser704Cys (rs821618 single nucleotide polymorphisms. We tested our hypothesis by automatically identifying the striatum in fifty-four healthy volunteers recruited for this study. We also performed an exploratory analysis of cortical thickness, cortical surface area, and structure volume. Our results demonstrate that Phe allele carriers have larger striatal volume bilaterally (left striatum: p=0.017; right striatum: p=0.016. From the exploratory analyses we found that Phe carriers also had larger right hemisphere volumes and right occipital lobe surface area (p=0.014 compared to LeuLeu homozygotes (p=0.0074. However, these exploratory findings do not survive a conservative correction for multiple comparisons. Our findings demonstrate that a functional DISC1 variant influences striatal volumes. Taken together with animal data that this gene influences D2 receptor levels in striatum, a key risk pathway for mental illnesses such as schizophrenia and bipolar disorder may be conferred via DISC1’s effects on the striatum .

  16. High performance of poly(dopamine)-functionalized graphene oxide/poly(vinyl alcohol) nanocomposites

    Science.gov (United States)

    Ma, Jiaojiao; Pan, Jingkai; Yue, Jia; Xu, Yu; Bao, Jianjun

    2018-01-01

    In this paper, poly(vinyl alcohol) (PVA)/poly(dopamine)-functionalized graphene oxide (PGO) nanocomposites with high performance were prepared by an environment-friendly and facile strategy. GO was firstly functionalized and simultaneously reduced by poly(dopamine) to yield PGO. Then it was mixed with PVA in aqueous solution to make PVA/PGO nanocomposites. Transmission electron microscopy revealed that the PGO nanosheets are well dispersed and randomly oriented throughout the PVA matrix. At the same time, the thermal properties and water barrier properties of the PVA/PGO nanocomposites have been strikingly enhanced by the incorporation of PGO. The degradation temperature of the nanocomposites is more than 30 °C higher than that of pure PVA by the addition of 0.7 wt% PGO, which shows good thermal stability. The water vapor permeability of the nanocomposites also decreases to 0.71 × 10-12 g cm/(cm2 s Pa), corresponding to 80% reduction than that of pure PVA. Moreover, the PVA/PGO nanocomposites also present enhanced conductive properties. The PVA/PGO nanocomposites with such outstanding properties show great promising applications in the fields of packaging, electronics, fuel cell industry, fiber, and so on.

  17. BMI modulates calorie-dependent dopamine changes in accumbens from glucose intake.

    Directory of Open Access Journals (Sweden)

    Gene-Jack Wang

    Full Text Available Dopamine mediates the rewarding effects of food that can lead to overeating and obesity, which then trigger metabolic neuroadaptations that further perpetuate excessive food consumption. We tested the hypothesis that the dopamine response to calorie intake (independent of palatability in striatal brain regions is attenuated with increases in weight.We used positron emission tomography with [11C]raclopride to measure dopamine changes triggered by calorie intake by contrasting the effects of an artificial sweetener (sucralose devoid of calories to that of glucose to assess their association with body mass index (BMI in nineteen healthy participants (BMI range 21-35.Neither the measured blood glucose concentrations prior to the sucralose and the glucose challenge days, nor the glucose concentrations following the glucose challenge vary as a function of BMI. In contrast the dopamine changes in ventral striatum (assessed as changes in non-displaceable binding potential of [11C]raclopride triggered by calorie intake (contrast glucose - sucralose were significantly correlated with BMI (r = 0.68 indicating opposite responses in lean than in obese individuals. Specifically whereas in normal weight individuals (BMI <25 consumption of calories was associated with increases in dopamine in the ventral striatum in obese individuals it was associated with decreases in dopamine.These findings show reduced dopamine release in ventral striatum with calorie consumption in obese subjects, which might contribute to their excessive food intake to compensate for the deficit between the expected and the actual response to food consumption.

  18. 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

    2016-01-01

    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. PMID:27035941

  19. Basal ganglia disorders associated with imbalances in the striatal striosome and matrix compartments

    Directory of Open Access Journals (Sweden)

    Jill R. Crittenden

    2011-09-01

    Full Text Available The striatum is composed principally of GABAergic, medium spiny projection neurons (MSNs that can be categorized based on their gene expression, electrophysiological profiles and input-output circuits. Major subdivisions of MSN populations include 1 those in ventromedial and dorsolateral striatal regions, 2 those giving rise to the direct and indirect pathways, and 3 those that lie in the striosome and matrix compartments. The first two classificatory schemes have enabled advances in understanding of how basal ganglia circuits contribute to disease. However, despite the large number of molecules that are differentially expressed in the striosomes or the extra-striosomal matrix, and the evidence that these compartments have different input-output connections, our understanding of how this compartmentalization contributes to striatal function is still not clear. A broad view is that the matrix contains the direct and indirect pathway MSNs that form parts of sensorimotor and associative circuits, whereas striosomes contain MSNs that receive input from parts of limbic cortex and project directly or indirectly to the dopamine-containing neurons of the substantia nigra, pars compacta. Striosomes are widely distributed within the striatum and are thought to exert global, as well as local, influences on striatal processing by exchanging information with the surrounding matrix, including through interneurons that send processes into both compartments. It has been suggested that striosomes exert and maintain limbic control over behaviors driven by surrounding sensorimotor and associative parts of the striatal matrix. Consistent with this possibility, imbalances between striosome and matrix functions have been reported in relation to neurological disorders, including Huntington’s disease, L-DOPA-induced dyskinesias, dystonia and drug addiction. Here, we consider how signaling imbalances between the striosomes and matrix might relate to symptomatology in

  20. Chronic Nicotine Mitigates Aberrant Inhibitory Motor Learning Induced by Motor Experience under Dopamine Deficiency.

    Science.gov (United States)

    Koranda, Jessica L; Krok, Anne C; Xu, Jian; Contractor, Anis; McGehee, Daniel S; Beeler, Jeff A; Zhuang, Xiaoxi

    2016-05-11

    Although dopamine receptor antagonism has long been associated with impairments in motor performance, more recent studies have shown that dopamine D2 receptor (D2R) antagonism, paired with a motor task, not only impairs motor performance concomitant with the pharmacodynamics of the drug, but also impairs future motor performance once antagonism has been relieved. We have termed this phenomenon "aberrant motor learning" and have suggested that it may contribute to motor symptoms in movement disorders such as Parkinson's disease (PD). Here, we show that chronic nicotine (cNIC), but not acute nicotine, treatment mitigates the acquisition of D2R-antagonist-induced aberrant motor learning in mice. Although cNIC mitigates D2R-mediated aberrant motor learning, cNIC has no effect on D1R-mediated motor learning. β2-containing nicotinic receptors in dopamine neurons likely mediate the protective effect of cNIC against aberrant motor learning, because selective deletion of β2 nicotinic subunits in dopamine neurons reduced D2R-mediated aberrant motor learning. Finally, both cNIC treatment and β2 subunit deletion blunted postsynaptic responses to D2R antagonism. These results suggest that a chronic decrease in function or a downregulation of β2-containing nicotinic receptors protects the striatal network against aberrant plasticity and aberrant motor learning induced by motor experience under dopamine deficiency. Increasingly, aberrant plasticity and aberrant learning are recognized as contributing to the development and progression of movement disorders. Here, we show that chronic nicotine (cNIC) treatment or specific deletion of β2 nicotinic receptor subunits in dopamine neurons mitigates aberrant motor learning induced by dopamine D2 receptor (D2R) blockade in mice. Moreover, both manipulations also reduced striatal dopamine release and blunt postsynaptic responses to D2R antagonists. These results suggest that chronic downregulation of function and/or receptor

  1. Dopamine D2-like receptors (DRD2 and DRD4) in chickens: Tissue distribution, functional analysis, and their involvement in dopamine inhibition of pituitary prolactin expression.

    Science.gov (United States)

    Lv, Can; Mo, Chunheng; Liu, Haikun; Wu, Chao; Li, Zhengyang; Li, Juan; Wang, Yajun

    2018-04-20

    Dopamine (DA) D2-like (and D1-like) receptors are suggested to mediate the dopamine actions in the anterior pituitary and/or CNS of birds. However, the information regarding the structure, functionality, and expression of avian D2-like receptors have not been fully characterized. In this study, we cloned two D2-like receptors (cDRD2, cDRD4) from chicken brain using RACE PCR. The cloned cDRD4 is a 378-amino acid receptor, which shows 57% amino acid (a.a.) identity with mouse DRD4. As in mammals, two cDRD2 isoforms, cDRD2L (long isoform, 437 a.a.) and cDRD2S (short isoform, 408 a.a.), which differ in their third intracellular loop, were identified in chickens. Using cell-based luciferase reporter assays or Western blot, we demonstrated that cDRD4, cDRD2L and cDRD2S could be activated by dopamine and quinpirole (a D2-like receptor agonist) dose-dependently, and their activation inhibits cAMP signaling pathway and stimulates MAPK/ERK signaling cascade, indicating that they are functional receptors capable of mediating dopamine actions. Quantitative real-time PCR revealed that cDRD2 and cDRD4 are widely expressed in chicken tissues with abundant expression noted in anterior pituitary, and their expressions are likely controlled by their promoters near exon 1, as demonstrated by dual-luciferase reporter assays in DF-1 cells. In accordance with cDRD2/cDRD4 expression in the pituitary, DA or quinpirole could partially inhibit vasoactive intestinal peptide-induced prolactin expression in cultured chick pituitary cells. Together, our data proves the functionality of DRD2 and DRD4 in birds and aids to uncover the conserved roles of DA/D2-like receptor system in vertebrates, such as its action on the pituitary. Copyright © 2018. Published by Elsevier B.V.

  2. The association between heroin expenditure and dopamine transporter availability--a single-photon emission computed tomography study.

    Science.gov (United States)

    Lin, Shih-Hsien; Chen, Kao Chin; Lee, Sheng-Yu; Chiu, Nan Tsing; Lee, I Hui; Chen, Po See; Yeh, Tzung Lieh; Lu, Ru-Band; Chen, Chia-Chieh; Liao, Mei-Hsiu; Yang, Yen Kuang

    2015-03-30

    One of the consequences of heroin dependency is a huge expenditure on drugs. This underlying economic expense may be a grave burden for heroin users and may lead to criminal behavior, which is a huge cost to society. The neuropsychological mechanism related to heroin purchase remains unclear. Based on recent findings and the established dopamine hypothesis of addiction, we speculated that expenditure on heroin and central dopamine activity may be associated. A total of 21 heroin users were enrolled in this study. The annual expenditure on heroin was assessed, and the availability of the dopamine transporter (DAT) was assessed by single-photon emission computed tomography (SPECT) using [(99m)TC]TRODAT-1. Parametric and nonparametric correlation analyses indicated that annual expenditure on heroin was significantly and negatively correlated with the availability of striatal DAT. After adjustment for potential confounders, the predictive power of DAT availability was significant. Striatal dopamine function may be associated with opioid purchasing behavior among heroin users, and the cycle of spiraling dysfunction in the dopamine reward system could play a role in this association. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  3. Limonene inhibits methamphetamine-induced locomotor activity via regulation of 5-HT neuronal function and dopamine release.

    Science.gov (United States)

    Yun, Jaesuk

    2014-05-15

    Methamphetamine is a psychomotor stimulant that produces hyperlocomotion in rodents. Limonene (a cyclic terpene from citrus essential oils) has been reported to induce sedative effects. In this study, we demonstrated that limonene administration significantly inhibited serotonin (5-hydroxytryptamine, 5-HT)-induced head twitch response in mice. In rats, pretreatment with limonene decreased hyperlocomotion induced by methamphetamine injection. In addition, limonene reversed the increase in dopamine levels in the nucleus accumbens of rats given methamphetamine. These results suggest that limonene may inhibit stimulant-induced behavioral changes via regulating dopamine levels and 5-HT receptor function. Copyright © 2013 Elsevier GmbH. All rights reserved.

  4. Cortico-Striatal Spike-Timing Dependent Plasticity After Activation of Subcortical Pathways

    OpenAIRE

    Schulz, Jan M.; Redgrave, Peter; Reynolds, John N. J.

    2010-01-01

    Cortico-striatal spike-timing dependent plasticity (STDP) is modulated by dopamine in vitro. The present study investigated STDP in vivo using alternative procedures for modulating dopaminergic inputs. Postsynaptic potentials (PSP) were evoked in intracellularly recorded spiny neurons by electrical stimulation of the contralateral motor cortex. PSPs often consisted of up to three distinct components, likely representing distinct cortico-striatal pathways. After baseline recording, bicucullin...

  5. Opposite Effects of Stimulant and Antipsychotic Drugs on Striatal Fast-Spiking Interneurons

    OpenAIRE

    Wiltschko, Alexander B; Pettibone, Jeffrey R; Berke, Joshua D

    2010-01-01

    Psychomotor stimulants and typical antipsychotic drugs have powerful but opposite effects on mood and behavior, largely through alterations in striatal dopamine signaling. Exactly how these drug actions lead to behavioral change is not well understood, as previous electrophysiological studies have found highly heterogeneous changes in striatal neuron firing. In this study, we examined whether part of this heterogeneity reflects the mixture of distinct cell types present in the striatum, by di...

  6. Dopamine, reward, and frontostriatal circuitry in impulse control disorders in Parkinson's disease: insights from functional imaging.

    Science.gov (United States)

    Ray, Nicola; Strafella, Antonio P

    2010-04-01

    Dopamine agonists have been implicated in the development of impulse control disorders (ICDs). This may be due to the ability of agonists to tonically stimulate dopamine receptors. Recent neuroimaging data provided evidence that dopamine agonists induce significant changes in those frontostriatal circuits that process reward and mediate our ability to control impulses. Tonic stimulation of dopamine receptors via agonists may impair reward processing and inhibitory control mechanisms in ways that promote pathological repetition of behaviors. We will provide an overview of the current understanding of the neurobiology underlying ICDs in Parkinson's disease (PD).

  7. Microwave-assisted deposition of silver nanoparticles on bamboo pulp fabric through dopamine functionalization

    Energy Technology Data Exchange (ETDEWEB)

    Peng, Linghui [College of Light Industry, Textile and Food Engineering, Sichuan University, No.24 South Section 1, Yihuan Road, Chengdu (China); Guo, Ronghui, E-mail: ronghuiguo214@126.com [College of Light Industry, Textile and Food Engineering, Sichuan University, No.24 South Section 1, Yihuan Road, Chengdu (China); Lan, Jianwu [College of Light Industry, Textile and Food Engineering, Sichuan University, No.24 South Section 1, Yihuan Road, Chengdu (China); Jiang, Shouxiang [Institute of Textiles and Clothing, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong (China); Lin, Shaojian [Institute for Technical and Macromolecular Chemistry, University of Hamburg Bundesstrasse 45, D-20146 Hamburg (Germany)

    2016-11-15

    Highlights: • Silver nanoparticles were synthesized on bamboo pulp fabric using dopamine as an adhesive and reducing agent under microwave radiation. • Silver coated bamboo pulp fabric modified with dopamine has good UV protection and hydrophobic property. • Silver nanoparticles can be strongly fixed on dopamine modified bamboo pulp fabric. - Abstract: Silver nanoparticles were synthesized on bamboo pulp fabric with dopamine as the adhesive and reducing agent under microwave radiation. The silver nanoparticle coated bamboo pulp fabrics were characterized by X-ray photoelectron spectroscopy, scanning electron microscope and X-ray diffraction. Ultraviolet (UV) protection, color and water contact angles of the silver nanoparticle coated bamboo pulp fabrics were evaluated. In addition, the influences of concentrations of dopamine and treatment time on color strength (K/S values) of the silver nanoparticle coated fabric were investigated. Fastness to washing was employed to evaluate the adhesive strength between the silver coating and the bamboo pulp fabric modified with dopamine. The results show that the dopamine modified bamboo pulp fabric is evenly covered with silver nanoparticles. The silver nanoparticle coated bamboo pulp fabric modified with dopamine shows the excellent UV protection with an ultraviolet protection factor of 157.75 and the hydrophobicity with a water contact angle of 132.4°. In addition, the adhesive strength between the silver nanoparticles and bamboo pulp fabric is significantly improved. Silver nanoparticles coating on bamboo pulp fabric modified with dopamine is environmentally friendly, easy to carry out and highly efficient.

  8. Prefrontal dopamine and behavioral flexibility: shifting from an inverted-U towards a family of functions

    Directory of Open Access Journals (Sweden)

    Stan B Floresco

    2013-04-01

    Full Text Available Studies on prefrontal cortex (PFC dopamine (DA function have revealed its essential role in mediating a variety of cognitive and executive functions. A general principle that has emerged (primarily from studies on working memory is that PFC DA, acting on D1 receptors, regulates cognition in accordance to an inverted-U shaped function, so that too little or too much activity has detrimental effects on performance. However, contemporary studies have indicated that the receptor mechanisms through which mesocortical DA regulates different aspects of behavioral flexibility can vary considerably across different DA receptors and cognitive operations. This article will review psychopharmacological and neurochemical data comparing and contrasting the cognitive effects of antagonism and stimulation of different DA receptors in the medial PFC. Thus, set-shifting is dependent on a co-operative interaction between PFC D1 and D2 receptors, yet, supranormal stimulation of these receptors does not appear to have detrimental effects on this function. On the other hand, modification of cost/benefit decision biases in situations involving reward uncertainty is regulated in complex and sometimes opposing ways by PFC D1 versus D2 receptors. When viewed collectively, these findings suggest that the inverted-U shaped dose-response curve underlying D1 receptor modulation of working memory is not a one-size-fits-all function. Rather, it appears that mesocortical DA exerts its effects via a family of functions, wherein reduced or excessive DA activity can have a variety of effects across different cognitive domains.

  9. Norepinephrine versus dopamine and their interaction in modulating synaptic function in the prefrontal cortex.

    Science.gov (United States)

    Xing, Bo; Li, Yan-Chun; Gao, Wen-Jun

    2016-06-15

    Among the neuromodulators that regulate prefrontal cortical circuit function, the catecholamine transmitters norepinephrine (NE) and dopamine (DA) stand out as powerful players in working memory and attention. Perturbation of either NE or DA signaling is implicated in the pathogenesis of several neuropsychiatric disorders, including attention deficit hyperactivity disorder (ADHD), post-traumatic stress disorder (PTSD), schizophrenia, and drug addiction. Although the precise mechanisms employed by NE and DA to cooperatively control prefrontal functions are not fully understood, emerging research indicates that both transmitters regulate electrical and biochemical aspects of neuronal function by modulating convergent ionic and synaptic signaling in the prefrontal cortex (PFC). This review summarizes previous studies that investigated the effects of both NE and DA on excitatory and inhibitory transmissions in the prefrontal cortical circuitry. Specifically, we focus on the functional interaction between NE and DA in prefrontal cortical local circuitry, synaptic integration, signaling pathways, and receptor properties. Although it is clear that both NE and DA innervate the PFC extensively and modulate synaptic function by activating distinctly different receptor subtypes and signaling pathways, it remains unclear how these two systems coordinate their actions to optimize PFC function for appropriate behavior. Throughout this review, we provide perspectives and highlight several critical topics for future studies. This article is part of a Special Issue entitled SI: Noradrenergic System. Copyright © 2016 Elsevier B.V. All rights reserved.

  10. Striatal cholinergic interneuron regulation and circuit effects

    Directory of Open Access Journals (Sweden)

    Sean Austin Lim

    2014-10-01

    Full Text Available The striatum plays a central role in motor control and motor learning. Appropriate responses to environmental stimuli, including pursuit of reward or avoidance of aversive experience all require functional striatal circuits. These pathways integrate synaptic inputs from limbic and cortical regions including sensory, motor and motivational information to ultimately connect intention to action. Although many neurotransmitters participate in striatal circuitry, one critically important player is acetylcholine (ACh. Relative to other brain areas, the striatum contains exceptionally high levels of ACh, the enzymes that catalyze its synthesis and breakdown, as well as both nicotinic and muscarinic receptor types that mediate its postsynaptic effects. The principal source of striatal ACh is the cholinergic interneuron (ChI, which comprises only about 1-2% of all striatal cells yet sends dense arbors of projections throughout the striatum. This review summarizes recent advances in our understanding of the factors affecting the excitability of these neurons through acute effects and long term changes in their synaptic inputs. In addition, we discuss the physiological effects of ACh in the striatum, and how changes in ACh levels may contribute to disease states during striatal dysfunction.

  11. Dissecting the functions of conserved prolines within transmembrane helices of the D2 dopamine receptor.

    Science.gov (United States)

    Van Arnam, Ethan B; Lester, Henry A; Dougherty, Dennis A

    2011-10-21

    G protein-coupled receptors (GPCRs) contain a number of conserved proline residues in their transmembrane helices, and it is generally assumed these play important functional and/or structural roles. Here we use unnatural amino acid mutagenesis, employing α-hydroxy acids and proline analogues, to examine the functional roles of five proline residues in the transmembrane helices of the D2 dopamine receptor. The well-known tendency of proline to disrupt helical structure is important at all sites, while we find no evidence for a functional role for backbone amide cis-trans isomerization, another feature associated with proline. At most proline sites, the loss of the backbone NH is sufficient to explain the role of the proline. However, at one site, P210(5.50), a substituent on the backbone N appears to be essential for proper function. Interestingly, the pattern in functional consequences that we see is mirrored in the pattern of structural distortions seen in recent GPCR crystal structures.

  12. Effects of Smoking Cessation on Presynaptic Dopamine Function of Addicted Male Smokers

    DEFF Research Database (Denmark)

    Rademacher, Lena; Prinz, Susanne; Winz, Oliver

    2016-01-01

    putamen of consuming smokers. CONCLUSIONS: The results suggest a lower dopamine synthesis capacity in nicotine-dependent smokers that appears to normalize with abstinence. Further investigations are needed to clarify the role of dopamine in nicotine addiction to help develop smoking prevention...

  13. Dopamine modulates risk-taking as a function of baseline sensation-seeking trait.

    Science.gov (United States)

    Norbury, Agnes; Manohar, Sanjay; Rogers, Robert D; Husain, Masud

    2013-08-07

    Trait sensation-seeking, defined as a need for varied, complex, and intense sensations, represents a relatively underexplored hedonic drive in human behavioral neuroscience research. It is related to increased risk for a range of behaviors including substance use, gambling, and risky sexual practice. Individual differences in self-reported sensation-seeking have been linked to brain dopamine function, particularly at D2-like receptors, but so far no causal evidence exists for a role of dopamine in sensation-seeking behavior in humans. Here, we investigated the effects of the selective D2/D3 agonist cabergoline on performance of a probabilistic risky choice task in healthy humans using a sensitive within-subject, placebo-controlled design. Cabergoline significantly influenced the way participants combined different explicit signals regarding probability and loss when choosing between response options associated with uncertain outcomes. Importantly, these effects were strongly dependent on baseline sensation-seeking score. Overall, cabergoline increased sensitivity of choice to information about probability of winning; while decreasing discrimination according to magnitude of potential losses associated with different options. The largest effects of the drug were observed in participants with lower sensation-seeking scores. These findings provide evidence that risk-taking behavior in humans can be directly manipulated by a dopaminergic drug, but that the effectiveness of such a manipulation depends on baseline differences in sensation-seeking trait. This emphasizes the importance of considering individual differences when investigating manipulation of risky decision-making, and may have relevance for the development of pharmacotherapies for disorders involving excessive risk-taking in humans, such as pathological gambling.

  14. Mechanisms of Kappa Opioid Receptor Potentiation of Dopamine D2 Receptor Function in Quinpirole-Induced Locomotor Sensitization in Rats

    Science.gov (United States)

    Escobar, Angélica P; González, Marcela P; Meza, Rodrigo C; Noches, Verónica; Henny, Pablo; Gysling, Katia; España, Rodrigo A; Fuentealba, José A

    2017-01-01

    Abstract Background Increased locomotor activity in response to the same stimulus is an index of behavioral sensitization observed in preclinical models of drug addiction and compulsive behaviors. Repeated administration of quinpirole, a D2/D3 dopamine agonist, induces locomotor sensitization. This effect is potentiated and accelerated by co-administration of U69593, a kappa opioid receptor agonist. The mechanism underlying kappa opioid receptor potentiation of quinpirole-induced locomotor sensitization remains to be elucidated. Methods Immunofluorescence anatomical studies were undertaken in mice brain slices and rat presynaptic synaptosomes to reveal kappa opioid receptor and D2R pre- and postsynaptic colocalization in the nucleus accumbens. Tonic and phasic dopamine release in the nucleus accumbens of rats repeatedly treated with U69593 and quinpirole was assessed by microdialysis and fast scan cyclic voltammetry. Results Anatomical data show that kappa opioid receptor and D2R colocalize postsynaptically in medium spiny neurons of the nucleus accumbens and the highest presynaptic colocalization occurs on the same dopamine terminals. Significantly reduced dopamine levels were observed in quinpirole, and U69593-quinpirole treated rats, explaining sensitization of D2R. Presynaptic inhibition induced by kappa opioid receptor and D2R of electrically evoked dopamine release was faster in U69593-quinpirole compared with quinpirole-repeatedly treated rats. Conclusions Pre- and postsynaptic colocalization of kappa opioid receptor and D2R supports a role for kappa opioid receptor potentiating both the D2R inhibitory autoreceptor function and the inhibitory action of D2R on efferent medium spiny neurons. Kappa opioid receptor co-activation accelerates D2R sensitization by contributing to decrease dopamine release in the nucleus accumbens. PMID:28531297

  15. A comparison of the effects of the dopamine partial agonists aripiprazole and (-)-3-PPP with quinpirole on stimulated dopamine release in the rat striatum: Studies using fast cyclic voltammetry in vitro.

    Science.gov (United States)

    O'Connor, John J; Lowry, John P

    2012-07-05

    The effects of aripiprazole, (-)-(3-hydroxyphenyl)-N-n-propylpiperidine ((-)-3-PPP) and quinpirole on single and multiple pulse stimulated dopamine release were investigated using the technique of fast cyclic voltammetry (FCV) in isolated rat striatal slices. Aripiprazole and (-)-3-PPP had no significant effect on single pulse dopamine release at concentrations from 10nM to 10μM indicating low agonist activity. The compounds failed to potentiate 5 pulse stimulated release of dopamine although inhibitory effects were seen at 10μM for aripiprazole. Both compounds were tested against the concentration-response curve for quinpirole's inhibition of stimulated single pulse dopamine release. Aripiprazole and (-)-3-PPP shifted the concentration-response curve for quinpirole to the right. In each case this was greater than a 100-fold shift for the 10μM test compound. Whilst these results indicate that both compounds show little agonist activity on dopamine release and significant antagonism of the inhibitory effect of quinpirole on dopamine release, whether they are functionally selective dopamine D(2) ligands remains controversial. Copyright © 2012 Elsevier B.V. All rights reserved.

  16. A Genetic Polymorphism of the Human Dopamine Transporter Determines the Impact of Sleep Deprivation on Brain Responses to Rewards and Punishments.

    Science.gov (United States)

    Greer, Stephanie M; Goldstein, Andrea N; Knutson, Brian; Walker, Matthew P

    2016-06-01

    Despite an emerging link between alterations in motivated behavior and a lack of sleep, the impact of sleep deprivation on human brain mechanisms of reward and punishment remain largely unknown, as does the role of trait dopamine activity in modulating such effects in the mesolimbic system. Combining fMRI with an established incentive paradigm and individual genotyping, here, we test the hypothesis that trait differences in the human dopamine transporter (DAT) gene-associated with altered synaptic dopamine signalling-govern the impact of sleep deprivation on neural sensitivity to impending monetary gains and losses. Consistent with this framework, markedly different striatal reward responses were observed following sleep loss depending on the DAT functional polymorphisms. Only participants carrying a copy of the nine-repeat DAT allele-linked to higher phasic dopamine activity-expressed amplified striatal response during anticipation of monetary gain following sleep deprivation. Moreover, participants homozygous for the ten-repeat DAT allele-linked to lower phasic dopamine activity-selectively demonstrated an increase in sensitivity to monetary loss within anterior insula following sleep loss. Together, these data reveal a mechanistic dependency on human of trait dopaminergic function in determining the interaction between sleep deprivation and neural processing of rewards and punishments. Such findings have clinical implications in disorders where the DAT genetic polymorphism presents a known risk factor with comorbid sleep disruption, including attention hyperactive deficit disorder and substance abuse.

  17. Dopamine Transporters in Striatum Correlate with Deactivation in the Default Mode Network during Visuospatial Attention

    International Nuclear Information System (INIS)

    Tomasi, D.; Fowler, J.; Tomasi, D.; Volkow, N.D.; Wang, R.L.; Telang, F.; Wang, Chang L.; Ernst, T.; Fowler, J.S.

    2009-01-01

    Dopamine and dopamine transporters (DAT, which regulate extracellular dopamine in the brain) are implicated in the modulation of attention but their specific roles are not well understood. Here we hypothesized that dopamine modulates attention by facilitation of brain deactivation in the default mode network (DMN). Thus, higher striatal DAT levels, which would result in an enhanced clearance of dopamine and hence weaker dopamine signals, would be associated to lower deactivation in the DMN during an attention task. For this purpose we assessed the relationship between DAT in striatum (measured with positron emission tomography and [ 11 C]cocaine used as DAT radiotracer) and brain activation and deactivation during a parametric visual attention task (measured with blood oxygenation level dependent functional magnetic resonance imaging) in healthy controls. We show that DAT availability in caudate and putamen had a negative correlation with deactivation in ventral parietal regions of the DMN (precuneus, BA 7) and a positive correlation with deactivation in a small region in the ventral anterior cingulate gyrus (BA 24/32). With increasing attentional load, DAT in caudate showed a negative correlation with load-related deactivation increases in precuneus. These findings provide evidence that dopamine transporters modulate neural activity in the DMN and anterior cingulate gyrus during visuospatial attention. Our findings suggest that dopamine modulates attention in part by regulating neuronal activity in posterior parietal cortex including precuneus (region involved in alertness) and cingulate gyrus (region deactivated in proportion to emotional interference). These findings suggest that the beneficial effects of stimulant medications (increase dopamine by blocking DAT) in inattention reflect in part their ability to facilitate the deactivation of the DMN.

  18. Dopamine transporters in striatum correlate with deactivation in the default mode network during visuospatial attention.

    Directory of Open Access Journals (Sweden)

    Dardo Tomasi

    2009-06-01

    Full Text Available Dopamine and dopamine transporters (DAT, which regulate extracellular dopamine in the brain are implicated in the modulation of attention but their specific roles are not well understood. Here we hypothesized that dopamine modulates attention by facilitation of brain deactivation in the default mode network (DMN. Thus, higher striatal DAT levels, which would result in an enhanced clearance of dopamine and hence weaker dopamine signals, would be associated to lower deactivation in the DMN during an attention task.For this purpose we assessed the relationship between DAT in striatum (measured with positron emission tomography and [(11C]cocaine used as DAT radiotracer and brain activation and deactivation during a parametric visual attention task (measured with blood oxygenation level dependent functional magnetic resonance imaging in healthy controls. We show that DAT availability in caudate and putamen had a negative correlation with deactivation in ventral parietal regions of the DMN (precuneus, BA 7 and a positive correlation with deactivation in a small region in the ventral anterior cingulate gyrus (BA 24/32. With increasing attentional load, DAT in caudate showed a negative correlation with load-related deactivation increases in precuneus.These findings provide evidence that dopamine transporters modulate neural activity in the DMN and anterior cingulate gyrus during visuospatial attention. Our findings suggest that dopamine modulates attention in part by regulating neuronal activity in posterior parietal cortex including precuneus (region involved in alertness and cingulate gyrus (region deactivated in proportion to emotional interference. These findings suggest that the beneficial effects of stimulant medications (increase dopamine by blocking DAT in inattention reflect in part their ability to facilitate the deactivation of the DMN.

  19. Dopamine Transporters in Striatum Correlated with Deactivation in the Default Mode Network during Visuospatial Attention

    Energy Technology Data Exchange (ETDEWEB)

    Tomasi, D.; Fowler, J.; Tomasi, D.; Volkow, N.D.; Wang, R.L.; Telang, F.; Wang, Chang, L.; Ernst, T.; /Fowler, J.S.

    2009-06-01

    Dopamine and dopamine transporters (DAT, which regulate extracellular dopamine in the brain) are implicated in the modulation of attention but their specific roles are not well understood. Here we hypothesized that dopamine modulates attention by facilitation of brain deactivation in the default mode network (DMN). Thus, higher striatal DAT levels, which would result in an enhanced clearance of dopamine and hence weaker dopamine signals, would be associated to lower deactivation in the DMN during an attention task. For this purpose we assessed the relationship between DAT in striatum (measured with positron emission tomography and [{sup 11}C]cocaine used as DAT radiotracer) and brain activation and deactivation during a parametric visual attention task (measured with blood oxygenation level dependent functional magnetic resonance imaging) in healthy controls. We show that DAT availability in caudate and putamen had a negative correlation with deactivation in ventral parietal regions of the DMN (precuneus, BA 7) and a positive correlation with deactivation in a small region in the ventral anterior cingulate gyrus (BA 24/32). With increasing attentional load, DAT in caudate showed a negative correlation with load-related deactivation increases in precuneus. These findings provide evidence that dopamine transporters modulate neural activity in the DMN and anterior cingulate gyrus during visuospatial attention. Our findings suggest that dopamine modulates attention in part by regulating neuronal activity in posterior parietal cortex including precuneus (region involved in alertness) and cingulate gyrus (region deactivated in proportion to emotional interference). These findings suggest that the beneficial effects of stimulant medications (increase dopamine by blocking DAT) in inattention reflect in part their ability to facilitate the deactivation of the DMN.

  20. Simultaneous 99mTC and 123I Dual-Isotope Brain Striatal Phantom Single Photon Emission Computed Tomography: Validation of 99mTC-Trodat-1 and 123I-IBZM Simultaneous Dopamine System Brain Imaging

    OpenAIRE

    Pan-Fu Kao; Shiaw-Pyng Wey; An-Shoei Yang

    2009-01-01

    [2[[2-[[[3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3,2,1]-oct-2-yl]-methyl](2-mercaptoethyl)amino]ethyl]amino]ethanethiolato(3-)-N2,N2′,S2,S2]oxo-[1R-exo-exo)])-[99mTc]-technetium (99mTc-TRODAT-1) and 123I-iodobenzamide (123I-IBZM) are radiotracers for brain dopamine preand postsynaptic neuron imaging. The purpose of this study was to evaluate imaging parameters and crossed energy interference using simultaneous single photon emission computed tomography (SPECT) 99mTc and 123I data acquisition...

  1. Hypercholesterolemia causes psychomotor abnormalities in mice and alterations in cortico-striatal biogenic amine neurotransmitters: Relevance to Parkinson's disease.

    Science.gov (United States)

    Paul, Rajib; Choudhury, Amarendranath; Chandra Boruah, Dulal; Devi, Rajlakshmi; Bhattacharya, Pallab; Choudhury, Manabendra Dutta; Borah, Anupom

    2017-09-01

    The symptoms of Parkinson's disease (PD) include motor behavioral abnormalities, which appear as a result of the extensive loss of the striatal biogenic amine, dopamine. Various endogenous molecules, including cholesterol, have been put forward as putative contributors in the pathogenesis of PD. Earlier reports have provided a strong link between the elevated level of plasma cholesterol (hypercholesterolemia) and onset of PD. However, the role of hypercholesterolemia on brain functions in terms of neurotransmitter metabolism and associated behavioral manifestations remain elusive. We tested in Swiss albino mice whether hypercholesterolemia induced by high-cholesterol diet would affect dopamine and serotonin metabolism in discrete brain regions that would precipitate in psychomotor behavioral manifestations. High-cholesterol diet for 12 weeks caused a significant increase in blood total cholesterol level, which validated the model as hypercholesterolemic. Tests for akinesia, catalepsy, swimming ability and gait pattern (increased stride length) have revealed that hypercholesterolemic mice develop motor behavioral abnormalities, which are similar to the behavioral phenotypes of PD. Moreover, hypercholesterolemia caused depressive-like behavior in mice, as indicated by the increased immobility time in the forced swim test. We found a significant depletion of dopamine in striatum and serotonin in cortex of hypercholesterolemic mice. The significant decrease in tyrosine hydroxylase immunoreactivity in striatum supports the observed depleted level dopamine in striatum, which is relevant to the pathophysiology of PD. In conclusion, hypercholesterolemia-induced depleted levels of cortical and striatal biogenic amines reported hereby are similar to the PD pathology, which might be associated with the observed psychomotor behavioral abnormalities. Copyright © 2017 Elsevier Ltd. All rights reserved.

  2. Adenosine A₂A receptors in striatal glutamatergic terminals and GABAergic neurons oppositely modulate psychostimulant action and DARPP-32 phosphorylation.

    Directory of Open Access Journals (Sweden)

    Hai-Ying Shen

    Full Text Available Adenosine A2A receptors (A2AR are located postsynaptically in striatopallidal GABAergic neurons, antagonizing dopamine D2 receptor functions, and are also located presynaptically at corticostriatal terminals, facilitating glutamate release. To address the hypothesis that these two A2AR populations differently control the action of psychostimulants, we characterized A2AR modulation of cocaine-induced effects at the level of DARPP-32 phosphorylation at Thr-34 and Thr-75, c-Fos expression, and psychomotor activity using two lines of cell-type selective A2AR knockout (KO mice with selective A2AR deletion in GABAergic neurons (striatum-A2AR-KO mice, or with A2AR deletion in both striatal GABAergic neurons and projecting cortical glutamatergic neurons (forebrain-A2AR-KO mice. We demonstrated that striatum-A2AR KO mice lacked A2ARs exclusively in striatal GABAergic terminals whereas forebrain-A2AR KO mice lacked A2ARs in both striatal GABAergic and glutamatergic terminals leading to a blunted A2AR-mediated facilitation of synaptosomal glutamate release. The inactivation of A2ARs in GABAergic neurons reduced striatal DARPP-32 phosphorylation at Thr-34 and increased its phosphorylation at Thr-75. Conversely, the additional deletion of corticostriatal glutamatergic A2ARs produced opposite effects on DARPP-32 phosphorylation at Thr-34 and Thr-75. This distinct modulation of DARPP-32 phosphorylation was associated with opposite responses to cocaine-induced striatal c-Fos expression and psychomotor activity in striatum-A2AR KO (enhanced and forebrain-A2AR KO mice (reduced. Thus, A2ARs in glutamatergic corticostriatal terminals and in GABAergic striatal neurons modulate the action of psychostimulants and DARPP-32 phosphorylation in opposite ways. We conclude that A2ARs in glutamatergic terminals prominently control the action of psychostimulants and define a novel mechanism by which A2ARs fine-tune striatal activity by integrating GABAergic, dopaminergic and

  3. Regulation of GABA and benzodiazepine receptors following neurotoxin-induced striatal and medial forebrain bundle lesions

    International Nuclear Information System (INIS)

    Pan, H.S.I.

    1985-01-01

    GABA, a major inhibitory transmitter, is used by many projection neurons of the striatum. To investigate the role of GABA in striatal function, the GABA receptor complex was studied after lesions of the striatum or the nigrostriatal neurons. Quantitative receptor autoradiography using thaw-mounted tissue slices was developed for the study of GABA and benzodiazepine (BDZ) receptors. With the technique established, binding to GABA and BDZ receptors after unilateral striatal kainate lesions was examined. Subsequently, changes in GABA and BDZ receptors were studied following the destruction of dopaminergic nigrostriatal cells by unilateral 6-hydroxydopamine lesion of the medial forebrain bundle. In summary, quantitative receptor autoradiography allowed the detection of GABA and BDZ receptor changes in multiple small areas in each lesioned brain. This technique made it feasible to carry out kinetic saturation, and competition studies using less than 1 mg of tissue. The data suggest that dopamine is functionally inhibitory on striatopallidal neurons but is functionally excitatory on striatoentopeduncular and striatonigral cells which in turn inhibit the thalamus. This quantitative autoradiographic technique can be generalized to study other transmitter receptors and can be combined with 2-deoxyglucose uptake studies

  4. Delusional parasitosis and the dopamine transporter. A new insight of etiology?

    Science.gov (United States)

    Huber, M; Kirchler, E; Karner, M; Pycha, R

    2007-01-01

    Delusional parasitosis (DP) is a psychotic condition in which a person has the unshakeable and mistaken belief (delusion) and/or aberrant perception (hallucination) of being infested with parasites. The disorder will be usually classified in a primary DP-group without a detectable cause (so-called pure forms), while secondary DP-groups are associated with general organic conditions, psychiatric illnesses and drugs (substance induced). Etiology and pathophysiology of DP remain however unknown. In the present paper we hypothesize for the first time a decreased striatal dopamine transporter (DAT)-functioning (corresponding with an increased extracellular dopamine-level) as etiologic condition for DP (primary and secondary groups). The DAT as key regulator of the dopamine-reuptake in the human brain is well known (regulation of the extracellular dopamine concentration). It is a presynaptic plasma membrane protein highly dense represented in the striatum. The hypothesis of a decreased DAT-functioning as etiologic condition by DP is revealed in case reports which show that DAT-inhibitors, such as cocaine, pemoline, methylphenidate and other amphetamine-derivatives can induce the clinical expression of DP. Several other associated causes of secondary DP-groups (medications, parkinson, chorea huntington, multiple system atrophy, diabetes, cerebrovascular diseases, alcoholism, traumatic brain injury, hyperuricemia, human immunodeficiency virus, iron deficiency, schizophrenia, depression) suggest that the clinical expression of DP may be related to a decreased striatal DAT-functioning (blocking, reduced ligand binding, reduced density, reduced activity). Our examined DP-cases (2-females) show means of magnetic resonance imaging a structurally damaged striatum. Furthermore, we presume that by the primary DP-group, the physiologically age-related decline of the DAT-density is pathologically elevated. Based on this hypothesis we show in the present paper the relation between DP

  5. Au nanoparticles on tryptophan-functionalized graphene for sensitive detection of dopamine

    Energy Technology Data Exchange (ETDEWEB)

    Lian, Qianwen; Luo, Ai; An, Zhenzhen; Li, Zhuang; Guo, Yongyang; Zhang, Dongxia [Key Laboratory of Bioelectrochemistry & Environmental Analysis of Gansu Province, College of Geography and Environment Science, Northwest Normal University, 730070, Lanzhou (China); Xue, Zhonghua [College of Chemistry and Chemical Engineering, Northwest Normal University, 730070, Lanzhou (China); Zhou, Xibin, E-mail: zhouxb@nwnu.edu.cn [Key Laboratory of Bioelectrochemistry & Environmental Analysis of Gansu Province, College of Geography and Environment Science, Northwest Normal University, 730070, Lanzhou (China); Lu, Xiaoquan, E-mail: Luxq@nwnu.edu.cn [College of Chemistry and Chemical Engineering, Northwest Normal University, 730070, Lanzhou (China)

    2015-09-15

    Graphical abstract: - Highlights: • A novel AuNPs/Trp-GR composite was fabricated by directly electrochemical deposition. • The composite exhibited excellent electrocatalytic activity towards DA. • The proposed method was applied to real samples. - Abstract: A novel and uniform gold nanoparticles/tryptophan-functionalized graphene nanocomposite (AuNPs/Trp-GR) has been successfully fabricated by directly electrochemical depositing gold onto the surface of tryptophan-functionalized graphene (Trp-GR). The nanostructure of AuNPs/Trp-GR was characterized by using scanning electron microscopy (SEM) and energy dispersive X-ray spectroscopy (EDS). It was demonstrated that Au nanoparticles were well dispersed on the surface of Trp-GR which might attribute to the more binding sites provided by Trp-GR for the formation of Au nanoparticles. The electrocatalytic activity of the AuNPs/Trp-GR towards the dopamine (DA) was systematically investigated using cyclic voltammetry (CV) and differential pulse voltammetry (DPV). Under optimum conditions, a wide and valuable linear range (0.5–411 μM), a low detection limit (0.056 μM, S/N = 3), good repeatability and stability were obtained for the determination of DA. Furthermore, the modified electrode was successfully applied to real samples analysis.

  6. Recognition of benztropine by the dopamine transporter (DAT) differs from that of the classical dopamine uptake inhibitors cocaine, methylphenidate, and mazindol as a function of a DAT transmembrane 1 aspartic acid residue.

    Science.gov (United States)

    Ukairo, Okechukwu T; Bondi, Corry D; Newman, Amy Hauck; Kulkarni, Santosh S; Kozikowski, Alan P; Pan, Stephen; Surratt, Christopher K

    2005-08-01

    Binding of cocaine to the dopamine transporter (DAT) protein blocks synaptic dopamine clearance, triggering the psychoactive effects associated with the drug; the discrete drug-protein interactions, however, remain poorly understood. A longstanding postulate holds that cocaine inhibits DAT-mediated dopamine transport via competition with dopamine for formation of an ionic bond with the DAT transmembrane aspartic acid residue D79. In the present study, DAT mutations of this residue were generated and assayed for translocation of radiolabeled dopamine and binding of radiolabeled DAT inhibitors under identical conditions. When feasible, dopamine uptake inhibition potency and apparent binding affinity K(i) values were determined for structurally diverse DAT inhibitors. The glutamic acid substitution mutant (D79E) displayed values indistinguishable from wild-type DAT in both assays for the charge-neutral cocaine analog 8-oxa-norcocaine, a finding not supportive of the D79 "salt bridge" ligand-docking model. In addressing whether the D79 side chain contributes to the DAT binding sites of other portions of the cocaine pharmacophore, only inhibitors with modifications of the tropane ring C-3 substituent, i.e., benztropine and its analogs, displayed a substantially altered dopamine uptake inhibition potency as a function of the D79E mutation. A single conservative amino acid substitution thus differentiated structural requirements for benztropine function relative to those for all other classical DAT inhibitors. Distinguishing the precise mechanism of action of this DAT inhibitor with relatively low abuse liability from that of cocaine may be attainable using DAT mutagenesis and other structure-function studies, opening the door to rational design of therapeutic agents for cocaine abuse.

  7. Effects of dopamine on renal haemodynamics tubular function and sodium excretion in normal humans

    DEFF Research Database (Denmark)

    Olsen, Niels Vidiendal

    1998-01-01

    of critically ill patients with low cardiac output states and/or acute oliguric renal failure. Pharmacological effects of dopamine are dose dependent. Low doses of dopamine predominantly stimulate dopaminergic receptors, but with increasing doses actions secondary to stimulation of adrenergic beta(1) and alpha...... to a decrease in peripheral vascular resistance, independent of effects of beta(1) receptors on cardiac contractility and heart rate. Dose-response studies demonstrated that the dopamine-induced increase in effective renal plasma flow (ERPF) reaches its maximum at 3 micrograms/kg/min. The increase in ERPF...... ranging from 1 to 5 micrograms/kg/min caused about a two-fold increase in sodium excretion. At doses at and above 7.5 micrograms/kg/min which increased mean arterial pressure, dopamine further increased sodium clearance (CNa) while ERPF was decreasing, indicating the contribution of pressure natriuresis...

  8. Renal rescue of dopamine D2 receptor function reverses renal injury and high blood pressure

    Science.gov (United States)

    Konkalmatt, Prasad R.; Asico, Laureano D.; Zhang, Yanrong; Yang, Yu; Drachenberg, Cinthia; Zheng, Xiaoxu; Han, Fei; Jose, Pedro A.; Armando, Ines

    2016-01-01

    Dopamine D2 receptor (DRD2) deficiency increases renal inflammation and blood pressure in mice. We show here that long-term renal-selective silencing of Drd2 using siRNA increases renal expression of proinflammatory and profibrotic factors and blood pressure in mice. To determine the effects of renal-selective rescue of Drd2 expression in mice, the renal expression of DRD2 was first silenced using siRNA and 14 days later rescued by retrograde renal infusion of adeno-associated virus (AAV) vector with DRD2. Renal Drd2 siRNA treatment decreased the renal expression of DRD2 protein by 55%, and DRD2 AAV treatment increased the renal expression of DRD2 protein by 7.5- to 10-fold. Renal-selective DRD2 rescue reduced the expression of proinflammatory factors and kidney injury, preserved renal function, and normalized systolic and diastolic blood pressure. These results demonstrate that the deleterious effects of renal-selective Drd2 silencing on renal function and blood pressure were rescued by renal-selective overexpression of DRD2. Moreover, the deleterious effects of 45-minute bilateral ischemia/reperfusion on renal function and blood pressure in mice were ameliorated by a renal-selective increase in DRD2 expression by the retrograde ureteral infusion of DRD2 AAV immediately after the induction of ischemia/reperfusion injury. Thus, 14 days after ischemia/reperfusion injury, the renal expression of profibrotic factors, serum creatinine, and blood pressure were lower in mice infused with DRD2 AAV than in those infused with control AAV. These results indicate an important role of renal DRD2 in limiting renal injury and preserving normal renal function and blood pressure. PMID:27358912

  9. Dopamine-independent locomotor actions of amphetamines in a novel acute mouse model of Parkinson disease.

    Directory of Open Access Journals (Sweden)

    2005-08-01

    Full Text Available Brain dopamine is critically involved in movement control, and its deficiency is the primary cause of motor symptoms in Parkinson disease. Here we report development of an animal model of acute severe dopamine deficiency by using mice lacking the dopamine transporter. In the absence of transporter-mediated recycling mechanisms, dopamine levels become entirely dependent on de novo synthesis. Acute pharmacological inhibition of dopamine synthesis in these mice induces transient elimination of striatal dopamine accompanied by the development of a striking behavioral phenotype manifested as severe akinesia, rigidity, tremor, and ptosis. This phenotype can be reversed by administration of the dopamine precursor, L-DOPA, or by nonselective dopamine agonists. Surprisingly, several amphetamine derivatives were also effective in reversing these behavioral abnormalities in a dopamine-independent manner. Identification of dopamine transporter- and dopamine-independent locomotor actions of amphetamines suggests a novel paradigm in the search for prospective anti-Parkinsonian drugs.

  10. 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

  11. Cognitive function is related to fronto-striatal serotonin transporter levels--a brain PET study in young healthy subjects

    DEFF Research Database (Denmark)

    Madsen, Karine; Erritzøe, David Frederik; Mortensen, Erik Lykke

    2011-01-01

    Pharmacological manipulation of serotonergic neurotransmission in healthy volunteers impacts on cognitive test performance. Specifically, markers of serotonin function are associated with attention and executive functioning, long-term memory, and general cognitive ability. The serotonin transporter...

  12. Increased Motor Activity During REM Sleep Is Linked with Dopamine Function in Idiopathic REM Sleep Behaviour Disorder and Parkinson Disease

    DEFF Research Database (Denmark)

    Zoetmulder, Marielle; Nikolic, Miki; Biernat, Heidi

    2016-01-01

    STUDY OBJECTIVES: Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia characterized by impaired motor inhibition during REM sleep, and dream-enacting behavior. RBD is especially associated with α-synucleinopathies, such as Parkinson disease (PD). Follow-up studies have shown...... that patients with idiopathic RBD (iRBD) have an increased risk of developing an α-synucleinopathy in later life. Although abundant studies have shown that degeneration of the nigrostriatal dopaminergic system is associated with daytime motor function in Parkinson disease, only few studies have investigated...... in the putamen. In PD patients, EMG-activity was correlated to anti-Parkinson medication. CONCLUSIONS: Our results support the hypothesis that increased EMG-activity during REM sleep is at least partly linked to the nigrostriatal dopamine system in iRBD, and with dopamine function in PD....

  13. Increased Motor Activity During REM Sleep Is Linked with Dopamine Function in Idiopathic REM Sleep Behavior Disorder and Parkinson Disease

    DEFF Research Database (Denmark)

    Zoetmulder, Marielle; Nikolic, Miki; Biernat, Heidi B

    2016-01-01

    STUDY OBJECTIVES: Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia characterized by impaired motor inhibition during REM sleep, and dream-enacting behavior. RBD is especially associated with α-synucleinopathies, such as Parkinson disease (PD). Follow-up studies have shown...... that patients with idiopathic RBD (iRBD) have an increased risk of developing an α-synucleinopathy in later life. Although abundant studies have shown that degeneration of the nigrostriatal dopaminergic system is associated with daytime motor function in Parkinson disease, only few studies have investigated......-FP-CIT uptake in the putamen. In PD patients, EMG-activity was correlated to anti-Parkinson medication. CONCLUSIONS: Our results support the hypothesis that increased EMG-activity during REM sleep is at least partly linked to the nigrostriatal dopamine system in iRBD, and with dopamine function in PD....

  14. COMT Val(158) met genotype and striatal D(2/3) receptor binding in adults with 22q11 deletion syndrome.

    LENUS (Irish Health Repository)

    Boot, Erik

    2011-09-01

    Although catechol-O-methyltransferase (COMT) activity evidently affects dopamine function in prefrontal cortex, the contribution is assumed less significant in striatum. We studied whether a functional polymorphism in the COMT gene (Val(158) Met) influences striatal D(2\\/3) R binding ratios (D(2\\/3) R BP(ND) ) in 15 adults with 22q11 deletion syndrome and hemizygous for this gene, using single photon emission computed tomography and the selective D(2\\/3) radioligand [(123) I]IBZM. Met hemizygotes had significantly lower mean D(2\\/3) R BPND than Val hemizygotes. These preliminary data suggest that low COMT activity may affect dopamine levels in striatum in humans and this may have implications for understanding the contribution of COMT activity to psychiatric disorders.

  15. Syntaxin 1A interaction with the dopamine transporter promotes amphetamine-induced dopamine efflux

    DEFF Research Database (Denmark)

    Binda, Francesca; Dipace, Concetta; Bowton, Erica

    2008-01-01

    of the dopamine (DA) transporter (DAT) as the site of direct interaction with SYN1A. Amphetamine (AMPH) increases the association of SYN1A with human DAT (hDAT) in a heterologous expression system (hDAT cells) and with native DAT in murine striatal synaptosomes. Immunoprecipitation of DAT from the biotinylated...

  16. Altered resting-state functional connectivity of the frontal-striatal reward system in social anxiety disorder.

    Directory of Open Access Journals (Sweden)

    Joshua Manning

    Full Text Available We investigated differences in the intrinsic functional brain organization (functional connectivity of the human reward system between healthy control participants and patients with social anxiety disorder. Functional connectivity was measured in the resting-state via functional magnetic resonance imaging (fMRI. 53 patients with social anxiety disorder and 33 healthy control participants underwent a 6-minute resting-state fMRI scan. Functional connectivity of the reward system was analyzed by calculating whole-brain temporal correlations with a bilateral nucleus accumbens seed and a ventromedial prefrontal cortex seed. Patients with social anxiety disorder, relative to the control group, had (1 decreased functional connectivity between the nucleus accumbens seed and other regions associated with reward, including ventromedial prefrontal cortex; (2 decreased functional connectivity between the ventromedial prefrontal cortex seed and lateral prefrontal regions, including the anterior and dorsolateral prefrontal cortices; and (3 increased functional connectivity between both the nucleus accumbens seed and the ventromedial prefrontal cortex seed with more posterior brain regions, including anterior cingulate cortex. Social anxiety disorder appears to be associated with widespread differences in the functional connectivity of the reward system, including markedly decreased functional connectivity between reward regions and between reward regions and lateral prefrontal cortices, and markedly increased functional connectivity between reward regions and posterior brain regions.

  17. Functionalized Ergot-alkaloids as potential dopamine D3 receptor agonists for treatment of schizophrenia

    Science.gov (United States)

    Ivanova, Bojidarka; Spiteller, Michael

    2012-12-01

    The relationship between the molecular structure and physical properties of functionalized naturally occurred Ergot-alkaloids as potential dopamine D3 receptor agonists is presented. The molecular modeling of the ergoline-skeleton is based on the comprehensive theoretical study of the binding affinity of the isolated chemicals towards the active sites of the D3 sub-type receptor (D3R) loops. The studied proton accepting ability under physiological conditions allows classifying four types of monocationics, characterizing with the different binding modes to D3R involving selected amino acid residues to the active sites. These results marked the pharmaceutical potential and clinical usage of the reported compounds as antipsychotic drugs for Schizophrenia treatment, since they allowed evaluating the highlights of the different hypothesizes of the biochemical causes the illness. The applied complex approach for theoretical and experimental elucidation, including quantum chemistry method, electrospray ionization (ESI) and matrix assisted laser desorption/ionization (MALDI) mass spectrometric (MS) methods, nuclear magnetic resonance and vibrational IR and Raman spectroscopy on the isolated fifteen novel derivatives (1)-(15) and their different protonated forms (1a)-(15a) evidenced a strong dependence of molecular conformation, physical properties and binding affinity. Thus, the semi-synthetic functionalization of the naturally occurred products (NPs), provided significant possibilities to further molecular drugs-design and development of novel derivatives with wanted biological function, using the established profile of selected classes/families of NPs. The work described chiefly the non-linear (NL) approach for the interpretation of the mass chromatograms on the performed hybrid high performance liquid chromatography (HPLC) tandem MS/MS and MS/MS/MS experiments, discussing the merits and great diversity of instrumentation flexibility, thus achieving fundamental

  18. Abnormal striatal dopaminergic neurotransmission during rest and task production in spasmodic dysphonia.

    Science.gov (United States)

    Simonyan, Kristina; Berman, Brian D; Herscovitch, Peter; Hallett, Mark

    2013-09-11

    Spasmodic dysphonia is a primary focal dystonia characterized by involuntary spasms in the laryngeal muscles during speech production. The pathophysiology of spasmodic dysphonia is thought to involve structural and functional abnormalities in the basal ganglia-thalamo-cortical circuitry; however, neurochemical correlates underpinning these abnormalities as well as their relations to spasmodic dysphonia symptoms remain unknown. We used positron emission tomography with the radioligand [(11)C]raclopride (RAC) to study striatal dopaminergic neurotransmission at the resting state and during production of symptomatic sentences and asymptomatic finger tapping in spasmodic dysphonia patients. We found that patients, compared to healthy controls, had bilaterally decreased RAC binding potential (BP) to striatal dopamine D2/D3 receptors on average by 29.2%, which was associated with decreased RAC displacement (RAC ΔBP) in the left striatum during symptomatic speaking (group average difference 10.2%), but increased RAC ΔBP in the bilateral striatum during asymptomatic tapping (group average difference 10.1%). Patients with more severe voice symptoms and subclinically longer reaction time to initiate the tapping sequence had greater RAC ΔBP measures, while longer duration of spasmodic dysphonia was associated with a decrease in task-induced RAC ΔBP. Decreased dopaminergic transmission during symptomatic speech production may represent a disorder-specific pathophysiological trait involved in symptom generation, whereas increased dopaminergic function during unaffected task performance may be explained by a compensatory adaptation of the nigrostriatal dopaminergic system possibly due to decreased striatal D2/D3 receptor availability. These changes can be linked to the clinical and subclinical features of spasmodic dysphonia and may represent the neurochemical basis of basal ganglia alterations in this disorder.

  19. A simple algorithm for subregional striatal uptake analysis with partial volume correction in dopaminergic PET imaging

    International Nuclear Information System (INIS)

    Lue Kunhan; Lin Hsinhon; Chuang Kehshih; Kao Chihhao, K.; Hsieh Hungjen; Liu Shuhsin

    2014-01-01

    In positron emission tomography (PET) of the dopaminergic system, quantitative measurements of nigrostriatal dopamine function are useful for differential diagnosis. A subregional analysis of striatal uptake enables the diagnostic performance to be more powerful. However, the partial volume effect (PVE) induces an underestimation of the true radioactivity concentration in small structures. This work proposes a simple algorithm for subregional analysis of striatal uptake with partial volume correction (PVC) in dopaminergic PET imaging. The PVC algorithm analyzes the separate striatal subregions and takes into account the PVE based on the recovery coefficient (RC). The RC is defined as the ratio of the PVE-uncorrected to PVE-corrected radioactivity concentration, and is derived from a combination of the traditional volume of interest (VOI) analysis and the large VOI technique. The clinical studies, comprising 11 patients with Parkinson's disease (PD) and 6 healthy subjects, were used to assess the impact of PVC on the quantitative measurements. Simulations on a numerical phantom that mimicked realistic healthy and neurodegenerative situations were used to evaluate the performance of the proposed PVC algorithm. In both the clinical and the simulation studies, the striatal-to-occipital ratio (SOR) values for the entire striatum and its subregions were calculated with and without PVC. In the clinical studies, the SOR values in each structure (caudate, anterior putamen, posterior putamen, putamen, and striatum) were significantly higher by using PVC in contrast to those without. Among the PD patients, the SOR values in each structure and quantitative disease severity ratings were shown to be significantly related only when PVC was used. For the simulation studies, the average absolute percentage error of the SOR estimates before and after PVC were 22.74% and 1.54% in the healthy situation, respectively; those in the neurodegenerative situation were 20.69% and 2

  20. Dopamine agonists and risk: impulse control disorders in Parkinson's disease.

    Science.gov (United States)

    Voon, Valerie; Gao, Jennifer; Brezing, Christina; Symmonds, Mkael; Ekanayake, Vindhya; Fernandez, Hubert; Dolan, Raymond J; Hallett, Mark

    2011-05-01

    Impulse control disorders are common in Parkinson's disease, occurring in 13.6% of patients. Using a pharmacological manipulation and a novel risk taking task while performing functional magnetic resonance imaging, we investigated the relationship between dopamine agonists and risk taking in patients with Parkinson's disease with and without impulse control disorders. During functional magnetic resonance imaging, subjects chose between two choices of equal expected value: a 'Sure' choice and a 'Gamble' choice of moderate risk. To commence each trial, in the 'Gain' condition, individuals started at $0 and in the 'Loss' condition individuals started at -$50 below the 'Sure' amount. The difference between the maximum and minimum outcomes from each gamble (i.e. range) was used as an index of risk ('Gamble Risk'). Sixteen healthy volunteers were behaviourally tested. Fourteen impulse control disorder (problem gambling or compulsive shopping) and 14 matched Parkinson's disease controls were tested ON and OFF dopamine agonists. Patients with impulse control disorder made more risky choices in the 'Gain' relative to the 'Loss' condition along with decreased orbitofrontal cortex and anterior cingulate activity, with the opposite observed in Parkinson's disease controls. In patients with impulse control disorder, dopamine agonists were associated with enhanced sensitivity to risk along with decreased ventral striatal activity again with the opposite in Parkinson's disease controls. Patients with impulse control disorder appear to have a bias towards risky choices independent of the effect of loss aversion. Dopamine agonists enhance sensitivity to risk in patients with impulse control disorder possibly by impairing risk evaluation in the striatum. Our results provide a potential explanation of why dopamine agonists may lead to an unconscious bias towards risk in susceptible individuals.

  1. Dopamine agonists and risk: impulse control disorders in Parkinson's; disease

    Science.gov (United States)

    Gao, Jennifer; Brezing, Christina; Symmonds, Mkael; Ekanayake, Vindhya; Fernandez, Hubert; Dolan, Raymond J.; Hallett, Mark

    2011-01-01

    Impulse control disorders are common in Parkinson's; disease, occurring in 13.6% of patients. Using a pharmacological manipulation and a novel risk taking task while performing functional magnetic resonance imaging, we investigated the relationship between dopamine agonists and risk taking in patients with Parkinson's; disease with and without impulse control disorders. During functional magnetic resonance imaging, subjects chose between two choices of equal expected value: a ‘Sure’ choice and a ‘Gamble’ choice of moderate risk. To commence each trial, in the ‘Gain’ condition, individuals started at $0 and in the ‘Loss’ condition individuals started at −$50 below the ‘Sure’ amount. The difference between the maximum and minimum outcomes from each gamble (i.e. range) was used as an index of risk (‘Gamble Risk’). Sixteen healthy volunteers were behaviourally tested. Fourteen impulse control disorder (problem gambling or compulsive shopping) and 14 matched Parkinson's; disease controls were tested ON and OFF dopamine agonists. Patients with impulse control disorder made more risky choices in the ‘Gain’ relative to the ‘Loss’ condition along with decreased orbitofrontal cortex and anterior cingulate activity, with the opposite observed in Parkinson's; disease controls. In patients with impulse control disorder, dopamine agonists were associated with enhanced sensitivity to risk along with decreased ventral striatal activity again with the opposite in Parkinson's; disease controls. Patients with impulse control disorder appear to have a bias towards risky choices independent of the effect of loss aversion. Dopamine agonists enhance sensitivity to risk in patients with impulse control disorder possibly by impairing risk evaluation in the striatum. Our results provide a potential explanation of why dopamine agonists may lead to an unconscious bias towards risk in susceptible individuals. PMID:21596771

  2. Transcriptional regulation of renal dopamine D1 receptor function during oxidative stress.

    Science.gov (United States)

    Banday, Anees A; Lokhandwala, Mustafa F

    2015-05-01

    There exists a strong link between oxidative stress, renal dopaminergic system, and hypertension. It is reported that reactive oxygen species attenuate renal proximal tubular dopamine receptor (D1R) function, which disrupts sodium regulation and leads to hypertension. However, the mechanisms for renal D1R dysfunction are not clear. We investigated the role of redox-sensitive transcription factors AP1 and SP3 in transcriptional suppression of D1R gene and subsequent D1R signaling. Human kidney proximal tubular cells were treated with a pro-oxidant l-buthionine sulfoximine (BSO) with and without an antioxidant tempol. In human kidney cells, BSO caused oxidative stress and reduced D1R mRNA and membrane receptor expression. Incubation of human kidney cells with SKF38393, a D1R agonist, caused a concentration-dependent inhibition of Na/K-ATPase. However, SKF38393 failed to inhibit Na/K-ATPase in BSO-treated cells. BSO increased AP1 and SP3 nuclear expression. Transfection with AP1- or SP3-specific siRNA abolished BSO-induced D1R downregulation. Treatment of rats with BSO for 4 weeks increased oxidative stress and SP3-AP1 expression and reduced D1R numbers in renal proximal tubules. These rats exhibited high blood pressure, and SKF38393 failed to inhibit proximal tubular Na/K-ATPase activity. Control rats were kept on tap water. Tempol per se had no effect on D1R expression or other signaling molecules but prevented BSO-induced oxidative stress, SP3-AP1 upregulation, and D1R dysfunction in both human kidney cells and rats. These data show that oxidative stress via AP1-SP3 activation suppresses D1R transcription and function. Tempol mitigates oxidative stress, blocks AP1-SP3 activation, and prevents D1R dysfunction and hypertension. © 2015 American Heart Association, Inc.

  3. Tunable fabrication of hierarchical hybrids via the incorporation of poly(dopamine) functional interlayer

    Energy Technology Data Exchange (ETDEWEB)

    Xu, Ting; Zhao, Xin; Zhang, Junxian; Dong, Jie; Zhang, Qinghua, E-mail: qhzhang@dhu.edu.cn

    2016-04-30

    Highlights: • PS/PDA with well-defined core/shell structures was prepared in aqueous solution. • Au NPs were coated on PS/PDA by in-situ reduction and self-assembly approach. • PS/PDA/Au had homogeneous and dense Au coatings with different shape. • Hierarchical spheres exhibited a well-defined core/shell structure maintaining the spherical morphology. - Abstract: Two kinds of ternary hybrids were prepared by anchoring different shapes and loadings of Au nanoparticles (NPs) on poly(dopamine) (PDA) functionalized polystyrene (PS) microspheres with two different strategies, i.e., in situ reduction and self-assembly approach. PDA coatings were firstly introduced to functionalize the hydrophobic PS surface with sufficient amino and hydroxyl groups, which enhanced the interaction between Au NPs and the polymer spheres. Thus, Au NPs could be easily immobilized onto the surface of the PDA/PS microspheres, and the hierarchical composite microspheres exhibited a well-defined core/shell structure without sacrificing the spherical PS morphology. PS/PDA/Au-R and PS/PDA/Au-A microspheres fabricated by in situ reduction and self-assembly approach showed different distinct Au nano-shell morphology with the corresponding optical, catalytic and electrochemical properties. Field emission scanning electron microscopy and transmission electronic microscopy verified these hierarchical structures with the ultrathin PDA film incorporating between the inner PS core and the outer Au NPs shell. X-ray diffraction and X-ray photoelectron spectroscopy confirmed the presence of PDA and Au layer on the surface of the composite particles. These green and facile methods with mild experimental conditions can extend to fabricate other polymer or inorganic substrates coated by various noble metals.

  4. Synthesis and binding to striatal membranes of non carrier added I-123 labeled 4'-iodococaine

    International Nuclear Information System (INIS)

    Metwally, S.A.M.; Gatley, S.J.; Wolf, A.P.; Yu, D.-W.

    1992-01-01

    An 123 I labeled cocaine analog, 4'-[ 123 I]iodococaine, has been prepared by oxidative destannylation of the tributyltin analog and shown to interact with cocaine binding sites in rat brain striatal membranes. It may thus be a suitable SPECT radiotracer for studies of the dopamine reuptake site in neurodegenerative diseases. (Author)

  5. DRD4 and striatal modulation of the link between childhood behavioral inhibition and adolescent anxiety

    Science.gov (United States)

    Hardee, Jillian E.; Guyer, Amanda E.; Benson, Brenda E.; Nelson, Eric E.; Gorodetsky, Elena; Goldman, David; Fox, Nathan A.; Pine, Daniel S.; Ernst, Monique

    2014-01-01

    Behavioral inhibition (BI), a temperament characterized by vigilance to novelty, sensitivity to approach–withdrawal cues and social reticence in childhood, is associated with risk for anxiety in adolescence. Independent studies link reward hyper-responsivity to BI, adolescent anxiety and dopamine gene variants. This exploratory study extends these observations by examining the impact of DRD4 genotype and reward hyper-responsivity on the BI–anxiety link. Adolescents (N = 78) completed a monetary incentive delay task in the fMRI environment. Participants were characterized based on a continuous score of BI and the 7-repeat allele (7R+) of the DRD4 functional polymorphism. Parent-report and self-report measures of anxiety were also collected. Across the entire sample, striatal activation increased systematically with increases in the magnitude of anticipated monetary gains and losses. DRD4 status moderated the relation between BI and activation in the caudate nucleus. Childhood BI was associated with parent report of adolescent anxiety among 7R+ participants with elevated levels of striatal response to incentive cues. DRD4 genotype influenced the relations among neural response to incentives, early childhood BI and anxiety. The findings help refine our understanding of the role reward-related brain systems play in the emergence of anxiety in temperamentally at-risk individuals, building a foundation for future larger scale studies. PMID:23314010

  6. Subcellular Location of PKA Controls Striatal Plasticity: Stochastic Simulations in Spiny Dendrites

    Science.gov (United States)

    Oliveira, Rodrigo F.; Kim, MyungSook; Blackwell, Kim T.

    2012-01-01

    Dopamine release in the striatum has been implicated in various forms of reward dependent learning. Dopamine leads to production of cAMP and activation of protein kinase A (PKA), which are involved in striatal synaptic plasticity and learning. PKA and its protein targets are not diffusely located throughout the neuron, but are confined to various subcellular compartments by anchoring molecules such as A-Kinase Anchoring Proteins (AKAPs). Experiments have shown that blocking the interaction of PKA with AKAPs disrupts its subcellular location and prevents LTP in the hippocampus and striatum; however, these experiments have not revealed whether the critical function of anchoring is to locate PKA near the cAMP that activates it or near its targets, such as AMPA receptors located in the post-synaptic density. We have developed a large scale stochastic reaction-diffusion model of signaling pathways in a medium spiny projection neuron dendrite with spines, based on published biochemical measurements, to investigate this question and to evaluate whether dopamine signaling exhibits spatial specificity post-synaptically. The model was stimulated with dopamine pulses mimicking those recorded in response to reward. Simulations show that PKA colocalization with adenylate cyclase, either in the spine head or in the dendrite, leads to greater phosphorylation of DARPP-32 Thr34 and AMPA receptor GluA1 Ser845 than when PKA is anchored away from adenylate cyclase. Simulations further demonstrate that though cAMP exhibits a strong spatial gradient, diffusible DARPP-32 facilitates the spread of PKA activity, suggesting that additional inactivation mechanisms are required to produce spatial specificity of PKA activity. PMID:22346744

  7. A subpopulation of neuronal M4 muscarinic acetylcholine receptors plays a critical role in modulating dopamine-dependent behaviors.

    Science.gov (United States)

    Jeon, Jongrye; Dencker, Ditte; Wörtwein, Gitta; Woldbye, David P D; Cui, Yinghong; Davis, Albert A; Levey, Allan I; Schütz, Günther; Sager, Thomas N; Mørk, Arne; Li, Cuiling; Deng, Chu-Xia; Fink-Jensen, Anders; Wess, Jürgen

    2010-02-10

    Acetylcholine (ACh) regulates many key functions of the CNS by activating cell surface receptors referred to as muscarinic ACh receptors (M(1)-M(5) mAChRs). Like other mAChR subtypes, the M(4) mAChR is widely expressed in different regions of the forebrain. Interestingly, M(4) mAChRs are coexpressed with D(1) dopamine receptors in a specific subset of striatal projection neurons. To investigate the physiological relevance of this M(4) mAChR subpopulation in modulating dopamine-dependent behaviors, we used Cre/loxP technology to generate mutant mice that lack M(4) mAChRs only in D(1) dopamine receptor-expressing cells. The newly generated mutant mice displayed several striking behavioral phenotypes, including enhanced hyperlocomotor activity and increased behavioral sensitization following treatment with psychostimulants. These behavioral changes were accompanied by a lack of muscarinic inhibition of D(1) dopamine receptor-mediated cAMP stimulation in the striatum and an increase in dopamine efflux in the nucleus accumbens. These novel findings demonstrate that a distinct subpopulation of neuronal M(4) mAChRs plays a critical role in modulating several important dopamine-dependent behaviors. Since enhanced central dopaminergic neurotransmission is a hallmark of several severe disorders of the CNS, including schizophrenia and drug addiction, our findings have substantial clinical relevance.

  8. Regulation of dopamine transporter function by protein-protein interactions: new discoveries and methodological challenges

    DEFF Research Database (Denmark)

    Eriksen, Jacob; Jørgensen, Trine Nygaard; Gether, Ulrik

    2010-01-01

    The dopamine transporter (DAT) plays a key role in regulating dopaminergic signalling in the brain by mediating rapid clearance of dopamine from the synaptic clefts. The psychostimulatory actions of cocaine and amphetamine are primarily the result of a direct interaction of these compounds with DAT...... cells have also recently become available such as fluorescently tagged cocaine analogues and fluorescent substrates. Here we review the current knowledge about the role of protein-protein interactions in DAT regulation as well as we describe the most recent methodological developments that have been...

  9. Simultaneous determination of ascorbic acid, dopamine and uric acid based on tryptophan functionalized graphene

    Energy Technology Data Exchange (ETDEWEB)

    Lian, Qianwen; He, Zhifang; He, Qian; Luo, Ai; Yan, Kaiwang; Zhang, Dongxia [Key Laboratory of Bioelectrochemistry and Environmental Analysis of Gansu Province, College of Geography and Environment Science, Northwest Normal University, Lanzhou, 730070 (China); Lu, Xiaoquan, E-mail: Luxq@nwnu.edu.cn [Key Laboratory of Bioelectrochemistry and Environmental Analysis of Gansu Province, College of Chemistry and Chemical Engineering, Northwest Normal University, Lanzhou, 730070 (China); Zhou, Xibin, E-mail: zhouxb@nwnu.edu.cn [Key Laboratory of Bioelectrochemistry and Environmental Analysis of Gansu Province, College of Geography and Environment Science, Northwest Normal University, Lanzhou, 730070 (China)

    2014-05-01

    Highlights: • Trp-GR was synthesized by utilizing a facile ultrasonic method. • The material as prepared had well dispersivity in water and better conductivity than pure GR. • Trp-GR/GCE showed excellent potential for the determination of AA, DA and UA. • The proposed method was applied for the analysis of AA, DA and UA in real samples. - Abstract: A new type of tryptophan-functionalized graphene nanocomposite (Trp-GR) was synthesized by utilizing a facile ultrasonic method via π–π conjugate action between graphene (GR) and tryptophan (Trp) molecule. The material as prepared had well dispersivity in water and better conductivity than pure GR. The surface morphology of Trp-GR was characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM) and Raman spectroscopy. The electrochemical behaviors of ascorbic acid (AA), dopamine (DA), and uric acid (UA) were investigated by cyclic voltammetry (CV) on the surface of Trp-GR. The separation of the oxidation peak potentials for AA–DA, DA–UA and UA–AA was about 182 mV, 125 mV and 307 mV, which allowed simultaneously determining AA, DA, and UA. Differential pulse voltammetery (DPV) was used for the determination of AA, DA, and UA in their mixture. Under optimum conditions, the linear response ranges for the determination of AA, DA, and UA were 0.2–12.9 mM, 0.5–110 μM, and 10–1000 μM, with the detection limits (S/N = 3) of 10.09 μM, 0.29 μM and 1.24 μM, respectively. Furthermore, the modified electrode was investigated for real sample analysis.

  10. Synthesis of palladium@gold nanoalloys/nitrogen and sulphur-functionalized multiple graphene aerogel for electrochemical detection of dopamine

    Energy Technology Data Exchange (ETDEWEB)

    Li, Ruiyi; Yang, Tingting [School of Chemical and Material Engineering, Jiangnan University, Wuxi 214122 (China); Li, Zaijun, E-mail: zaijunli@jiangnan.edu.cn [School of Chemical and Material Engineering, Jiangnan University, Wuxi 214122 (China); Key Laboratory of Food Colloids and Biotechnology, Ministry of Education, Wuxi 214122 (China); Gu, Zhiguo; Wang, Guangli; Liu, Junkang [School of Chemical and Material Engineering, Jiangnan University, Wuxi 214122 (China)

    2017-02-15

    Integration of noble metal nanomaterials on graphene nanosheets potentially paves one way to improve their electronic, chemical and electrochemical properties. The study reported synthesis of palladium@gold nanoalloys/nitrogen and sulphur-functionalized multiple graphene aerogel composite (Pd@Au/N,S-MGA). The as-prepared composite offers a well-defined three-dimensional architecture with rich of mesopores. The Pd@Au nanoalloys were dispersed on the graphene framework networks and their active sites were fully exposed. The unique structure achieves to ultra high electron/ion conductivity, electrocatalytic activity and structural stability. The sensor based on the Pd@Au/N,S-MGA creates ultrasensitive electrochemical response towards dopamine due to significantly electrochemical synergy between Pd, Au and N,S-MGA. Its differential pulse voltammetric signal linearly increases with the increase of dopamine concentration in the range from 1.0 × 10{sup −9} M to 4.0 × 10{sup −5} M with the detection limit of 3.6 × 10{sup −10} M (S/N = 3). The analytical method provides the advantage of sensitivity, reproducibility, rapidity and long-term stability. It has been successfully applied in the detection of trace dopamine in biological samples. The study also opens a window on the electronic properties of graphene aerogel and metal nanomaterials as well their nanohybrids to meet needs of further applications as nanoelectronics in diagnosis, bioanalysis and catalysis. - Graphical abstract: We reported a new palladium@gold nanoalloys/nitrogen and sulphur-functionalized multiple graphene aerogel. The sensor based on the nanohybrid exhibits ultrahigh sensitivity, reproducibility and stability to electrochemical detection of dopamine. - Highlights: • We reported Pd@A/nitrogen and sulphur-functionalized multiple graphene aerogel. • The nanohybrid offers unique three-dimensional architecture with rich of mesopores. • The architecture achieve to ultrahigh

  11. The Role of Dopamine in Anticipatory Pursuit Eye Movements: Insights from Genetic Polymorphisms in Healthy Adults.

    Science.gov (United States)

    Billino, Jutta; Hennig, Jürgen; Gegenfurtner, Karl R

    2016-01-01

    There is a long history of eye movement research in patients with psychiatric diseases for which dysfunctions of neurotransmission are considered to be the major pathologic mechanism. However, neuromodulation of oculomotor control is still hardly understood. We aimed to investigate in particular the impact of dopamine on smooth pursuit eye movements. Systematic variability in dopaminergic transmission due to genetic polymorphisms in healthy subjects offers a noninvasive opportunity to determine functional associations. We measured smooth pursuit in 110 healthy subjects genotyped for two well-documented polymorphisms, the COMT Val 158 Met polymorphism and the SLC6A3 3'-UTR-VNTR polymorphism. Pursuit paradigms were chosen to particularly assess the ability of the pursuit system to initiate tracking when target motion onset is blanked, reflecting the impact of extraretinal signals. In contrast, when following a fully visible target sensory, retinal signals are available. Our results highlight the crucial functional role of dopamine for anticipatory, but not for sensory-driven, pursuit processes. We found the COMT Val 158 Met polymorphism specifically associated with anticipatory pursuit parameters, emphasizing the dominant impact of prefrontal dopamine activity on complex oculomotor control. In contrast, modulation of striatal dopamine activity by the SLC6A3 3'-UTR-VNTR polymorphism had no significant functional effect. Though often neglected so far, individual differences in healthy subjects provide a promising approach to uncovering functional mechanisms and can be used as a bridge to understanding deficits in patients.

  12. Probing dopamine transporter structure and function by Zn2+-site engineering

    DEFF Research Database (Denmark)

    Loland, Claus Juul; Norgaard-Nielsen, Kristine; Gether, Ulrik

    2003-01-01

    The biogenic amine transporters belong to the class of Na+/Cl--coupled solute carriers and include the transporters for dopamine (DAT), norepinephrine (NET), and serotonin (SERT). These transporters are the primary targets for the action of many psychoactive compounds including the most commonly ...

  13. INVESTIGATING THE ROLE OF PDZ-DOMAIN INTERACTIONS FOR DOPAMINE TRANSPORTER FUNCTION

    DEFF Research Database (Denmark)

    Fog, Jacob; Vægter, Christian Bjerggaard; Gether, Ulrik

    PICK1 has been shown to interact with the distal dopamine transporter (DAT) C-terminus via its PDZ domain. Although we recently have shown that ER export and targeting of the DAT to the cell surface is critically dependent on discrete epitopes in the distal C-terminus, these events do not require...

  14. Visual functions in phenylketonuria-evaluating the dopamine and long-chain polyunsaturated fatty acids depletion hypotheses.

    Science.gov (United States)

    Gramer, Gwendolyn; Förl, Birgit; Springer, Christina; Weimer, Petra; Haege, Gisela; Mackensen, Friederike; Müller, Edith; Völcker, Hans Eberhard; Hoffmann, Georg Friedrich; Lindner, Martin; Krastel, Hermann; Burgard, Peter

    2013-01-01

    In phenylketonuria presymptomatic treatment following newborn screening prevents severe mental and physical impairment. The reasons for subtle impairments of cerebral functions despite early treatment remain unclear. We assessed a broad spectrum of visual functions in early-treated patients with phenylketonuria and evaluated two hypotheses-the dopamine and the long-chain polyunsaturated fatty acids (LCPUFAs) depletion hypotheses. Contrast sensitivity, colour vision, electroretinography, frequency doubling technology campimetry (FDT), and their relation with blood phenylalanine and docosahexaenoic acid levels were assessed in 36 patients with phenylketonuria and 18 age-matched healthy controls. Contrast sensitivity was significantly lower and total error scores in colour vision significantly higher in patients than controls. Electroretinography results differed significantly between patients and controls. We found a trend for the effect of phenylalanine-levels on contrast sensitivity and a significant effect on colour vision/FDT results. Docosahexaenoic acid levels in erythrocytes were not associated with visual functions. This is the first evaluation of visual functions in phenylketonuria using a comprehensive ophthalmological test battery. We found no evidence supporting the long-chain polyunsaturated fatty acids depletion hypothesis. However, the effect of phenylalanine-levels on visual functions suggests that imbalance between phenylalanine and tyrosine may affect retinal dopamine levels in phenylketonuria. This is supported by the similar patterns of visual functions in patients with phenylketonuria observed in our study and patients with Parkinson's disease. Copyright © 2012 Elsevier Inc. All rights reserved.

  15. Brain Dopamine Transporter Binding and Glucose Metabolism in Progressive Supranuclear Palsy-Like Creutzfeldt-Jakob Disease

    Directory of Open Access Journals (Sweden)

    Eero Rissanen

    2014-01-01

    Full Text Available Here, we present a patient with Creutzfeldt-Jakob disease (CJD who developed initial symptoms mimicking progressive supranuclear palsy (PSP. Before the development of typical CJD symptoms, functional imaging supported a diagnosis of PSP when [123I]-FP-CIT-SPECT showed a defect in striatal dopamine transporter binding, while [18F]-fluorodeoxyglucose PET showed cortical hypometabolism suggestive of Lewy body dementia. However, the postmortem neuropathological examination was indicative of CJD only, without tau protein or Lewy body findings. This case demonstrates that CJD should be taken into account in rapidly progressing atypical cases of parkinsonism, even when functional imaging supports a diagnosis of a movement disorder.

  16. Predicting treatment response in Schizophrenia: the role of stratal and frontal dopamine D2/D3 receptor binding potential

    DEFF Research Database (Denmark)

    Wulff, Sanne; Nørbak-Emig, Henrik; Nielsen, Mette Ødegaard

    2014-01-01

    relationship between frontal and striatal dopamine activity. Data also emphasize that there might be gender differences. The data analysis is ongoing. (1) Glenthøj BY, Mackeprang T et al. Frontal dopamine D2/3 receptor binding in drug-naïve first-episode schizophrenic patients correlates with positive...... cortex in antipsychotic-naïve first-episode male schizophrenia patients(1). Preclinical studies suggest an inverse relationship between frontal and striatal dopamine activity. This activity can indirectly be expressed by the BP of dopamine receptors using Single Photon Emission Computed Tomography (SPECT......-up. There was a negative correlation between striatal BP and improvement of the PANSS total score (Rho=-0,553 P=0.009). Furthermore we found a negative correlation between striatal BP and improvement of positive symptoms among the male patients only (P=0.020). The same relationship was found at trend level for the entire...

  17. Inflammation Effects on Motivation and Motor Activity: Role of Dopamine.

    Science.gov (United States)

    Felger, Jennifer C; Treadway, Michael T

    2017-01-01

    Motivational and motor deficits are common in patients with depression and other psychiatric disorders, and are related to symptoms of anhedonia and motor retardation. These deficits in motivation and motor function are associated with alterations in corticostriatal neurocircuitry, which may reflect abnormalities in mesolimbic and mesostriatal dopamine (DA). One pathophysiologic pathway that may drive changes in DAergic corticostriatal circuitry is inflammation. Biomarkers of inflammation such as inflammatory cytokines and acute-phase proteins are reliably elevated in a significant proportion of psychiatric patients. A variety of inflammatory stimuli have been found to preferentially target basal ganglia function to lead to impaired motivation and motor activity. Findings have included inflammation-associated reductions in ventral striatal neural responses to reward anticipation, decreased DA and DA metabolites in cerebrospinal fluid, and decreased availability, and release of striatal DA, all of which correlated with symptoms of reduced motivation and/or motor retardation. Importantly, inflammation-associated symptoms are often difficult to treat, and evidence suggests that inflammation may decrease DA synthesis and availability, thus circumventing the efficacy of standard pharmacotherapies. This review will highlight the impact of administration of inflammatory stimuli on the brain in relation to motivation and motor function. Recent data demonstrating similar relationships between increased inflammation and altered DAergic corticostriatal circuitry and behavior in patients with major depressive disorder will also be presented. Finally, we will discuss the mechanisms by which inflammation affects DA neurotransmission and relevance to novel therapeutic strategies to treat reduced motivation and motor symptoms in patients with high inflammation.

  18. Modeling the dopamine system in vivo

    International Nuclear Information System (INIS)

    Gjedde, A.

    1991-01-01

    Positron Emission Tomography (PET) can be used to measure several steps in the synthesis, binding, and metabolism of dopamine in the normal or abnormal living human brain. Fluorodopa is a PET tracer of DOPA metabolism. Recent evidence suggests that only a fraction of striatal fluorodopamine accumulates in the large, static pool of dopamine. Hence, the accumulation of FDOPA-derived radioactivity in striatum reflects the dopamine turnover of this pool. Labeled L-deprenyl is a PET tracer of monoamine oxidase B. The accumulation in striatum and other regions of the human brain reflects the number of reactive sites on the enzyme. The densities of dopamine-binding neuroreceptors may be calculated from the accumulation of reversibly binding tracers by equilibrium kinetics or from the accumulation of irreversibly binding tracers by transient analysis. The reversible tracers include labeled SCH 23390 and raclopride. An irreversibly binding tracer is N- methylspiperone

  19. Dopamine, psychosis and schizophrenia

    DEFF Research Database (Denmark)

    Kesby, J P; Eyles, D W; McGrath, J J

    2018-01-01

    The stagnation in drug development for schizophrenia highlights the need for better translation between basic and clinical research. Understanding the neurobiology of schizophrenia presents substantial challenges but a key feature continues to be the involvement of subcortical dopaminergic...... dysfunction in those with psychotic symptoms. Our contemporary knowledge regarding dopamine dysfunction has clarified where and when dopaminergic alterations may present in schizophrenia. For example, clinical studies have shown patients with schizophrenia show increased presynaptic dopamine function...... in the associative striatum, rather than the limbic striatum as previously presumed. Furthermore, subjects deemed at high risk of developing schizophrenia show similar presynaptic dopamine abnormalities in the associative striatum. Thus, our view of subcortical dopamine function in schizophrenia continues to evolve...

  20. Single photon emission tomography (SPET) imaging of dopamine D2 receptors in the course of dopamine replacement therapy in patients with nocturnal myoclonus syndrome (NMS)

    International Nuclear Information System (INIS)

    Staedt, J.; Stoppe, G.; Riemann, H.; Hajak, G.; Ruether, E.; Koegler, A.; Emrich, D.

    1995-01-01

    Single photon emission tomography (SPET) permits the in vivo measurements of regional cerebral radioactivity in the human brain following the administration of compounds labeled with photon-emitting isotopes. According to our SPET findings of a reduced binding of [ 123 I]labeled (S)-2-hydroxy-3-iodo-6-methoxy-([1-ethyl-2-pyrrolidinyl]methyl) benzamide (IBZM) (a highly selective CNS D 2 dopamine receptor ligand) to D 2 dopamine receptors in striatal structures in untreated patients with nocturnal myoclonus syndrome (NMS) it seemed to be of interest to investigate whether there are changes in D 2 receptor binding under dopamine replacement therapy or not. We studied the uptake and distribution of [ 123 I]IBZM before and in the course of dopamine replacement therapy in four patients with severe insomnia caused by nocturnal myoclonus syndrome (NMS). We found an increase of the IBZM binding to D 2 receptors in the course of treatment, which was associated with an improvement of sleep quality. Reasons for this are discussed. The [ 123 I]IBZM SPET technique in conclusion offers an interesting tool for in vivo investigations of functional changes in the dopaminergic neurotransmitter system in longitudinal studies. (author)

  1. Endogenous versus exogenous lithium clearance for evaluation of dopamine-induced changes in renal tubular function

    DEFF Research Database (Denmark)

    Olsen, Niels Vidiendal; Fogh-Andersen, N; Strandgaard, S

    1996-01-01

    or 450 mg or 600 mg of lithium given in random order at 22.00 hours. After an overnight fast, renal clearance studies were performed during a 1 h baseline period and subsequently during the second hour of an infusion of 3 micrograms min-1 kg-1 of dopamine. 2. Baseline values of endogenous CLi.......2 (40.8-45.6) ml/min (450 mg of lithium, P infusion did not differ...

  2. Serotonin and dopamine transporters in relation to neuropsychological functioning, personality traits and mood in young adult healthy subjects

    NARCIS (Netherlands)

    Burke, S. M.; van de Giessen, E.; de Win, M.; Schilt, T.; van Herk, M.; van den Brink, W.; Booij, J.

    2011-01-01

    BACKGROUND: Serotonin and dopamine neurotransmitter systems are implicated in the regulation of mood, cognition and personality traits and their dysfunction is thought to be implicated in diverse psychopathologies. However, in healthy subjects the relationship between the serotonin and dopamine

  3. Characterization of SNPs in the dopamine-β-hydroxylase gene providing new insights into its structure-function relationship.

    Science.gov (United States)

    Punchaichira, Toyanji Joseph; Dey, Sanjay Kumar; Mukhopadhyay, Anirban; Kundu, Suman; Thelma, B K

    2017-07-01

    Dopamine-β-hydroxylase (DBH, EC 1.14.17.1), an oxido-reductase that catalyses the conversion of dopamine to norepinephrine, is largely expressed in sympathetic neurons and adrenal medulla. Several regulatory and structural variants in DBH associated with various neuropsychiatric, cardiovascular diseases and a few that may determine enzyme activity have also been identified. Due to paucity of studies on functional characterization of DBH variants, its structure-function relationship is poorly understood. The purpose of the study was to characterize five non-synonymous (ns) variants that were prioritized either based on previous association studies or Sorting Tolerant From Intolerant (SIFT) algorithm. The DBH ORF with wild type (WT) and site-directed mutagenized variants were transfected into HEK293 cells to generate transient and stable lines expressing these variant enzymes. Activity was determined by UPLC-PDA and corresponding quantity by MRM HR on a TripleTOF 5600 MS respectively of spent media from stable cell lines. Homospecific activity computed for the WT and variant proteins showed a marginal decrease in A318S, W544S and R549C variants. In transient cell lines, differential secretion was observed in the case of L317P, W544S and R549C. Secretory defect in L317P was confirmed by localization in ER. R549C exhibited both decreased homospecific activity and differential secretion. Of note, all the variants were seen to be destabilizing based on in silico folding analysis and molecular dynamics (MD) simulation, lending support to our experimental observations. These novel genotype-phenotype correlations in this gene of considerable pharmacological relevance have implications for dopamine-related disorders.

  4. Rostrocaudal gradients of dopamine D2/3 receptor binding in striatal subregions measured with [11C]raclopride and high-resolution positron emission tomography

    DEFF Research Database (Denmark)

    Alakurtti, Kati; Johansson, Jarkko J; Tuokkola, Terhi

    2013-01-01

    of striatum; this method is superior to the sectioning used in previous post mortem studies. Regarding the functional organization of the striatum, our findings can inform future investigations of normal neurophysiology as well as efforts to differentiate neuropsychiatric disorders affecting the brain...

  5. A Population of Indirect Pathway Striatal Projection Neurons Is Selectively Entrained to Parkinsonian Beta Oscillations.

    Science.gov (United States)

    Sharott, Andrew; Vinciati, Federica; Nakamura, Kouichi C; Magill, Peter J

    2017-10-11

    Classical schemes of basal ganglia organization posit that parkinsonian movement difficulties presenting after striatal dopamine depletion stem from the disproportionate firing rates of spiny projection neurons (SPNs) therein. There remains, however, a pressing need to elucidate striatal SPN firing in the context of the synchronized network oscillations that are abnormally exaggerated in cortical-basal ganglia circuits in parkinsonism. To address this, we recorded unit activities in the dorsal striatum of dopamine-intact and dopamine-depleted rats during two brain states, respectively defined by cortical slow-wave activity (SWA) and activation. Dopamine depletion escalated striatal net output but had contrasting effects on "direct pathway" SPNs (dSPNs) and "indirect pathway" SPNs (iSPNs); their firing rates became imbalanced, and they disparately engaged in network oscillations. Disturbed striatal activity dynamics relating to the slow (∼1 Hz) oscillations prevalent during SWA partly generalized to the exaggerated beta-frequency (15-30 Hz) oscillations arising during cortical activation. In both cases, SPNs exhibited higher incidences of phase-locked firing to ongoing cortical oscillations, and SPN ensembles showed higher levels of rhythmic correlated firing, after dopamine depletion. Importantly, in dopamine-depleted striatum, a widespread population of iSPNs, which often displayed excessive firing rates and aberrant phase-locked firing to cortical beta oscillations, preferentially and excessively synchronized their firing at beta frequencies. Conversely, dSPNs were neither hyperactive nor synchronized to a large extent during cortical activation. These data collectively demonstrate a cell type-selective entrainment of SPN firing to parkinsonian beta oscillations. We conclude that a population of overactive, excessively synchronized iSPNs could orchestrate these pathological rhythms in basal ganglia circuits. SIGNIFICANCE STATEMENT Chronic depletion of dopamine

  6. Molecular Regulation of Striatal Development: A Review

    Directory of Open Access Journals (Sweden)

    A. E. Evans

    2012-01-01

    Full Text Available The central nervous system is composed of the brain and the spinal cord. The brain is a complex organ that processes and coordinates activities of the body in bilaterian, higher-order animals. The development of the brain mirrors its complex function as it requires intricate genetic signalling at specific times, and deviations from this can lead to brain malformations such as anencephaly. Research into how the CNS is specified and patterned has been studied extensively in chick, fish, frog, and mice, but findings from the latter will be emphasised here as higher-order mammals show most similarity to the human brain. Specifically, we will focus on the embryonic development of an important forebrain structure, the striatum (also known as the dorsal striatum or neostriatum. Over the past decade, research on striatal development in mice has led to an influx of new information about the genes involved, but the precise orchestration between the genes, signalling molecules, and transcription factors remains unanswered. We aim to summarise what is known to date about the tightly controlled network of interacting genes that control striatal development. This paper will discuss early telencephalon patterning and dorsal ventral patterning with specific reference to the genes involved in striatal development.

  7. Neurovascular coupling to D2/D3 dopamine receptor occupancy using simultaneous PET/functional MRI

    DEFF Research Database (Denmark)

    Sander, Christin Y; Hooker, Jacob M; Catana, Ciprian

    2013-01-01

    caused increases in CBV and reductions in binding potential that were localized to the dopamine-rich striatum. Moreover, similar temporal profiles were observed for specific binding estimates and changes in CBV. Injection of graded raclopride mass doses revealed a monotonic coupling between neurovascular...... a basis for models that relate dopaminergic occupancies to hemodynamic changes in the basal ganglia. Overall, these data demonstrate the utility of simultaneous PET/fMRI for investigations of neurovascular coupling that correlate neurochemistry with hemodynamic changes in vivo for any receptor system...

  8. Functional mapping of thalamic nuclei and their integration into cortico-striatal-thalamo-cortical loops via ultra-high resolution imaging- From animal anatomy to in vivo imaging in humans

    Directory of Open Access Journals (Sweden)

    Coraline D. Metzger

    2013-05-01

    Full Text Available The thalamus, a crucial node in the well-described cortico-striatal-thalamo-cortical circuits, has been the focus of functional and structural imaging studies investigating human emotion, cognition and memory. Invasive work in animals and post-mortem investigations have revealed the rich cytoarchitectonics and functional specificity of the thalamus. Given current restrictions in the spatial resolution of non-invasive imaging modalities, there is, however, a translational gap between functional and structural information on these circuits in humans and animals as well as between histological and cellular evidence and their relationship to psychological functioning.With the advance of higher field strengths for MR approaches, better spatial resolution is now available promising to overcome this conceptual problem.We here review these two levels, which exist for both neuroscientific and clinical investigations, and then focus on current attempts to overcome conceptual boundaries of these observations with the help of high-resolution imaging.

  9. Dopamine Does Not Appear to Affect Mental Rotation in Parkinson’s Disease

    Directory of Open Access Journals (Sweden)

    Gregory P. Crucian

    2014-10-01

    Full Text Available ObjectivePatients with Parkinson’s disease (PD often have deficits with mental rotation (MR. The neuropathological factors underlying these deficits, however, remain to be elucidated. One hypothesis suggests that dopamine depletion in nigro-striatal systems adversely influences MR. Another hypothesis suggests that deterioration of cortical (fronto-temporo-parietal basal ganglia networks that mediate this function are responsible for this deficit. The goal of this study was to test the dopamine hypothesis by determining if dopamine abstinence negatively influences MR performance. MethodsThirty three non-demented right-handed individuals with PD were assess for their ability to perform a pencil and paper MR test while “on” and “off” dopaminergic medications. Dopamine abstinence followed the typical overnight withdrawal procedures. ResultsNo differences in mental rotation abilities were found between “on” and “off” dopaminergic medications. ConclusionsThese results suggest that other neuropathological factors, such as cortical-basal ganglia neurodegeneration, or dysfunction of other neurotransmitters systems, might account for these cognitive deficits and future research will have to test these alternative hypotheses.

  10. 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

  11. Huntington's Disease and Striatal Signaling

    Directory of Open Access Journals (Sweden)

    Emmanuel eRoze

    2011-08-01

    Full Text Available Huntington’s Disease (HD is the most frequent neurodegenerative disease caused by an expansion of polyglutamines (CAG. The main clinical manifestations of HD are chorea, cognitive impairment and psychiatric disorders. The transmission of HD is autosomal dominant with a complete penetrance. HD has a single genetic cause, a well-defined neuropathology, and informative pre-manifest genetic testing of the disease is available. Striatal atrophy begins as early as 15 years before disease onset and continues throughout the period of manifest illness. Therefore, patients could theoretically benefit from therapy at early stages of the disease. One important characteristic of HD is the striatal vulnerability to neurodegeneration, despite similar expression of the protein in other brain areas. Aggregation of the mutated Huntingtin (HTT, impaired axonal transport, excitotoxicity, transcriptional dysregulation as well as mitochondrial dysfunction and energy deficits, are all part of the cellular events that underlie neuronal dysfunction and striatal death. Among these non-exclusive mechanisms, an alteration of striatal signaling is thought to orchestrate the downstream events involved in the cascade of striatal dysfunction.

  12. Transferrin Functionalized Liposomes Loading Dopamine HCl: Development and Permeability Studies across an In Vitro Model of Human Blood-Brain Barrier.

    Science.gov (United States)

    Lopalco, Antonio; Cutrignelli, Annalisa; Denora, Nunzio; Lopedota, Angela; Franco, Massimo; Laquintana, Valentino

    2018-03-20

    The transport of dopamine across the blood brain barrier represents a challenge for the management of Parkinson's disease. The employment of central nervous system targeted ligands functionalized nanocarriers could be a valid tactic to overcome this obstacle and avoid undesirable side effects. In this work, transferrin functionalized dopamine-loaded liposomes were made by a modified dehydration-rehydration technique from hydrogenated soy phosphatidylcoline, cholesterol and 1,2-stearoyl- sn -glycero-3-phosphoethanolamine- N -[carboxy(poly(ethylene glycol)-2000)]. The physical features of the prepared liposomes were established with successive determination of their endothelial permeability across an in vitro model of the blood-brain barrier, constituted by human cerebral microvascular endothelial cells (hCMEC/D3). Functionalized dopamine-loaded liposomes with encapsulation efficiency more than 35% were made with sizes in a range around 180 nm, polydispersity indices of 0.2, and positive zeta potential values (+7.5 mV). Their stability and drug release kinetics were also evaluated. The apparent permeability (P e ) values of encapsulated dopamine in functionalized and unfunctionalized liposomes showed that transferrin functionalized nanocarriers could represent appealing non-toxic candidates for brain delivery, thus improving benefits and decreasing complications to patients subjected to L-dopa chronical treatment.

  13. Nigrostriatal proteasome inhibition impairs dopamine neurotransmission and motor function in minipigs

    DEFF Research Database (Denmark)

    Lillethorup, Thea Pinholt; Glud, Andreas Nørgaard; Alstrup, Aage Kristian Olsen

    2018-01-01

    Parkinson's disease (PD) is characterized by degeneration of dopaminergic neurons in the substantia nigra leading to slowness and stiffness of limb movement with rest tremor. Using ubiquitin proteasome system inhibitors, rodent models have shown nigrostriatal degeneration and motor impairment. We...... displayed asymmetrical motor disability with spontaneous rotations in one of the animals. Immunoreactivity for tyrosine hydroxylase (TH) and HLA-DR-positive microglia confirmed asymmetrical reduction in nigral TH-positive neurons with an inflammatory response in the lactacystin-injected minipigs....... In conclusion, direct injection of lactacystin into the MFB of minipigs provides a model of PD with reduced dopamine neurotransmission, TH-positive neuron reduction, microglial activation and behavioural deficits. This large animal model could be useful in studies of symptomatic and neuroprotective therapies...

  14. Cholesterol contributes to dopamine-neuronal loss in MPTP mouse model of Parkinson's disease: Involvement of mitochondrial dysfunctions and oxidative stress.

    Directory of Open Access Journals (Sweden)

    Rajib Paul

    Full Text Available Hypercholesterolemia is a known contributor to the pathogenesis of Alzheimer's disease while its role in the occurrence of Parkinson's disease (PD is only conjecture and far from conclusive. Altered antioxidant homeostasis and mitochondrial functions are the key mechanisms in loss of dopaminergic neurons in the substantia nigra (SN region of the midbrain in PD. Hypercholesterolemia is reported to cause oxidative stress and mitochondrial dysfunctions in the cortex and hippocampus regions of the brain in rodents. However, the impact of hypercholesterolemia on the midbrain dopaminergic neurons in animal models of PD remains elusive. We tested the hypothesis that hypercholesterolemia in MPTP model of PD would potentiate dopaminergic neuron loss in SN by disrupting mitochondrial functions and antioxidant homeostasis. It is evident from the present study that hypercholesterolemia in naïve animals caused dopamine neuronal loss in SN with subsequent reduction in striatal dopamine levels producing motor impairment. Moreover, in the MPTP model of PD, hypercholesterolemia exacerbated MPTP-induced reduction of striatal dopamine as well as dopaminergic neurons in SN with motor behavioral depreciation. Activity of mitochondrial complexes, mainly complex-I and III, was impaired severely in the nigrostriatal pathway of hypercholesterolemic animals treated with MPTP. Hypercholesterolemia caused oxidative stress in the nigrostriatal pathway with increased generation of hydroxyl radicals and enhanced activity of antioxidant enzymes, which were further aggravated in the hypercholesterolemic mice with Parkinsonism. In conclusion, our findings provide evidence of increased vulnerability of the midbrain dopaminergic neurons in PD with hypercholesterolemia.

  15. Synaptic vesicle glycoprotein 2C (SV2C) modulates dopamine release and is disrupted in Parkinson disease.

    Science.gov (United States)

    Dunn, Amy R; Stout, Kristen A; Ozawa, Minagi; Lohr, Kelly M; Hoffman, Carlie A; Bernstein, Alison I; Li, Yingjie; Wang, Minzheng; Sgobio, Carmelo; Sastry, Namratha; Cai, Huaibin; Caudle, W Michael; Miller, Gary W

    2017-03-14

    Members of the synaptic vesicle glycoprotein 2 (SV2) family of proteins are involved in synaptic function throughout the brain. The ubiquitously expressed SV2A has been widely implicated in epilepsy, although SV2C with its restricted basal ganglia distribution is poorly characterized. SV2C is emerging as a potentially relevant protein in Parkinson disease (PD), because it is a genetic modifier of sensitivity to l-DOPA and of nicotine neuroprotection in PD. Here we identify SV2C as a mediator of dopamine homeostasis and report that disrupted expression of SV2C within the basal ganglia is a pathological feature of PD. Genetic deletion of SV2C leads to reduced dopamine release in the dorsal striatum as measured by fast-scan cyclic voltammetry, reduced striatal dopamine content, disrupted α-synuclein expression, deficits in motor function, and alterations in neurochemical effects of nicotine. Furthermore, SV2C expression is dramatically altered in postmortem brain tissue from PD cases but not in Alzheimer disease, progressive supranuclear palsy, or multiple system atrophy. This disruption was paralleled in mice overexpressing mutated α-synuclein. These data establish SV2C as a mediator of dopamine neuron function and suggest that SV2C disruption is a unique feature of PD that likely contributes to dopaminergic dysfunction.

  16. Preparation of alanine and tyrosine functionalized graphene oxide nanoflakes and their modified carbon paste electrodes for the determination of dopamine

    Energy Technology Data Exchange (ETDEWEB)

    Kumar, Mohan [Department of P.G. Studies and Research in Industrial Chemistry, Kuvempu University, Shankaraghatta, 577 451, Shimoga, Karnataka (India); Swamy, B.E. Kumara, E-mail: kumaraswamy21@yahoo.com [Department of P.G. Studies and Research in Industrial Chemistry, Kuvempu University, Shankaraghatta, 577 451, Shimoga, Karnataka (India); Asif, M.H. Mohammed [Nanoscience and Technology, Kuvempu University, Shankaraghatta, 577451, Shimoga, Karnataka (India); Viswanath, C.C. [Department of P.G. Studies and Research in Industrial Chemistry, Kuvempu University, Shankaraghatta, 577 451, Shimoga, Karnataka (India)

    2017-03-31

    Highlights: • The prepared graphene oxide was functionalized by alanine and tyrosine. • The prepared materials were used for sensor for dopamine. • The functionalized graphene oxide modified carbon paste electrodes shows good sensitivity, stability and repeatability. - Abstract: Herein, established the synthesis of graphene oxide (GO) by Hummers Method with addition of KMnO{sub 4} followed by thermal heating at 80 °C. The obtained GO was further functionalized by alanine and tyrosine. The prepared GO, alanine functionalized GO nanoflakes (AGONF) and tyrosine functionalized GO nanoflakes (TGONF) were characterized by spectroscopic technique using energy-dispersive spectroscopy (EDS), quantitatively by scanning electron microscopy (SEM) and structural studies along with interlayer distance verified through X-ray diffraction technique. Afterwards, the prepared AGONF and TGONF were used as the modifier for the carbon paste electrode (CPE). The electrochemical behavior of the AGONF and TGONF modified carbon paste electrodes (MCPEs) towards dopamine (DA) in phosphate buffer solution (PBS) were examined by cyclic voltammetric (CV) technique and the obtained consequences showed good electrocatalytic activity of MCPEs by increasing the redox peak current with a lower potential difference compared to the bare CPE (BCPE). The AGONF and TGONF MCPEs were further used for the optimization studies. From the pH studies, it was found that the equal number of proton and electron transfer reaction involved in both the modified electrodes. The scan rate studies demonstrate the adsorption controlled electrode process at AGONF MCPE and diffusion controlled at TGONF MCPE. The oxidation peak current increased linearly with two concentration interval of DA at a range of 2–7 μM and 10–30 μM in presence of PBS (pH 7.4) at MCPEs and the limit of detection (LOD) were found to be 0.84 μM and 0.96 μM for first interval DA concentration range (2–7 μM) at AGONF and TGONF MCPE

  17. Re-emergence of striatal cholinergic interneurons in movement disorders.

    Science.gov (United States)

    Pisani, Antonio; Bernardi, Giorgio; Ding, Jun; Surmeier, D James

    2007-10-01

    Twenty years ago, striatal cholinergic neurons were central figures in models of basal ganglia function. But since then, they have receded in importance. Recent studies are likely to lead to their re-emergence in our thinking. Cholinergic interneurons have been implicated as key players in the induction of synaptic plasticity and motor learning, as well as in motor dysfunction. In Parkinson's disease and dystonia, diminished striatal dopaminergic signalling leads to increased release of acetylcholine by interneurons, distorting network function and inducing structural changes that undoubtedly contribute to the symptoms. By contrast, in Huntington's disease and progressive supranuclear palsy, there is a fall in striatal cholinergic markers. This review gives an overview of these recent experimental and clinical studies, placing them within the context of the pathogenesis of movement disorders.

  18. Effect of small-dose dopamine on mesenteric blood flow and renal function in a pig model of cardiopulmonary resuscitation with vasopressin.

    Science.gov (United States)

    Voelckel, W G; Lindner, K H; Wenzel, V; Bonatti, J O; Krismer, A C; Miller, E A; Lurie, K G

    1999-12-01

    Vasopressin (antidiuretic hormone) seems a promising alternative to epinephrine for cardiopulmonary resuscitation (CPR) in cardiac arrest victims, mediating a pronounced blood flow shift toward vital organs. We evaluated the effects of small-dose dopamine on splanchnic blood flow and renal function after successful resuscitation with this potent vasoconstrictor in an established porcine CPR model. After 4 min of cardiac arrest and 3 min of CPR, animals received 0.4 U/kg vasopressin and were continuously infused with either dopamine 4 microg x kg(-1) x min(-1) (n = 6), or saline placebo (n = 6). Defibrillation was performed 5 min after drug administration; all animals were observed for 6 h after return of spontaneous circulation. During the postresuscitation phase, average mean +/- SD superior mesenteric artery blood flow was significantly (P = 0.002) higher in the dopamine group compared with the placebo group (1185+/-130 vs 740+/-235 mL/min), whereas renal blood flow was comparable between groups (255+/-40 vs 250+/-85 mL/min). The median calculated glomerular filtration rate had higher values in the dopamine group (70-120 mL/min) than in the placebo group (40-70 mL/min; P = 0.1 at 0 min and P = 0.08 at 360 min). We conclude that small-dose dopamine administration may be useful in improving superior mesenteric artery blood flow and renal function after successful resuscitation with vasopressin. Long-term survival after cardiac arrest may be determined by the ability to ensure adequate organ perfusion during cardiopulmonary resuscitation and in the postresuscitation phase. In this regard, small-dose dopamine improved postresuscitation blood flow to the mesenteric bed when vasopressin was used as an alternative vasopressor in an animal model of cardiac arrest.

  19. Youth at risk for obesity show greater activation of striatal and somatosensory regions to food.

    Science.gov (United States)

    Stice, Eric; Yokum, Sonja; Burger, Kyle S; Epstein, Leonard H; Small, Dana M

    2011-03-23

    Obese humans, compared with normal-weight humans, have less striatal D2 receptors and striatal response to food intake; weaker striatal response to food predicts weight gain for individuals at genetic risk for reduced dopamine (DA) signaling, consistent with the reward-deficit theory of obesity. Yet these may not be initial vulnerability factors, as overeating reduces D2 receptor density, D2 sensitivity, reward sensitivity, and striatal response to food. Obese humans also show greater striatal, amygdalar, orbitofrontal cortex, and somatosensory region response to food images than normal-weight humans do, which predicts weight gain for those not at genetic risk for compromised dopamine signaling, consonant with the reward-surfeit theory of obesity. However, after pairings of palatable food intake and predictive cues, DA signaling increases in response to the cues, implying that eating palatable food contributes to increased responsivity. Using fMRI, we tested whether normal-weight adolescents at high- versus low-risk for obesity showed aberrant activation of reward circuitry in response to receipt and anticipated receipt of palatable food and monetary reward. High-risk youth showed greater activation in the caudate, parietal operculum, and frontal operculum in response to food intake and in the caudate, putamen, insula, thalamus, and orbitofrontal cortex in response to monetary reward. No differences emerged in response to anticipated food or monetary reward. Data indicate that youth at risk for obesity show elevated reward circuitry responsivity in general, coupled with elevated somatosensory region responsivity to food, which may lead to overeating that produces blunted dopamine signaling and elevated responsivity to food cues.

  20. Radioiodinated ligands for dopamine receptors

    International Nuclear Information System (INIS)

    Kung, H.F.

    1994-01-01

    The dopamine receptor system is important for normal brain function; it is also the apparent action site for various neuroleptic drugs for the treatment of schizophrenia and other metal disorders. In the past few years radioiodinated ligands for single photon emission tomography (SPECT) have been successfully developed and tested in humans: [ 123 I]TISCH for D1 dopamine receptors; [ 123 I]IBZM, epidepride, IBF and FIDA2, four iodobenzamide derivatives, for D2/D3 dopamine receptors. In addition, [ 123 I]β-CIT (RTI-55) and IPT, cocaine derivatives, for the dopamine reuptake site are potentially useful for diagnosis of loss of dopamine neurons. The first iodinated ligand, (R)trans-7-OH-PIPAT, for D3 dopamine receptors, was synthesized and characterized with cloned cell lines (Spodoptera frugiperda, Sf9) expressing the D2 and D3 dopamine receptors and with rat basal forebrain membrane preparations. Most of the known iodobenzamides displayed similar potency in binding to both D2 and D3 dopamine receptors expressed in the cell lines. Initial studies appear to suggest that by fine tuning the structures it may be possible to develop agents specific for D2 and D3 dopamine receptors. It is important to investigate D2/D3 selectivity for this series of potent ligands

  1. The roles of dopamine and serotonin in decision making: evidence from pharmacological experiments in humans.

    Science.gov (United States)

    Rogers, Robert D

    2011-01-01

    Neurophysiological experiments in primates, alongside neuropsychological and functional magnetic resonance investigations in humans, have significantly enhanced our understanding of the neural architecture of decision making. In this review, I consider the more limited database of experiments that have investigated how dopamine and serotonin activity influences the choices of human adults. These include those experiments that have involved the administration of drugs to healthy controls, experiments that have tested genotypic influences upon dopamine and serotonin function, and, finally, some of those experiments that have examined the effects of drugs on the decision making of clinical samples. Pharmacological experiments in humans are few in number and face considerable methodological challenges in terms of drug specificity, uncertainties about pre- vs post-synaptic modes of action, and interactions with baseline cognitive performance. However, the available data are broadly consistent with current computational models of dopamine function in decision making and highlight the dissociable roles of dopamine receptor systems in the learning about outcomes that underpins value-based decision making. Moreover, genotypic influences on (interacting) prefrontal and striatal dopamine activity are associated with changes in choice behavior that might be relevant to understanding exploratory behaviors and vulnerability to addictive disorders. Manipulations of serotonin in laboratory tests of decision making in human participants have provided less consistent results, but the information gathered to date indicates a role for serotonin in learning about bad decision outcomes, non-normative aspects of risk-seeking behavior, and social choices involving affiliation and notions of fairness. Finally, I suggest that the role played by serotonin in the regulation of cognitive biases, and representation of context in learning, point toward a role in the cortically mediated cognitive

  2. Role of dopamine on functional recovery in the contralateral hemisphere after focal stroke in the somatosensory cortex.

    Science.gov (United States)

    Obi, Kisho; Amano, Izuki; Takatsuru, Yusuke

    2018-01-01

    Functional recovery after a stroke is important for patients' quality of life. Not only medical care during the acute phase, but also rehabilitation during the chronic phase after a stroke is important. However, the mechanisms underlying functional recovery, particularly the chronic phase after stroke, are still not fully understood. Thus, further basic study on brain after focal stroke is necessary. In this study, we found that the concentration of dopamine (DA) increased during first week after a stroke in the hemisphere contralateral in the site of stroke by in vivo microdialysis. When we applied haloperidol (HPD), a potent DA receptor blocker, functional recovery was inhibited. Interestingly, administration of aripiprazole (ARP), a novel partial agonist of the DA receptor, during the chronic phase improved the remodeling of neuronal circuits in somatosensory cortex (SSC). These findings indicate that the DAergic system play a critical role in functional compensation by the non-infarcted hemisphere after a focal stroke in SSC. It is also revealed that administration of HPD/ARP to stroke patients affects functional recovery after a stroke, and stimulation of the DAergic system during the chronic phase of stroke potentially benefits stroke patients. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. Dopamine D1 and adenosine A1 receptors form functionally interacting heteromeric complexes

    Science.gov (United States)

    Ginés, Silvia; Hillion, Joëlle; Torvinen, Maria; Le Crom, Stèphane; Casadó, Vicent; Canela, Enric I.; Rondin, Sofia; Lew, Jow Y.; Watson, Stanley; Zoli, Michele; Agnati, Luigi Francesco; Vernier, Philippe; Lluis, Carmen; Ferré, Sergi; Fuxe, Kjell; Franco, Rafael

    2000-01-01

    The possible molecular basis for the previously described antagonistic interactions between adenosine A1 receptors (A1R) and dopamine D1 receptors (D1R) in the brain have been studied in mouse fibroblast Ltk− cells cotransfected with human A1R and D1R cDNAs or with human A1R and dopamine D2 receptor (long-form) (D2R) cDNAs and in cortical neurons in culture. A1R and D1R, but not A1R and D2R, were found to coimmunoprecipitate in cotransfected fibroblasts. This selective A1R/D1R heteromerization disappeared after pretreatment with the D1R agonist, but not after combined pretreatment with D1R and A1R agonists. A high degree of A1R and D1R colocalization, demonstrated in double immunofluorescence experiments with confocal laser microscopy, was found in both cotransfected fibroblast cells and cortical neurons in culture. On the other hand, a low degree of A1R and D2R colocalization was observed in cotransfected fibroblasts. Pretreatment with the A1R agonist caused coclustering (coaggregation) of A1R and D1R, which was blocked by combined pretreatment with the D1R and A1R agonists in both fibroblast cells and in cortical neurons in culture. Combined pretreatment with D1R and A1R agonists, but not with either one alone, substantially reduced the D1R agonist-induced accumulation of cAMP. The A1R/D1R heteromerization may be one molecular basis for the demonstrated antagonistic modulation of A1R of D1R receptor signaling in the brain. The persistence of A1R/D1R heteromerization seems to be essential for the blockade of A1R agonist-induced A1R/D1R coclustering and for the desensitization of the D1R agonist-induced cAMP accumulation seen on combined pretreatment with D1R and A1R agonists, which indicates a potential role of A1R/D1R heteromers also in desensitization mechanisms and receptor trafficking. PMID:10890919

  4. Concomitant Appearance of Pisa Syndrome and Striatal Hand in Parkinson’s Disease

    Directory of Open Access Journals (Sweden)

    Sanjay Pandey

    2011-10-01

    Full Text Available Pisa syndrome is (PS usually seen in patients receiving antipsychotic drugs and characterised by lateral flexion of trunk and axial dystonia. It is believed that antipsychotic drugs lead to dopamine blockage causing PS. We describe a Parkinson’s disease patient who was doing well with levodopa/carbidopa for 3 years and developed lateral flexion of trunk. His abnormal posture used to completely improve upon lying down position. He also had striatal hand deformity suggestive of focal dystonia.

  5. Human Bacterial Artificial Chromosome (BAC) Transgenesis Fully Rescues Noradrenergic Function in Dopamine β-Hydroxylase Knockout Mice.

    Science.gov (United States)

    Cubells, Joseph F; Schroeder, Jason P; Barrie, Elizabeth S; Manvich, Daniel F; Sadee, Wolfgang; Berg, Tiina; Mercer, Kristina; Stowe, Taylor A; Liles, L Cameron; Squires, Katherine E; Mezher, Andrew; Curtin, Patrick; Perdomo, Dannie L; Szot, Patricia; Weinshenker, David

    2016-01-01

    Dopamine β-hydroxylase (DBH) converts dopamine (DA) to norepinephrine (NE) in noradrenergic/adrenergic cells. DBH deficiency prevents NE production and causes sympathetic failure, hypotension and ptosis in humans and mice; DBH knockout (Dbh -/-) mice reveal other NE deficiency phenotypes including embryonic lethality, delayed growth, and behavioral defects. Furthermore, a single nucleotide polymorphism (SNP) in the human DBH gene promoter (-970C>T; rs1611115) is associated with variation in serum DBH activity and with several neurological- and neuropsychiatric-related disorders, although its impact on DBH expression is controversial. Phenotypes associated with DBH deficiency are typically treated with L-3,4-dihydroxyphenylserine (DOPS), which can be converted to NE by aromatic acid decarboxylase (AADC) in the absence of DBH. In this study, we generated transgenic mice carrying a human bacterial artificial chromosome (BAC) encompassing the DBH coding locus as well as ~45 kb of upstream and ~107 kb of downstream sequence to address two issues. First, we characterized the neuroanatomical, neurochemical, physiological, and behavioral transgenic rescue of DBH deficiency by crossing the BAC onto a Dbh -/- background. Second, we compared human DBH mRNA abundance between transgenic lines carrying either a "C" or a "T" at position -970. The BAC transgene drove human DBH mRNA expression in a pattern indistinguishable from the endogenous gene, restored normal catecholamine levels to the peripheral organs and brain of Dbh -/- mice, and fully rescued embryonic lethality, delayed growth, ptosis, reduced exploratory activity, and seizure susceptibility. In some cases, transgenic rescue was superior to DOPS. However, allelic variation at the rs1611115 SNP had no impact on mRNA levels in any tissue. These results indicate that the human BAC contains all of the genetic information required for tissue-specific, functional expression of DBH and can rescue all measured Dbh deficiency

  6. Human Bacterial Artificial Chromosome (BAC Transgenesis Fully Rescues Noradrenergic Function in Dopamine β-Hydroxylase Knockout Mice.

    Directory of Open Access Journals (Sweden)

    Joseph F Cubells

    Full Text Available Dopamine β-hydroxylase (DBH converts dopamine (DA to norepinephrine (NE in noradrenergic/adrenergic cells. DBH deficiency prevents NE production and causes sympathetic failure, hypotension and ptosis in humans and mice; DBH knockout (Dbh -/- mice reveal other NE deficiency phenotypes including embryonic lethality, delayed growth, and behavioral defects. Furthermore, a single nucleotide polymorphism (SNP in the human DBH gene promoter (-970C>T; rs1611115 is associated with variation in serum DBH activity and with several neurological- and neuropsychiatric-related disorders, although its impact on DBH expression is controversial. Phenotypes associated with DBH deficiency are typically treated with L-3,4-dihydroxyphenylserine (DOPS, which can be converted to NE by aromatic acid decarboxylase (AADC in the absence of DBH. In this study, we generated transgenic mice carrying a human bacterial artificial chromosome (BAC encompassing the DBH coding locus as well as ~45 kb of upstream and ~107 kb of downstream sequence to address two issues. First, we characterized the neuroanatomical, neurochemical, physiological, and behavioral transgenic rescue of DBH deficiency by crossing the BAC onto a Dbh -/- background. Second, we compared human DBH mRNA abundance between transgenic lines carrying either a "C" or a "T" at position -970. The BAC transgene drove human DBH mRNA expression in a pattern indistinguishable from the endogenous gene, restored normal catecholamine levels to the peripheral organs and brain of Dbh -/- mice, and fully rescued embryonic lethality, delayed growth, ptosis, reduced exploratory activity, and seizure susceptibility. In some cases, transgenic rescue was superior to DOPS. However, allelic variation at the rs1611115 SNP had no impact on mRNA levels in any tissue. These results indicate that the human BAC contains all of the genetic information required for tissue-specific, functional expression of DBH and can rescue all measured Dbh

  7. Adsorbent for resorcinol removal based on cellulose functionalized with magnetic poly(dopamine).

    Science.gov (United States)

    Ding, Chaofan; Sun, Yuanling; Wang, Yanhui; Li, Jianbo; Lin, Yanna; Sun, Weiyan; Luo, Chuannan

    2017-06-01

    A simple chemical bonding method to synthesize magnetic cellulose-poly(dopamine) (Fe 3 O 4 @CMC@PDA) was reported. The adsorption behaviors of resorcinol in aqueous solution on Fe 3 O 4 @CMC@PDA were systematically investigated. As the results shown that, with the advantage of high surface area, abundant hydroxyl and amino groups of Fe 3 O 4 @CMC@PDA, and the magnetic property of Fe 3 O 4 , the resorcinol can be easily and rapidly extracted from the water by magnetic attraction under investigation. The adsorption equilibrium of Fe 3 O 4 @CMC@PDA for resorcinol corresponded with Freundlich isotherm, and the novel adsorbent exhibited better resorcinol removal efficiency in solutions with low pH. It was found that the resorcinol adsorption performance of Fe 3 O 4 @CMC@PDA strongly depends on their surface charge concentration and specific surface area. These results provide evidences for estimating and optimizing the removal of phenols from the wastewater by using of Fe 3 O 4 @CMC@PDA composites in the future. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Imaging of dopamine transporters in rats using high-resolution pinhole single-photon emission tomography

    Energy Technology Data Exchange (ETDEWEB)

    Booij, Jan; Bruin, Kora de; Habraken, Jan B.A. [Department of Nuclear Medicine, F2N, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam (Netherlands); Voorn, Pieter [Department of Anatomy, Vrije Universiteit Medical Center, Amsterdam (Netherlands)

    2002-09-01

    To date, the vast majority of investigations on the dopaminergic system in small animals have been in vitro studies. In comparison with in vitro studies, single-photon emission tomography (SPET) or positron emission tomography (PET) imaging of the dopaminergic system in small animals has the advantage of permitting repeated studies within the same group of animals. Dopamine transporter imaging is a valuable non-invasive tool with which to investigate the integrity of dopaminergic neurons. The purpose of this study was to investigate the feasibility of assessing dopamine transporter density semi-quantitatively in rats using a recently developed high-resolution pinhole SPET system. This system was built exclusively for imaging of small animals. In this unique single-pinhole system, the animal rotates instead of the collimated detector. The system has proven to have a high spatial resolution. We performed SPET imaging with [{sup 123}I]FP-CIT to quantify striatal dopamine transporters in rat brain. In all seven studied control rats, symmetrical striatal binding to dopamine transporters was seen 2 h after injection of the radiotracer, with striatal-to-cerebellar binding ratios of approximately 3.5. In addition, test/retest variability of the striatal-to-cerebellar binding ratios was studied and found to be 14.5%. Finally, in unilaterally 6-hydroxydopamine-lesioned rats, striatal binding was only visible on the non-lesioned side. Quantitative analysis revealed that striatal-to-cerebellar SPET ratios were significantly lower on the lesioned (mean binding ratio 2.2{+-}0.2) than on the non-lesioned (mean ratio 3.1{+-}0.4) side. The preliminary results of this study indicate that semi-quantitative assessment of striatal dopamine transporter density using our recently developed high-resolution single-pinhole SPET system is feasible in living rat brain. (orig.)

  9. Transcription factors Foxa1 and Foxa2 are required for adult dopamine neurons maintenance

    Directory of Open Access Journals (Sweden)

    Andrii eDomanskyi

    2014-09-01

    Full Text Available The proteins Foxa1 and Foxa2 belong to the forkhead family of transcription factors and are involved in the development of several tissues, including liver, pancreas, lung, prostate, and the neural system. Both Foxa1 and Foxa2 are also crucial for the specification and differentiation of dopamine (DA neurons during embryonic development, while about 30% of mice with an embryonic deletion of a single allele of the Foxa2 gene exhibit an age-related asymmetric loss of DA neurons and develop locomotor symptoms resembling Parkinson’s disease (PD. Notably, both Foxa1 and Foxa2 factors continue to be expressed in the adult dopamine system. To directly assess their functions selectively in adult DA neurons, we induced genetic deletions of Foxa1/2 transcription factors in mice using a tamoxifen inducible tissue-specific CreERT2 recombinase expressed under control of the dopamine transporter (DAT promoter (DATCreERT2. The conditional DA neurons-specific ablation of both genes, but not of Foxa2 alone, in early adulthood, caused a decline of striatal dopamine and its metabolites, along with locomotor deficits. At early pre-symptomatic stages, we observed a decline in aldehyde dehydrogenase family 1, subfamily A1 (Aldh1a1 protein expression in DA neurons. Further analyses revealed a decline of aromatic amino acid decarboxylase (AADC and a complete loss of DAT expression in these neurons. These molecular changes ultimately led to a reduction of DA neuron numbers in the substantia nigra pars compacta (SNpc of aged cFoxa1/2-/- mice, resembling the progressive course of PD in humans. Altogether, in this study, we address the molecular, cellular and functional role of both Foxa1 and Foxa2 factors in the maintenance of the adult dopamine system which may help to find better approaches for PD treatment.

  10. Transcription factors Foxa1 and Foxa2 are required for adult dopamine neurons maintenance.

    Science.gov (United States)

    Domanskyi, Andrii; Alter, Heike; Vogt, Miriam A; Gass, Peter; Vinnikov, Ilya A

    2014-01-01

    The proteins Foxa1 and Foxa2 belong to the forkhead family of transcription factors and are involved in the development of several tissues, including liver, pancreas, lung, prostate, and the neural system. Both Foxa1 and Foxa2 are also crucial for the specification and differentiation of dopamine (DA) neurons during embryonic development, while about 30% of mice with an embryonic deletion of a single allele of the Foxa2 gene exhibit an age-related asymmetric loss of DA neurons and develop locomotor symptoms resembling Parkinson's disease (PD). Notably, both Foxa1 and Foxa2 factors continue to be expressed in the adult dopamine system. To directly assess their functions selectively in adult DA neurons, we induced genetic deletions of Foxa1/2 transcription factors in mice using a tamoxifen inducible tissue-specific CreERT2 recombinase expressed under control of the dopamine transporter (DAT) promoter (DATCreERT2). The conditional DA neurons-specific ablation of both genes, but not of Foxa2 alone, in early adulthood, caused a decline of striatal dopamine and its metabolites, along with locomotor deficits. At early pre-symptomatic stages, we observed a decline in aldehyde dehydrogenase family 1, subfamily A1 (Aldh1a1) protein expression in DA neurons. Further analyses revealed a decline of aromatic amino acid decarboxylase (AADC) and a complete loss of DAT expression in these neurons. These molecular changes ultimately led to a reduction of DA neuron numbers in the substantia nigra pars compacta (SNpc) of aged cFoxa1/2 (-/-) mice, resembling the progressive course of PD in humans. Altogether, in this study, we address the molecular, cellular, and functional role of both Foxa1 and Foxa2 factors in the maintenance of the adult dopamine system which may help to find better approaches for PD treatment.

  11. Common Variation in the DOPA Decarboxylase (DDC) Gene and Human Striatal DDC Activity In Vivo.

    Science.gov (United States)

    Eisenberg, Daniel P; Kohn, Philip D; Hegarty, Catherine E; Ianni, Angela M; Kolachana, Bhaskar; Gregory, Michael D; Masdeu, Joseph C; Berman, Karen F

    2016-08-01

    The synthesis of multiple amine neurotransmitters, such as dopamine, norepinephrine, serotonin, and trace amines, relies in part on DOPA decarboxylase (DDC, AADC), an enzyme that is required for normative neural operations. Because rare, loss-of-function mutations in the DDC gene result in severe enzymatic deficiency and devastating autonomic, motor, and cognitive impairment, DDC common genetic polymorphisms have been proposed as a source of more moderate, but clinically important, alterations in DDC function that may contribute to risk, course, or treatment response in complex, heritable neuropsychiatric illnesses. However, a direct link between common genetic variation in DDC and DDC activity in the living human brain has never been established. We therefore tested for this association by conducting extensive genotyping across the DDC gene in a large cohort of 120 healthy individuals, for whom DDC activity was then quantified with [(18)F]-FDOPA positron emission tomography (PET). The specific uptake constant, Ki, a measure of DDC activity, was estimated for striatal regions of interest and found to be predicted by one of five tested haplotypes, particularly in the ventral striatum. These data provide evidence for cis-acting, functional common polymorphisms in the DDC gene and support future work to determine whether such variation might meaningfully contribute to DDC-mediated neural processes relevant to neuropsychiatric illness and treatment.

  12. Adolescent THC Exposure Causes Enduring Prefrontal Cortical Disruption of GABAergic Inhibition and Dysregulation of Sub-Cortical Dopamine Function.

    Science.gov (United States)

    Renard, Justine; Szkudlarek, Hanna J; Kramar, Cecilia P; Jobson, Christina E L; Moura, Kyra; Rushlow, Walter J; Laviolette, Steven R

    2017-09-12

    Chronic adolescent marijuana use has been linked to the later development of psychiatric diseases such as schizophrenia. GABAergic hypofunction in the prefrontal cortex (PFC) is a cardinal pathological feature of schizophrenia and may be a mechanism by which the PFC loses its ability to regulate sub-cortical dopamine (DA) resulting in schizophrenia-like neuropsychopathology. In the present study, we exposed adolescent rats to Δ-9-tetra-hydrocannabinol (THC), the psychoactive component in marijuana. At adulthood, we characterized the functionality of PFC GABAergic neurotransmission and its regulation of sub-cortical DA function using molecular, behavioral and in-vivo electrophysiological analyses. Our findings revealed a persistent attenuation of PFC GABAergic function combined with a hyperactive neuronal state in PFC neurons and associated disruptions in cortical gamma oscillatory activity. These PFC abnormalities were accompanied by hyperactive DAergic neuronal activity in the ventral tegmental area (VTA) and behavioral and cognitive abnormalities similar to those observed in psychiatric disorders. Remarkably, these neuronal and behavioral effects were reversed by pharmacological activation of GABA A receptors in the PFC. Together, these results identify a mechanistic link between dysregulated frontal cortical GABAergic inhibition and sub-cortical DAergic dysregulation, characteristic of well-established neuropsychiatric endophenotypes.

  13. Interaction between childhood adversity and functional polymorphisms in the dopamine pathway on first-episode psychosis.

    Science.gov (United States)

    Trotta, Antonella; Iyegbe, Conrad; Yiend, Jenny; Dazzan, Paola; David, Anthony S; Pariante, Carmine; Mondelli, Valeria; Colizzi, Marco; Murray, Robin M; Di Forti, Marta; Fisher, Helen L

    2018-04-10

    There is consistent evidence of a cumulative relationship between childhood adversity and psychosis, with number of adversities experienced increasing the probability of psychosis onset. It is possible that genetic factors moderate the association between childhood adversity and psychosis, potentially by influencing how an individual reacts biologically and/or psychologically following exposure to adversity, in such a way as to set them off on the path to psychosis. However, identifying the specific genetic variants involved and how they interact with childhood adversity remains challenging. We examined whether the association between cumulative exposure to childhood adversity and development of psychotic disorder was moderated by the COMT Val 158 Met, AKT1 rs2494732 or DRD2 rs1076560 polymorphisms, known to affect dopamine levels. Participants were 285 first-presentation psychosis cases and 256 geographically-matched controls drawn from the Genetics and Psychosis (GAP) study. Childhood adversity was assessed using the Childhood Experience of Care and Abuse Questionnaire (CECA.Q) and blood- and cheek-derived genotype data were collected. Our findings revealed no main effect of COMT Val 158 Met, AKT1 rs2494732 and DRD2 rs1076560 polymorphisms on psychosis case status or reports of childhood adversity. Individuals reporting a history of multiple adversities were more likely to be psychosis patients than controls, regardless of their genetic risk. There was no evidence of candidate genotype by childhood adversity interactions in relation to psychosis onset. These findings did not provide evidence of a possible role of COMT Val 158 Met, AKT1 rs2494732 or DRD2 rs1076560 genotypes in modifying the association between childhood adversity and onset of psychosis. Copyright © 2018 Elsevier B.V. All rights reserved.

  14. Pauses in Striatal Cholinergic Interneurons: What is Revealed by Their Common Themes and Variations?

    Directory of Open Access Journals (Sweden)

    Yan-Feng Zhang

    2017-10-01

    Full Text Available Striatal cholinergic interneurons, the so-called tonically active neurons (TANs, pause their firing in response to sensory cues and rewards during classical conditioning and instrumental tasks. The respective pause responses observed can demonstrate many commonalities, such as constant latency and duration, synchronous occurrence in a population of cells, and coincidence with phasic activities of midbrain dopamine neurons (DANs that signal reward predictions and errors. Pauses can however also show divergent properties. Pause latencies and durations can differ in a given TAN between appetitive vs. aversive outcomes in classical conditioning, initial excitation can be present or absent, and a second pause can variably follow a rebound. Despite more than 20 years of study, the functions of these pause responses are still elusive. Our understanding of pause function is hindered by an incomplete understanding of how pauses are generated. In this mini-review article, we compare pause types, as well as current key hypotheses for inputs underlying pauses that include dopamine-induced inhibition through D2-receptors, a GABA input from ventral tegmental area, and a prolonged afterhyperpolarization induced by excitatory input from the cortex or from the thalamus. We review how each of these mechanisms alone explains some but not all aspects of pause responses. These mechanisms might need to operate in specific but variable sets of sequences to generate a full range of pause responses. Alternatively, these mechanisms might operate in conjunction with an underlying control mechanism within cholinergic interneurons which could potentially provide a framework to generate the common themes and variations seen amongst pause responses.

  15. Free radical production induced by methamphetamine in rat striatal synaptosomes.

    Science.gov (United States)

    Pubill, David; Chipana, Carlos; Camins, Antonio; Pallàs, Mercè; Camarasa, Jordi; Escubedo, Elena

    2005-04-01

    The pro-oxidative effect of methamphetamine (METH) in dopamine terminals was studied in rat striatal synaptosomes. Flow cytometry analysis showed increased production of reactive oxygen species (ROS) in METH-treated synaptosomes, without reduction in the density of dopamine transporters. In synaptosomes from dopamine (DA)-depleted animals, METH did not induce ROS production. Reserpine, in vitro, completely inhibited METH-induced ROS production. These results point to endogenous DA as the main source of ROS induced by METH. Antioxidants and inhibitors of neuronal nitric oxide synthase and protein kinase C (PKC) prevented the METH-induced oxidative effect. EGTA and the specific antagonist methyllycaconitine (MLA, 50 microM) prevented METH-induced ROS production, thus implicating calcium and alpha7 nicotinic receptors in such effect. Higher concentrations of MLA (>100 microM) showed nonspecific antioxidant effect. Preincubation of synaptosomes with METH (1 microM) for 30 min reduced [(3)H]DA uptake by 0%. The METH effect was attenuated by MLA and EGTA and potentiated by nicotine, indicating that activation of alpha(7) nicotinic receptors and Ca(2+) entry are necessary and take place before DAT inhibition. From these findings, it can be postulated that, in our model, METH induces DA release from synaptic vesicles to the cytosol. Simultaneously, METH activates alpha(7) nicotinic receptors, probably inducing depolarization and an increase in intrasynaptosomal Ca(2+). This would lead to DAT inhibition and NOS and PKC activation, initiating oxidation of cytosolic DA.

  16. Dopaminergic control of attentional flexibility: inhibition of return is associated with the dopamine transporter gene (DAT1

    Directory of Open Access Journals (Sweden)

    Lorenza S Colzato

    2010-07-01

    Full Text Available Genetic variability related to the dopamine (DA transporter gene (DAT1 has received increasing attention as a possible modulator of human cognition. The 9-repeat allele of the DAT1 gene is presumably associated with higher striatal DA levels than the 10-repeat allele, which might support inhibitory control functions. We investigated the impact of the DAT1 gene on the inhibition of return (IOR effect, which refers to the fact that people are slower to detect a target if it appears in a previously attended location. 140 healthy adults, genotyped for the DAT1 gene, performed an IOR task with stimulus-onset asynchronies between attention cue and target of 150-1200 ms. 9-repeat carriers showed more pronounced IOR effect than 10/10 homozygous at short stimulus-onset asynchronies but both groups of subjects eventually reached the same magnitude of IOR. Our findings support the idea that striatal DA levels promote IOR, presumably by biasing the interplay between prefrontal and striatal networks towards greater cognitive flexibility.

  17. Peptide-functionalized poly[oligo(ethylene glycol) methacrylate] brushes on dopamine-coated stainless steel for controlled cell adhesion.

    Science.gov (United States)

    Alas, Guillermo R; Agarwal, Rachit; Collard, David M; García, Andrés J

    2017-09-01

    The modification of the surface of surgical implants with cell adhesion ligands has emerged as a promising approach to improve biomaterial-host interactions. However, these approaches are limited by the non-specific adsorption of biomolecules and uncontrolled presentation of desired bioactive ligands on implant surfaces. This leads to sub-optimal integration with host tissue and delayed healing. Here we present a strategy to grow non-fouling polymer brushes of oligo(ethylene glycol) methacrylate by atom transfer radical polymerization from dopamine-functionalized clinical grade 316 stainless steel. These brushes prevent non-specific adsorption of proteins and attachment of cells. Subsequently, the brushes can be modified with covalently tethered adhesive peptides that provide controlled cell adhesion. This approach may therefore have broad application to promote bone growth and improvements in osseointegration. Stainless steel (SS) implants are widely used clinically for orthopaedic, spinal, dental and cardiovascular applications. However, non-specific adsorption of biomolecules onto implant surfaces results in sub-optimal integration with host tissue. To allow controlled cell-SS interactions, we have developed a strategy to grow non-fouling polymer brushes that prevent protein adsorption and cell adhesion and can be subsequently functionalized with adhesive peptides to direct cell adhesion and signaling. This approach has broad application to improve osseointegration onto stainless steel implants in bone repair. Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

  18. Functionalized-graphene modified graphite electrode for the selective determination of dopamine in presence of uric acid and ascorbic acid.

    Science.gov (United States)

    Mallesha, Malledevaru; Manjunatha, Revanasiddappa; Nethravathi, C; Suresh, Gurukar Shivappa; Rajamathi, Michael; Melo, Jose Savio; Venkatesha, Thimmappa Venkatarangaiah

    2011-06-01

    Graphene is chemically synthesized by solvothermal reduction of colloidal dispersions of graphite oxide. Graphite electrode is modified with functionalized-graphene for electrochemical applications. Electrochemical characterization of functionalized-graphene modified graphite electrode (FGGE) is carried out by cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS). The behavior of FGGE towards ascorbic acid (AA), dopamine (DA) and uric acid (UA) has been investigated by CV, differential pulse voltammetry (DPV) and chronoamperommetry (CA). The FGGE showed excellent catalytic activity towards electrochemical oxidation of AA, DA and UA compared to that of the bare graphite electrode. The electrochemical oxidation signals of AA, DA and UA are well separated into three distinct peaks with peak potential separation of 193mv, 172mv and 264mV between AA-DA, DA-UA and AA-UA respectively in CV studies and the corresponding peak potential separations in DPV mode are 204mv, 141mv and 345mv. The FGGE is successfully used for the simultaneous detection of AA, DA and UA in their ternary mixture and DA in serum and pharmaceutical samples. The excellent electrocatalytic behavior of FGGE may lead to new applications in electrochemical analysis. Copyright © 2011 Elsevier B.V. All rights reserved.

  19. Reelin influences the expression and function of dopamine D2 and serotonin 5-HT2A receptors: a comparative study.

    Science.gov (United States)

    Varela, M J; Lage, S; Caruncho, H J; Cadavid, M I; Loza, M I; Brea, J

    2015-04-02

    Reelin is an extracellular matrix protein that plays a critical role in neuronal guidance during brain neurodevelopment and in synaptic plasticity in adults and has been associated with schizophrenia. Reelin mRNA and protein levels are reduced in various structures of post-mortem schizophrenic brains, in a similar way to those found in heterozygous reeler mice (HRM). Reelin is involved in protein expression in dendritic spines that are the major location where synaptic connections are established. Thus, we hypothesized that a genetic deficit in reelin would affect the expression and function of dopamine D2 and serotonin 5-HT2A receptors that are associated with the action of current antipsychotic drugs. In this study, D2 and 5-HT2A receptor expression and function were quantitated by using radioligand binding studies in the frontal cortex and striatum of HRM and wild-type mice (WTM). We observed increased expression (pHT2A receptors from HRM compared to WTM. Our results show parallel alterations of D2 and 5-HT2A receptors that are compatible with a possible hetero-oligomeric nature of these receptors. These changes are similar to changes described in schizophrenic patients and provide further support for the suitability of using HRM as a model for studying this disease and the effects of antipsychotic drugs. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

  20. Super-resolution microscopy reveals functional organization of dopamine transporters into cholesterol and neuronal activity-dependent nanodomains

    DEFF Research Database (Denmark)

    Rahbek-Clemmensen, Troels; Lycas, Matthew D.; Erlendsson, Simon

    2017-01-01

    to cholesterol depletion. Live photoactivated localization microscopy shows a similar dopamine transporter membrane organization in live heterologous cells. In neurons, dual-color dSTORM shows that tyrosine hydroxylase and vesicular monoamine transporter-2 are distinctively localized adjacent to...

  1. Mechanisms and Consequences of Dopamine Depletion-Induced Attenuation of the Spinophilin/Neurofilament Medium Interaction

    Directory of Open Access Journals (Sweden)

    Andrew C. Hiday

    2017-01-01

    Full Text Available Signaling changes that occur in the striatum following the loss of dopamine neurons in the Parkinson disease (PD are poorly understood. While increases in the activity of kinases and decreases in the activity of phosphatases have been observed, the specific consequences of these changes are less well understood. Phosphatases, such as protein phosphatase 1 (PP1, are highly promiscuous and obtain substrate selectivity via targeting proteins. Spinophilin is the major PP1-targeting protein enriched in the postsynaptic density of striatal dendritic spines. Spinophilin association with PP1 is increased concurrent with decreases in PP1 activity in an animal model of PD. Using proteomic-based approaches, we observed dopamine depletion-induced decreases in spinophilin binding to multiple protein classes in the striatum. Specifically, there was a decrease in the association of spinophilin with neurofilament medium (NF-M in dopamine-depleted striatum. Using a heterologous cell line, we determined that spinophilin binding to NF-M required overexpression of the catalytic subunit of protein kinase A and was decreased by cyclin-dependent protein kinase 5. Functionally, we demonstrate that spinophilin can decrease NF-M phosphorylation. Our data determine mechanisms that regulate, and putative consequences of, pathological changes in the association of spinophilin with NF-M that are observed in animal models of PD.

  2. Cryopreservation Maintains Functionality of Human iPSC Dopamine Neurons and Rescues Parkinsonian Phenotypes In Vivo

    Directory of Open Access Journals (Sweden)

    Dustin R. Wakeman

    2017-07-01

    Full Text Available A major challenge for clinical application of pluripotent stem cell therapy for Parkinson's disease (PD is large-scale manufacturing and cryopreservation of neurons that can be efficiently prepared with minimal manipulation. To address this obstacle, midbrain dopamine neurons were derived from human induced pluripotent stem cells (iPSC-mDA and cryopreserved in large production lots for biochemical and transplantation studies. Cryopreserved, post-mitotic iPSC-mDA neurons retained high viability with gene, protein, and electrophysiological signatures consistent with midbrain floor-plate lineage. To test therapeutic efficacy, cryopreserved iPSC-mDA neurons were transplanted without subculturing into the 6-OHDA-lesioned rat and MPTP-lesioned non-human-primate models of PD. Grafted neurons retained midbrain lineage with extensive fiber innervation in both rodents and monkeys. Behavioral assessment in 6-OHDA-lesioned rats demonstrated significant reversal in functional deficits up to 6 months post transplantation with reinnervation of the host striatum and no aberrant growth, supporting the translational development of pluripotent cell-based therapies in PD.

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

    DEFF Research Database (Denmark)

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

    2016-01-01

    activity of DA cell subpopulations and assessment of the down-stream functional effect ofDArelease. Because this is not yet possible solely by experimentation in vivo,we combine computational modeling and fast-scan cyclic voltammetry data to reconstruct the functionally relevantDAsignal in...

  4. Poly(zwitterionic liquids) functionalized polypyrrole/graphene oxide nanosheets for electrochemically detecting dopamine at low concentration

    Energy Technology Data Exchange (ETDEWEB)

    Mao, Hui; Liang, Jiachen; Ji, Chunguang; Zhang, Haifeng; Pei, Qi; Zhang, Yuyang; Zhang, Yu [Liaoning Key Laboratory for Green Synthesis and Preparative Chemistry of Advanced Materials, College of Chemistry, Liaoning University, Shenyang 110036 (China); Hisaeda, Yoshio [Department of Chemistry and Biochemistry, Graduate School of Engineering, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395 (Japan); Song, Xi-Ming, E-mail: songlab@lnu.edu.cn [Liaoning Key Laboratory for Green Synthesis and Preparative Chemistry of Advanced Materials, College of Chemistry, Liaoning University, Shenyang 110036 (China); Department of Chemistry and Biochemistry, Graduate School of Engineering, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395 (Japan)

    2016-08-01

    Poly(3-(1-vinylimidazolium-3-yl)propane-1-sulfonate) (PVIPS), a novel kind of poly(zwitterionic liquids) (PZILs) containing both imidazolium cation and sulfonate anion, was successfully modified on the surface of polypyrrole/graphene oxide nanosheets (PPy/GO) by covalent bonding. The obtained novel PZILs functionalized PPy/GO nanosheets (PVIPS/PPy/GO) modified glassy carbon electrode (GCE) presented the excellent electrochemical catalytic activity towards dopamine (DA) with high stability, sensitivity, selectivity and wide linear range (40–1220 nM), especially having a lower detection limit (17.3 nM). The excellent analytical performance is attributed to the strongly negative charges on the surface of modified GCE in aqueous solution, which is different from conventional poly(ionic liquids) modified GCE. DA cations could be quickly enriched on the electrode surface by electrostatic interaction in solution due to the existence of −SO{sub 3}{sup −} groups with negative charge at the end of pendant groups in zwitterionic PVIPS, resulting in a change of the electrons transmission mode in the oxidation of DA, that is, from a typical diffusion-controlled process at conventional poly(1-vinyl-3-ethylimidazole bromide) (PVEIB)/PPy/GO modified GCE to a typical surface-controlled process. - Graphical Abstract: Novel poly(zwitterionic liquids) functionalized polypyrrole/graphene oxide nanosheets were successfully synthesized and presented an excellent performance for determination to DA. Display Omitted - Highlights: • Zwitterionic PVIPS functionalized PPy/GO nanosheets were successfully synthesized. • Their surface charge property has been obviously changed to electronegativity. • The excellent electrochemical catalytic activities towards DA were achieved. • −SO{sub 3}{sup −} groups with negative charge changed the transmission mode of electrons. • PVIPS/PPy/GO can act as an electrode material for detecting DA at low concentration.

  5. An allosteric enhancer of M(4) muscarinic acetylcholine receptor function inhibits behavioral and neurochemical effects of cocaine

    DEFF Research Database (Denmark)

    Nielsen, Ditte Dencker; Weikop, Pia; Sørensen, Gunnar

    2012-01-01

    The mesostriatal dopamine system plays a key role in mediating the reinforcing effects of psychostimulant drugs like cocaine. The muscarinic M(4) acetylcholine receptor subtype is centrally involved in the regulation of dopamine release in striatal areas. Consequently, striatal M(4) receptors could...... be a novel target for modulating psychostimulant effects of cocaine....

  6. Regulation of drugs affecting striatal cholinergic activity by corticostriatal projections

    International Nuclear Information System (INIS)

    Ladinsky, H.

    1986-01-01

    Research demonstrates that the chronic degeneration of the corticostriatal excitatory pathway makes the cholinergic neurons of the striatum insensitive to the neuropharmacological action of a number of different drugs. Female rats were used; they were killed and after the i.v. infusion of tritium-choline precursor, choline acetyltransferase activity was measured. Striatal noradrenaline, dopamine and serotonin content was measured by electrochemical detection coupled with high pressure liquid chromatography. Uptake of tritium-glutamic acid was estimated. The data were analyzed statistically. It is shown that there is evidence that the effects of a number of drugs capable of depressing cholinergic activity through receptor-mediated responses are operative only if the corticostriatal pathway is integral. Neuropharmacological responses in the brain appear to be the result of an interaction between several major neurotransmitter systems

  7. Maternal obesity caused by overnutrition exposure leads to reversal learning deficits and striatal disturbance in rats.

    Directory of Open Access Journals (Sweden)

    Ting Wu

    Full Text Available Maternal obesity caused by overnutrition during pregnancy increases susceptibility to metabolic risks in adulthood, such as obesity, insulin resistance, and type 2 diabetes; however, whether and how it affects the cognitive system associated with the brain remains elusive. Here, we report that pregnant obesity induced by exposure to excessive high fatty or highly palatable food specifically impaired reversal learning, a kind of adaptive behavior, while leaving serum metabolic metrics intact in the offspring of rats, suggesting a much earlier functional and structural defects possibly occurred in the central nervous system than in the metabolic system in the offspring born in unfavorable intrauterine nutritional environment. Mechanically, we found that above mentioned cognitive inflexibility might be associated with significant striatal disturbance including impaired dopamine homeostasis and disrupted leptin signaling in the adult offspring. These collective data add a novel perspective of understanding the adverse postnatal sequelae in central nervous system induced by developmental programming and the related molecular mechanism through which priming of risk for developmental disorders may occur during early life.

  8. PET 6-[18F]fluoro-L-m-tyrosine studies of dopaminergic function in human and nonhuman primates

    Directory of Open Access Journals (Sweden)

    Jamie L Eberling

    2008-03-01

    Full Text Available Although positron emission tomography (PET and the aromatic L-amino acid decarboxylase (AADC tracer 6-[18F]fluoro-L-m-tyrosine (FMT has been used to assess the integrity of the presynaptic dopamine system in the brain, relatively little has been published in terms of brain FMT uptake values especially for normal human subjects. Twelve normal volunteer subjects were scanned using PET and FMT to determine the range of normal striatal uptake values using Patlak graphical analysis. For comparison, seven adult rhesus monkeys were studied and the data analyzed in the same way. A subset of monkeys that were treated with a unilateral intracarotid artery infusion of the dopamine neurotoxin MPTP showed an 87% decrease in striatal FMT uptake. These findings support the use of PET and FMT to image AADC distribution in both normal and diseased brains using Patlak graphical analysis and tissue input functions.

  9. Ratio of dopamine synthesis capacity to D2 receptor availability in ventral striatum correlates with central processing of affective stimuli

    International Nuclear Information System (INIS)

    Kienast, Thorsten; Rapp, Michael; Siessmeier, Thomas; Buchholz, Hans G.; Schreckenberger, Mathias; Wrase, Jana; Heinz, Andreas; Braus, Dieter F.; Smolka, Michael N.; Mann, Karl; Roesch, Frank; Cumming, Paul; Gruender, Gerhard; Bartenstein, Peter

    2008-01-01

    Dopaminergic neurotransmission in the ventral striatum may interact with limbic processing of affective stimuli, whereas dorsal striatal dopaminergic neurotransmission can affect habitual processing of emotionally salient stimuli in the pre-frontal cortex. We investigated the dopaminergic neurotransmission in the ventral and dorsal striatum with respect to central processing of affective stimuli in healthy subjects. Subjects were investigated with positron emission tomography and [ 18 F]DOPA for measurements of dopamine synthesis capacity and [ 18 F]DMFP for estimation of dopamine D2 receptor binding potential. Functional magnetic resonance imaging was used to assess the blood-oxygen-level-dependent (BOLD) response to affective pictures, which was correlated with the ratio of [ 18 F]DOPA net influx constant K in app /[ 18 F]DMFP-binding potential (BP N D) in the ventral and dorsal striatum. The magnitude of the ratio in the ventral striatum was positively correlated with BOLD signal increases elicited by negative versus neutral pictures in the right medial frontal gyrus (BA10), right inferior parietal lobe and left post-central gyrus. In the dorsal striatum, the ratio was positively correlated with BOLD signal activation elicited by negative versus neutral stimuli in the left post-central gyrus. The BOLD signal elicited by positive versus neutral stimuli in the superior parietal gyrus was positively correlated with the dorsal and ventral striatal ratio. The correlations of the ratio in the ventral and dorsal striatum with processing of affective stimuli in the named cortical regions support the hypothesis that dopamine transmission in functional divisions of the striatum modulates processing of affective stimuli in specific cortical areas. (orig.)

  10. Distinct presynaptic regulation of dopamine release through NMDA receptors in striosome- and matrix-enriched areas of the rat striatum

    International Nuclear Information System (INIS)

    Krebs, M.O.; Trovero, F.; Desban, M.; Gauchy, C.; Glowinski, J.; Kemel, M.L.

    1991-01-01

    Striosome- and matrix-enriched striatal zones were defined in coronal and sagittal brain sections of the rat, on the basis of 3 H-naloxone binding to mu-opiate receptors (a striosome-specific marker). Then, using a new in vitro microsuperfusion device, the NMDA (50 microM)-evoked release of newly synthesized 3 H-dopamine ( 3 H-DA) was examined in these four striatal areas under Mg(2+)-free conditions. The amplitudes of the responses were different in striosomal (171 +/- 6% and 161 +/- 5% of the spontaneous release) than in matrix areas (223 +/- 6% and 248 +/- 12%), even when glycine (1 or 100 microM) was coapplied (in the presence of 1 microM strychnine). In the four areas, the NMDA-evoked release of 3 H-DA was blocked completely by Mg 2+ (1 mM) or (+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine maleate (MK-801; 1 microM) and almost totally abolished by kynurenate (100 microM). Because the tetrodotoxin (TTX)-resistant NMDA-evoked release of 3 H-DA was similar in striosome- (148 +/- 5% and 152 +/- 6%) or matrix-enriched (161 +/- 5% and 156 +/- 7%) areas, the indirect (TTX-sensitive) component of NMDA-evoked responses, which involves striatal neurons and/or afferent fibers, seems more important in the matrix- than in the striosome-enriched areas. The modulation of DA release by cortical glutamate and/or aspartate-containing inputs through NMDA receptors in the matrix appears thus to be partly distinct from that observed in the striosomes, providing some functional basis for the histochemical striatal heterogeneity

  11. Distinct presynaptic regulation of dopamine release through NMDA receptors in striosome- and matrix-enriched areas of the rat striatum

    Energy Technology Data Exchange (ETDEWEB)

    Krebs, M.O.; Trovero, F.; Desban, M.; Gauchy, C.; Glowinski, J.; Kemel, M.L. (College de France, Paris (France))

    1991-05-01

    Striosome- and matrix-enriched striatal zones were defined in coronal and sagittal brain sections of the rat, on the basis of {sup 3}H-naloxone binding to mu-opiate receptors (a striosome-specific marker). Then, using a new in vitro microsuperfusion device, the NMDA (50 microM)-evoked release of newly synthesized {sup 3}H-dopamine ({sup 3}H-DA) was examined in these four striatal areas under Mg(2+)-free conditions. The amplitudes of the responses were different in striosomal (171 +/- 6% and 161 +/- 5% of the spontaneous release) than in matrix areas (223 +/- 6% and 248 +/- 12%), even when glycine (1 or 100 microM) was coapplied (in the presence of 1 microM strychnine). In the four areas, the NMDA-evoked release of {sup 3}H-DA was blocked completely by Mg{sup 2}{sup +} (1 mM) or (+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine maleate (MK-801; 1 microM) and almost totally abolished by kynurenate (100 microM). Because the tetrodotoxin (TTX)-resistant NMDA-evoked release of {sup 3}H-DA was similar in striosome- (148 +/- 5% and 152 +/- 6%) or matrix-enriched (161 +/- 5% and 156 +/- 7%) areas, the indirect (TTX-sensitive) component of NMDA-evoked responses, which involves striatal neurons and/or afferent fibers, seems more important in the matrix- than in the striosome-enriched areas. The modulation of DA release by cortical glutamate and/or aspartate-containing inputs through NMDA receptors in the matrix appears thus to be partly distinct from that observed in the striosomes, providing some functional basis for the histochemical striatal heterogeneity.

  12. Gastric Bypass Surgery Recruits a Gut PPAR-α-Striatal D1R Pathway to Reduce Fat Appetite in Obese Rats

    DEFF Research Database (Denmark)

    Hankir, Mohammed K; Seyfried, Florian; Hintschich, Constantin A

    2017-01-01

    Bariatric surgery remains the single most effective long-term treatment modality for morbid obesity, achieved mainly by lowering caloric intake through as yet ill-defined mechanisms. Here we show in rats that Roux-en-Y gastric bypass (RYGB)-like rerouting of ingested fat mobilizes lower small...... intestine production of the fat-satiety molecule oleoylethanolamide (OEA). This was associated with vagus nerve-driven increases in dorsal striatal dopamine release. We also demonstrate that RYGB upregulates striatal dopamine 1 receptor (D1R) expression specifically under high-fat diet feeding conditions....... Mechanistically, interfering with local OEA, vagal, and dorsal striatal D1R signaling negated the beneficial effects of RYGB on fat intake and preferences. These findings delineate a molecular/systems pathway through which bariatric surgery improves feeding behavior and may aid in the development of novel weight...

  13. Striatal lesions in delusional parasitosis revealed by magnetic resonance imaging.

    Science.gov (United States)

    Huber, Markus; Karner, Martin; Kirchler, Erwin; Lepping, Peter; Freudenmann, Roland W

    2008-12-12

    Delusional parasitosis (DP) is a syndrome characterized by the firm conviction that small living beings infest the skin. The etiology can be primary and secondary. Structural brain abnormalities in DP have only been reported in case reports often subcortical vascular encephalopathy and right-hemisphere strokes in the temporo-parietal cortex. Systematic brain imaging studies are lacking. We aimed to identify a brain region with structural lesions in patients with DP in order to better understand the pathophysiology of DP. Nine consecutive patients with DP in a psychiatric outpatient department were assessed clinically and by means of cranial magnetic resonance imaging (MRI). Five of the nine cases were diagnosed as having DP as psychotic disorders due to a general medical condition while three had DP arising from pre-existing psychiatric illness and one suffered from a delusional disorder, somatic type (primary form). Four of the five DP cases secondary to a general medical condition (one case could not be analyzed) had striatal lesions predominantly in the putamen. Thalamic or cortical lesions were found in one case, respectively. In the primary DP case and all cases secondary to another psychiatric disorder basal ganglia and subcortical gray matter lesions were absent. In all medical (secondary) DP cases subcortical white matter lesions were found mainly in the centrum semiovale. Three of the five medical DP cases showed severe generalized brain atrophy which was absent in the primary DP case and in the cases secondary to other psychiatric disorders. We present the findings of the first structural MRI study in DP. Our results suggest a possible relevance of structural lesions in the striatum, predominantly the putamen, in the medical (secondary) DP-subgroup. Our findings are in line with other studies demonstrating that the putamen, in addition to its role in motor regulation, represents a brain area that mediates visuo-tactile perception. Disturbed functioning of

  14. Towards trans-diagnostic mechanisms in psychiatry: neurobehavioral profile of rats with a loss-of-function point mutation in the dopamine transporter gene

    Directory of Open Access Journals (Sweden)

    Valentina Vengeliene

    2017-04-01

    Full Text Available The research domain criteria (RDoC matrix has been developed to reorient psychiatric research towards measurable behavioral dimensions and underlying mechanisms. Here, we used a new genetic rat model with a loss-of-function point mutation in the dopamine transporter (DAT gene (Slc6a3_N157K to systematically study the RDoC matrix. First, we examined the impact of the Slc6a3_N157K mutation on monoaminergic signaling. We then performed behavioral tests representing each of the five RDoC domains: negative and positive valence systems, cognitive, social and arousal/regulatory systems. The use of RDoC may be particularly helpful for drug development. We studied the effects of a novel pharmacological approach metabotropic glutamate receptor mGluR2/3 antagonism, in DAT mutants in a comparative way with standard medications. Loss of DAT functionality in mutant rats not only elevated subcortical extracellular dopamine concentration but also altered the balance of monoaminergic transmission. DAT mutant rats showed deficits in all five RDoC domains. Thus, mutant rats failed to show conditioned fear responses, were anhedonic, were unable to learn stimulus-reward associations, showed impaired cognition and social behavior, and were hyperactive. Hyperactivity in mutant rats was reduced by amphetamine and atomoxetine, which are well-established medications to reduce hyperactivity in humans. The mGluR2/3 antagonist LY341495 also normalized hyperactivity in DAT mutant rats without affecting extracellular dopamine levels. We systematically characterized an altered dopamine system within the context of the RDoC matrix and studied mGluR2/3 antagonism as a new pharmacological strategy to treat mental disorders with underlying subcortical dopaminergic hyperactivity.

  15. Introducing Thermal Wave Transport Analysis (TWTA): A Thermal Technique for Dopamine Detection by Screen-Printed Electrodes Functionalized with Molecularly Imprinted Polymer (MIP) Particles.

    Science.gov (United States)

    Peeters, Marloes M; van Grinsven, Bart; Foster, Christopher W; Cleij, Thomas J; Banks, Craig E

    2016-04-26

    A novel procedure is developed for producing bulk modified Molecularly Imprinted Polymer (MIP) screen-printed electrodes (SPEs), which involves the direct mixing of the polymer particles within the screen-printed ink. This allowed reduction of the sample preparation time from 45 min to 1 min, and resulted in higher reproducibility of the electrodes. The samples are measured with a novel detection method, namely, thermal wave transport analysis (TWTA), relying on the analysis of thermal waves through a functional interface. As a first proof-of-principle, MIPs for dopamine are developed and successfully incorporated within a bulk modified MIP SPE. The detection limits of dopamine within buffer solutions for the MIP SPEs are determined via three independent techniques. With cyclic voltammetry this was determined to be 4.7 × 10(-6) M, whereas by using the heat-transfer method (HTM) 0.35 × 10(-6) M was obtained, and with the novel TWTA concept 0.26 × 10(-6) M is possible. This TWTA technique is measured simultaneously with HTM and has the benefits of reducing measurement time to less than 5 min and increasing effect size by nearly a factor of two. The two thermal methods are able to enhance dopamine detection by one order of magnitude compared to the electrochemical method. In previous research, it was not possible to measure neurotransmitters in complex samples with HTM, but with the improved signal-to-noise of TWTA for the first time, spiked dopamine concentrations were determined in a relevant food sample. In summary, novel concepts are presented for both the sensor functionalization side by employing screen-printing technology, and on the sensing side, the novel TWTA thermal technique is reported. The developed bio-sensing platform is cost-effective and suitable for mass-production due to the nature of screen-printing technology, which makes it very interesting for neurotransmitter detection in clinical diagnostic applications.

  16. Increased expression of the dopamine transporter leads to loss of dopamine neurons, oxidative stress and L-DOPA reversible motor deficits

    OpenAIRE

    Masoud, ST; Vecchio, LM; Bergeron, Y; Hossain, MM; Nguyen, LT; Bermejo, MK; Kile, B; Sotnikova, TD; Siesser, WB; Gainetdinov, RR; Wightman, RM; Caron, MG; Richardson, JR; Miller, GW; Ramsey, AJ

    2014-01-01

    The dopamine transporter is a key protein responsible for regulating dopamine homeostasis. Its function is to transport dopamine from the extracellular space into the presynaptic neuron. Studies have suggested that accumulation of dopamine in the cytosol can trigger oxidative stress and neurotoxicity. Previously, ectopic expression of the dopamine transporter was shown to cause damage in non-dopaminergic neurons due to their inability to handle cytosolic dopamine. However, it is unknown wheth...

  17. The enemy within: propagation of aberrant corticostriatal learning to cortical function in Parkinson's disease

    Directory of Open Access Journals (Sweden)

    Jeff A Beeler

    2013-09-01

    Full Text Available Motor dysfunction in Parkinson’s disease is believed to arise primarily from pathophysiology in the dorsal striatum and its related corticostriatal and thalamostriatal circuits during progressive dopamine denervation. One function of these circuits is to provide a filter that selectively facilitates or inhibits cortical activity to optimize cortical processing, making motor responses rapid and efficient. Corticostriatal synaptic plasticity mediates the learning that underlies this performance-optimizing filter. Under dopamine denervation, corticostriatal plasticity is altered, resulting in aberrant learning that induces inappropriate basal ganglia filtering that impedes rather than optimizes cortical processing. Human imaging suggests that increased cortical activity may compensate for striatal dysfunction in PD patients. In this Perspective article, we consider how aberrant learning at corticostriatal synapses may impair cortical processing and learning and undermine potential cortical compensatory mechanisms. Blocking or remediating aberrant corticostriatal plasticity may protect cortical function and support cortical compensatory mechanisms mitigating the functional decline associated with progressive dopamine denervation.

  18. Functional Selectivity of Allosteric Interactions within G Protein–Coupled Receptor Oligomers: The Dopamine D1-D3 Receptor Heterotetramer

    Science.gov (United States)

    Guitart, Xavier; Navarro, Gemma; Moreno, Estefania; Yano, Hideaki; Cai, Ning-Sheng; Sánchez-Soto, Marta; Kumar-Barodia, Sandeep; Naidu, Yamini T.; Mallol, Josefa; Cortés, Antoni; Lluís, Carme; Canela, Enric I.; Casadó, Vicent; McCormick, Peter J.

    2014-01-01

    The dopamine D1 receptor–D3 receptor (D1R-D3R) heteromer is being considered as a potential therapeutic target for neuropsychiatric disorders. Previous studies suggested that this heteromer could be involved in the ability of D3R agonists to potentiate locomotor activation induced by D1R agonists. It has also been postulated that its overexpression plays a role in L-dopa–induced dyskinesia and in drug addiction. However, little is known about its biochemical properties. By combining bioluminescence resonance energy transfer, bimolecular complementation techniques, and cell-signaling experiments in transfected cells, evidence was obtained for a tetrameric stoichiometry of the D1R–D3R heteromer, constituted by two interacting D1R and D3R homodimers coupled to Gs and Gi proteins, respectively. Coactivation of both receptors led to the canonical negative interaction at the level of adenylyl cyclase signaling, to a strong recruitment of β-arrestin-1, and to a positive cross talk of D1R and D3R agonists at the level of mitogen-activated protein kinase (MAPK) signaling. Furthermore, D1R or D3R antagonists counteracted β-arrestin-1 recruitment and MAPK activation induced by D3R and D1R agonists, respectively (cross-antagonism). Positive cross talk and cross-antagonism at the MAPK level were counteracted by specific synthetic peptides with amino acid sequences corresponding to D1R transmembrane (TM) domains TM5 and TM6, which also selectively modified the quaternary structure of the D1R-D3R heteromer, as demonstrated by complementation of hemiproteins of yellow fluorescence protein fused to D1R and D3R. These results demonstrate functional selectivity of allosteric modulations within the D1R-D3R heteromer, which can be involved with the reported behavioral synergism of D1R and D3R agonists. PMID:25097189

  19. Grass Carp Follisatin: Molecular Cloning, Functional Characterization, Dopamine D1 Regulation at Pituitary Level, and Implication in Growth Hormone Regulation

    Directory of Open Access Journals (Sweden)

    Roger S. K. Fung

    2017-08-01

    Full Text Available Activin is involved in pituitary hormone regulation and its pituitary actions can be nullified by local production of its binding protein follistatin. In our recent study with grass carp, local release of growth hormone (GH was shown to induce activin expression at pituitary level, which in turn could exert an intrapituitary feedback to inhibit GH synthesis and secretion. To further examine the activin/follistatin system in the carp pituitary, grass carp follistatin was cloned and confirmed to be single-copy gene widely expressed at tissue level. At the pituitary level, follistatin signals could be located in carp somatotrophs, gonadotrophs, and lactotrophs. Functional expression also revealed that carp follistatin was effective in neutralizing activin’s action in stimulating target promoter with activin-responsive elements. In grass carp pituitary cells, follistatin co-treatment was found to revert activin inhibition on GH mRNA expression. Meanwhile, follistatin mRNA levels could be up-regulated by local production of activin but the opposite was true for dopaminergic activation with dopamine (DA or its agonist apomorphine. Since GH stimulation by DA via pituitary D1 receptor is well-documented in fish models, the receptor specificity for follistatin regulation by DA was also investigated. Using a pharmacological approach, the inhibitory effect of DA on follistatin gene expression was confirmed to be mediated by pituitary D1 but not D2 receptor. Furthermore, activation of D1 receptor by the D1-specific agonist SKF77434 was also effective in blocking follistatin mRNA expression induced by activin and GH treatment both in carp pituitary cells as well as in carp somatotrophs enriched by density gradient centrifugation. These results, as a whole, suggest that activin can interact with dopaminergic input from the hypothalamus to regulate follistatin expression in carp pituitary, which may contribute to GH regulation by activin/follistatin system

  20. Striatal mechanisms underlying movement, reinforcement, and punishment.

    Science.gov (United States)

    Kravitz, Alexxai V; Kreitzer, Anatol C

    2012-06-01

    Direct and indirect pathway striatal neurons are known to exert opposing control over motor output. In this review, we discuss a hypothetical extension of this framework, in which direct pathway striatal neurons also mediate reinforcement and reward, and indirect pathway neurons mediate punishment and aversion.

  1. Striatal Mechanisms Underlying Movement, Reinforcement, and Punishment

    OpenAIRE

    Kravitz, Alexxai V.; Kreitzer, Anatol C.

    2012-01-01

    Direct and indirect pathway striatal neurons are known to exert opposing control over motor output. In this review, we discuss a hypothetical extension of this framework, in which direct pathway striatal neurons also mediate reinforcement and reward, and indirect pathway neurons mediate punishment and aversion.

  2. Dopamine1 receptors in rat kidneys identified with 125I-Sch 23982

    International Nuclear Information System (INIS)

    Felder, R.A.; Jose, P.A.

    1988-01-01

    Dopamine1 receptors were studied in rat kidney using the selective dopamine1 antagonist 125I-labeled Sch 23982. The specific binding of 125I-Sch 23982 (defined by 5 microM Sch 23390) to renal cortical homogenates incubated at room temperature was rapid, saturable with time and ligand concentration, and reversible. Analysis of Rosenthal plots revealed a single class of receptors with an apparent dissociation constant of 12.2 +/- 1.9 nM and maximum receptor density of 1.03 +/- 0.15 pmol/mg protein (n = 6). However, competition experiments with the dopamine1 antagonist Sch 23390 revealed a low- and high-affinity binding site with inhibition constants of 1 x 10(-6) and 1 x 10(-8) M, respectively. The competition experiments were also indicative of dopamine1 receptors with stereoselectivity noted for dopamine1 but not for dopamine2 antagonists. The inhibition constants for dopamine1 antagonists and agonists were two orders of magnitude greater in renal cortical than striatal homogenates. Different buffers affected striatal but not renal cortical binding. Autoradiographic studies revealed 125I-Sch 23982 binding in renal cortical but not medullary tissue. These studies confirm the presence of dopamine1 receptors in the cortex of the rat kidney

  3. Human striatal recordings reveal abnormal discharge of projection neurons in Parkinson's disease.

    Science.gov (United States)

    Singh, Arun; Mewes, Klaus; Gross, Robert E; DeLong, Mahlon R; Obeso, José A; Papa, Stella M

    2016-08-23

    Circuitry models of Parkinson's disease (PD) are based on striatal dopamine loss and aberrant striatal inputs into the basal ganglia network. However, extrastriatal mechanisms have increasingly been the focus of attention, whereas the status of striatal discharges in the parkinsonian human brain remains conjectural. We now report the activity pattern of striatal projection neurons (SPNs) in patients with PD undergoing deep brain stimulation surgery, compared with patients with essential tremor (ET) and isolated dystonia (ID). The SPN activity in ET was very low (2.1 ± 0.1 Hz) and reminiscent of that found in normal animals. In contrast, SPNs in PD fired at much higher frequency (30.2 ± 1.2 Hz) and with abundant spike bursts. The difference between PD and ET was reproduced between 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated and normal nonhuman primates. The SPN activity was also increased in ID, but to a lower level compared with the hyperactivity observed in PD. These results provide direct evidence that the striatum contributes significantly altered signals to the network in patients with PD.

  4. A negative relationship between ventral striatal loss anticipation response and impulsivity in borderline personality disorder

    OpenAIRE

    Herbort, Maike C.; Soch, Joram; W?stenberg, Torsten; Krauel, Kerstin; Pujara, Maia; Koenigs, Michael; Gallinat, J?rgen; Walter, Henrik; Roepke, Stefan; Schott, Bj?rn H.

    2016-01-01

    Patients with borderline personality disorder (BPD) frequently exhibit impulsive behavior, and self-reported impulsivity is typically higher in BPD patients when compared to healthy controls. Previous functional neuroimaging studies have suggested a link between impulsivity, the ventral striatal response to reward anticipation, and prediction errors. Here we investigated the striatal neural response to monetary gain and loss anticipation and their relationship with impulsivity in 21 female BP...

  5. Central serotonin and dopamine transporters in overeating, obesity and insulin resistance

    NARCIS (Netherlands)

    Koopman, K.E.M.

    2014-01-01

    The objectives of this thesis were to study cerebral serotonin transporters (SERT) in the diencephalon and striatal dopamine transporters (DAT) in humans in different metabolic conditions (i.e. lean, obese and insulin resistant state) in relation to feeding behavior and to investigate the early

  6. Dopamine D2 receptor occupancy by olanzapine or risperidone in young patients with schizophrenia

    NARCIS (Netherlands)

    Lavalaye, J.; Linszen, D. H.; Booij, J.; Reneman, L.; Gersons, B. P.; van Royen, E. A.

    1999-01-01

    A crucial characteristic of antipsychotic medication is the occupancy of the dopamine (DA) D2 receptor. We assessed striatal DA D2 receptor occupancy by olanzapine and risperidone in 36 young patients [31 males, 5 females; mean age 21.1 years (16-28)] with first episode schizophrenia, using

  7. Mesolimbic dopamine function is not altered during continuous chronic treatment of rats with typical or atypical neuroleptic drugs

    International Nuclear Information System (INIS)

    Rupniak, N.M.J.; Hall, M.D.; Kelly, E.; Fleminger, S.; Kilpatrick, G.; Jenner, P.; Marsden, C.D.

    1985-01-01

    Rats were treated continuously for up to 20 months with either haloperidol (1.4-1.6 mg/kg/day), sulpiride (102-109 mg/kg/day) or clozapine (24-27 mg/kg/day). Bsub(max) for specific mesolimbic binding of 3 H-spiperone, 3 H-N, n-propylnorapomorphine or 3 H-piflutixol did not differ in tissue taken from animals treated for up to 12 months with haloperidol, sulpiride or clozapine by comparison to age-matched control rats. Mesolimbic dopamine (50 μM)-stimulated adenylate cyclase activity was not altered in any drug treatment group. Spontaneous locomotor activity was transiently decreased during treatment with haloperidol for 1 or 3 months, but not by chronic sulpiride or clozapine treatment. Locomotor activity was not consistently increased in any drug treatment group. After 20 months of continuous drug treatment, focal bilateral application of dopamine (12.5 or 25 μg) into the nucleus accumbens caused equivalent increases in locomotor activity in control rats and in animals receiving haloperidol, sulpiride of clozapine. These findings suggest that dopamine receptor blockade is not maintained in the mesolimbic area following chronic treatment with haloperidol, sulpiride or clozapine, and indicate that, under these conditions, clozapine and sulpiride may not act selectively on mesolimbic dopamine receptors. (Author)

  8. A Test of the Transdiagnostic Dopamine Hypothesis of Psychosis Using Positron Emission Tomographic Imaging in Bipolar Affective Disorder and Schizophrenia.

    Science.gov (United States)

    Jauhar, Sameer; Nour, Matthew M; Veronese, Mattia; Rogdaki, Maria; Bonoldi, Ilaria; Azis, Matilda; Turkheimer, Federico; McGuire, Philip; Young, Allan H; Howes, Oliver D

    2017-12-01

    The dopamine hypothesis suggests that dopamine abnormalities underlie psychosis, irrespective of diagnosis, implicating dopamine dysregulation in bipolar affective disorder and schizophrenia, in line with the research domain criteria approach. However, this hypothesis has not been directly examined in individuals diagnosed with bipolar disorder with psychosis. To test whether dopamine synthesis capacity is elevated in bipolar disorder with psychosis and how this compares with schizophrenia and matched controls and to examine whether dopamine synthesis capacity is associated with psychotic symptom severity, irrespective of diagnostic class. This cross-sectional case-control positron emission tomographic study was performed in the setting of first-episode psychosis services in an inner-city area (London, England). Sixty individuals participated in the study (22 with bipolar psychosis [18 antipsychotic naive or free], 16 with schizophrenia [14 antipsychotic naive or free], and 22 matched controls) and underwent fluorodihydroxyphenyl-l-alanine ([18F]-DOPA) positron emission tomography to examine dopamine synthesis capacity. Standardized clinical measures, including the Positive and Negative Syndrome Scale, Young Mania Rating Scale, and Global Assessment of Functioning, were administered. The study dates were March 2013 to November 2016. Dopamine synthesis capacity (Kicer) and clinical measures (Positive and Negative Syndrome Scale, Young Mania Rating Scale, and Global Assessment of Functioning). The mean (SD) ages of participants were 23.6 (3.6) years in 22 individuals with bipolar psychosis (13 male), 26.3 (4.4) years in 16 individuals with schizophrenia (14 male), and 24.5 (4.5) years in controls (14 male). There was a significant group difference in striatal dopamine synthesis capacity (Kicer) (F2,57 = 6.80, P = .002). Kicer was significantly elevated in both the bipolar group (mean [SD], 13.18 [1.08] × 10-3 min-1; P = .002) and the schizophrenia

  9. Molecular players in the development and maintenance of mesencephalic dopamine systems.

    Science.gov (United States)

    Burbach, J P; Cazorla, P; Smidt, M P

    1999-06-01

    Several psychiatric diseases are considered to be neuro-developmental disorders. Amongst these are schizophrenia and autism, in which genetic and environmental components have been indicated. In these disorders intrinsic molecular mechanisms of brain development may be deranged due to genetic predispositions, or modified by external influences. Brain development is a delicate process of well-tuned cellular proliferation and differentiation of multipotent neural progenitor cells driven by spatiotemporal cues. One of the fundamental mechanisms is the interaction between external signals, e.g. growth factors, and internal regulators, e.g. transcription factors. An important transmitter system involved in behavioural and affective functions relevant for psychiatric disorders is the mesencephalic dopamine (DA) system. The mesencephalic DA system is organized in two anatomically and functionally different systems. DA neurons in the ventral tegmental area project to the mesolimbic system and are mostly related to control of behaviour. It has been implicated in drug addiction and affective disorders like dipolar disorder and schizophrenia. The dopamine system of the substantia nigra (nigro-striatal pathway) is implicated in movement control. Degeneration of this system, as in Parkinson's disease, or altered function in tardive dyskinesia have highlighted its importance in human disease. Recent findings in molecular neurobiology have provided the first clues to molecular mechanisms involved in developing and mature DA neurons. These may have clinical implications in novel therapeutic strategies.

  10. Cortico-striatal spike-timing dependent plasticity after activation of subcortical pathways

    Directory of Open Access Journals (Sweden)

    Jan M Schulz

    2010-07-01

    Full Text Available Cortico-striatal spike-timing dependent plasticity (STDP is modulated by dopamine in vitro. The present study investigated STDP in vivo using alternative procedures for modulating dopaminergic inputs. Postsynaptic potentials (PSP were evoked in intracellularly recorded spiny neurons by electrical stimulation of the contralateral motor cortex. PSPs often consisted of up to three distinct components, likely representing distinct cortico-striatal pathways. After baseline recording, bicuculline (BIC was ejected into the superior colliculus (SC to disinhibit visual pathways to the dopamine cells and striatum. Repetitive cortical stimulation (~60; 0.2 Hz was then paired with postsynaptic spike discharge induced by an intracellular current pulse, with each pairing followed 250 ms later by a light flash to the contralateral eye (n=13. Changes in PSPs, measured as the maximal slope normalised to 5 min pre, ranged from potentiation (~120% to depression (~80%. The determining factor was the relative timing between PSP components and spike: PSP components coinciding or closely following the spike tended towards potentiation, whereas PSP components preceding the spike were depressed. Importantly, STDP was only seen in experiments with successful BIC-mediated disinhibition (n=10. Cortico-striatal high-frequency stimulation (50 pulses at 100 Hz followed 100 ms later by a light flash did not induce more robust synaptic plasticity (n=9. However, an elevated post-light spike rate correlated with depression across plasticity protocols (R2=0.55, p=0.009, n=11 active neurons. These results confirm that the direction of cortico-striatal plasticity is determined by the timing of pre- and postsynaptic activity and that synaptic modification is dependent on the activation of additional subcortical inputs.

  11. Striatal activation by optogenetics induces dyskinesias in the 6-hydroxydopamine rat model of Parkinson disease.

    Science.gov (United States)

    F Hernández, Ledia; Castela, Ivan; Ruiz-DeDiego, Irene; Obeso, Jose A; Moratalla, Rosario

    2017-04-01

    Long-term levodopa (l-dopa) treatment is associated with the development of l-dopa-induced dyskinesias in the majority of patients with Parkinson disease (PD). The etiopathogonesis and mechanisms underlying l-dopa-induced dyskinesias are not well understood. We used striatal optogenetic stimulation to induce dyskinesias in a hemiparkinsonian model of PD in rats. Striatal dopamine depletion was induced unilaterally by 6-hydroxydopamine injection into the medial forebrain bundle. For the optogenetic manipulation, we injected adeno-associated virus particles expressing channelrhodopsin to stimulate striatal medium spiny neurons with a laser source. Simultaneous optical activation of medium spiny neurons of the direct and indirect striatal pathways in the 6-hydroxydopamine lesion but l-dopa naïve rats induced involuntary movements similar to l-dopa-induced dyskinesias, labeled here as optodyskinesias. Noticeably, optodyskinesias were facilitated by l-dopa in animals that did not respond initially to the laser stimulation. In general, optodyskinesias lasted while the laser stimulus was applied, but in some instances remained ongoing for a few seconds after the laser was off. Postmortem tissue analysis revealed increased FosB expression, a molecular marker of l-dopa-induced dyskinesias, primarily in medium spiny neurons of the direct pathway in the dopamine-depleted hemisphere. Selective optogenetic activation of the dorsolateral striatum elicits dyskinesias in the 6-hydroxydopamine rat model of PD. This effect was associated with a preferential activation of the direct striato-nigral pathway. These results potentially open new avenues in the understanding of mechanisms involved in l-dopa-induced dyskinesias. © 2017 International Parkinson and Movement Disorder Society. © 2017 International Parkinson and Movement Disorder Society.

  12. Temporal Profiles Dissociate Regional Extracellular Ethanol versus Dopamine Concentrations

    Science.gov (United States)

    2015-01-01

    In vivo monitoring of dopamine via microdialysis has demonstrated that acute, systemic ethanol increases extracellular dopamine in regions innervated by dopaminergic neurons originating in the ventral tegmental area and substantia nigra. Simultaneous measurement of dialysate dopamine and ethanol allows comparison of the time courses of their extracellular concentrations. Early studies demonstrated dissociations between the time courses of brain ethanol concentrations and dopaminergic responses in the nucleus accumbens (NAc) elicited by acute ethanol administration. Both brain ethanol and extracellular dopamine levels peak during the first 5 min following systemic ethanol administration, but the dopamine response returns to baseline while brain ethanol concentrations remain elevated. Post hoc analyses examined ratios of the dopamine response (represented as a percent above baseline) to tissue concentrations of ethanol at different time points within the first 25–30 min in the prefrontal cortex, NAc core and shell, and dorsomedial striatum following a single intravenous infusion of ethanol (1 g/kg). The temporal patterns of these “response ratios” differed across brain regions, possibly due to regional differences in the mechanisms underlying the decline of the dopamine signal associated with acute intravenous ethanol administration and/or to the differential effects of acute ethanol on the properties of subpopulations of midbrain dopamine neurons. This Review draws on neurochemical, physiological, and molecular studies to summarize the effects of acute ethanol administration on dopamine activity in the prefrontal cortex and striatal regions, to explore the potential reasons for the regional differences observed in the decline of ethanol-induced dopamine signals, and to suggest directions for future research. PMID:25537116

  13. Functional selectivity of allosteric interactions within G protein-coupled receptor oligomers: the dopamine D1-D3 receptor heterotetramer.

    Science.gov (United States)

    Guitart, Xavier; Navarro, Gemma; Moreno, Estefania; Yano, Hideaki; Cai, Ning-Sheng; Sánchez-Soto, Marta; Kumar-Barodia, Sandeep; Naidu, Yamini T; Mallol, Josefa; Cortés, Antoni; Lluís, Carme; Canela, Enric I; Casadó, Vicent; McCormick, Peter J; Ferré, Sergi

    2014-10-01

    The dopamine D1 receptor-D3 receptor (D1R-D3R) heteromer is being considered as a potential therapeutic target for neuropsychiatric disorders. Previous studies suggested that this heteromer could be involved in the ability of D3R agonists to potentiate locomotor activation induced by D1R agonists. It has also been postulated that its overexpression plays a role in L-dopa-induced dyskinesia and in drug addiction. However, little is known about its biochemical properties. By combining bioluminescence resonance energy transfer, bimolecular complementation techniques, and cell-signaling experiments in transfected cells, evidence was obtained for a tetrameric stoichiometry of the D1R-D3R heteromer, constituted by two interacting D1R and D3R homodimers coupled to Gs and Gi proteins, respectively. Coactivation of both receptors led to the canonical negative interaction at the level of adenylyl cyclase signaling, to a strong recruitment of β-arrestin-1, and to a positive cross talk of D1R and D3R agonists at the level of mitogen-activated protein kinase (MAPK) signaling. Furthermore, D1R or D3R antagonists counteracted β-arrestin-1 recruitment and MAPK activation induced by D3R and D1R agonists, respectively (cross-antagonism). Positive cross talk and cross-antagonism at the MAPK level were counteracted by specific synthetic peptides with amino acid sequences corresponding to D1R transmembrane (TM) domains TM5 and TM6, which also selectively modified the quaternary structure of the D1R-D3R heteromer, as demonstrated by complementation of hemiproteins of yellow fluorescence protein fused to D1R and D3R. These results demonstrate functional selectivity of allosteric modulations within the D1R-D3R heteromer, which can be involved with the reported behavioral synergism of D1R and D3R agonists. U.S. Government work not protected by U.S. copyright.

  14. Imaging of D2 dopamine receptors of patients with Parkinson's disease using SPECT and 131I-IBZM

    International Nuclear Information System (INIS)

    Zhang Wei; Wang Jian; Jiang Yuping; Lu Chuanzhen

    2001-01-01

    Objective: To evaluate the usefulness of SPECT with 131 I-IBZM in imaging of D 2 Dopamine receptors in patients with Parkinson's disease (PD). Methods: Six patients which early unmedicated PD, six patients with moderate or advanced PD treated with long-term oral L-Dopa and Four control subjects were investigated with SPECT using 131 I-IBZM as dopamine receptor ligand. The ratio of basal ganglia to occipital cortex (BG/OC) and ratio of basal ganglia to frontal cortex (BG/FC) were calculated as semiquantitative parameter of striatal D 2 dopamine receptor's function. Results: The SPECT images revealed high uptake of IBZM in the basal ganglia. In the early unmedicated PD group, the BG/PC and BG/FC rates were significantly higher in the striatum contralateral to the parkinsonism. In the moderate or advanced PD group, no significant differences were observed bilaterally, and the BG/OC and the BG/FC rates in this group was lower than those of the control. Conclusion: 131 I-IBZM with SPECT imaging is useful in evaluating patients with Parkinson's disease

  15. Attenuation of antagonist-induced impairment of dopamine receptors by L-prolyl-L-leucyl-glycinamide

    International Nuclear Information System (INIS)

    Saleh, M.I.M.

    1988-01-01

    The present study was undertaken in order to determine whether chronic,long-term postnatal challenge of rat pups per se, with specific dopamine D1 and D2 receptor antagonists, would modify the ontogeny of the respective receptor types. Since the neuropeptide L-prolyl-L-leucyl-glycinamide (PLG) attenuates the effect of haloperidol on dopamine D2 receptors in adult rats it was of interest to determine whether PLG would modulate antagonists-induced alterations in the ontogeny of striatal dopamine D1 and D2 receptors. Half of the rats were treated daily for 32 days from birth with SCH-23390, a selective dopamine D1 antagonist; or spiroperidol, a selective dopamine D2 antagonists; or both SCH-23390 and spiroperidol; or saline. The other half of the litters were treated with PLG, in combination with the other treatments. Animals were decapitated at 5, 8, and 12 weeks from birth for neurochemical analysis of the striatum. Chronic SCH-23390 treatment produced a 70-80% decrease in the binding of [ 3 H] SCH-23390 to striatal homogenates. The alteration at 5 weeks was associated with a 78% decrease in the Bmax for [ 3 H] SCH-23390 binding, and no change in the K D . Similarly, at 5, 8, and 12 weeks, chronic spiroperidol treatment reduced the binding of [ 3 H] spiroperidol to striatal homogenates by 70-80%

  16. Neuronal Adaptation to Amphetamine and Dopamine: Molecular Mechanisms of Prodynorphin Gene Regulation in Rat Striatum

    Science.gov (United States)

    Cole, Rebecca L.; Konradi, Christine; Douglass, James; Hyman, Steven E.

    2014-01-01

    Summary Induction of prodynorphin gene expression by psychostimulant drugs may represent a compensatory adaptation to excessive dopamine stimulation and may contribute to the aversive aspects of withdrawal. We therefore investigated the molecular mechanisms by which dopamine psychostimulant drugs induce prodynorphin gene expression in vivo and in rat primary striatal cultures. We demonstrate that three recently described cAMP response elements (CREs), rather than a previously reported noncanonical AP-1 site, are critical for dopamine induction of the prodynorphin gene in striatal neurons. CRE-binding protein (CREB) binds to these CREs in striatal cell extracts and is phosphorylated on Ser-133 after dopamine stimulation in a D1 dopamine receptor-dependent manner. Surprisingly, following chronic administration of amphetamine, levels of phosphorylated CREB are increased above basal in rat striatum in vivo, whereas c-fos mRNA is suppressed below basal levels. D1 receptor-mediated CREB phosphorylation appears to mediate adaptations to psychostimulant drugs in the striatum. PMID:7718243

  17. Aspects of dopamine and acetylcholine release induced by glutamate receptors

    International Nuclear Information System (INIS)

    Paes, Paulo Cesar de Arruda

    2002-01-01

    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)

  18. Effect of lavender oil on motor function and dopamine receptor expression in the olfactory bulb of mice.

    Science.gov (United States)

    Kim, Younghee; Kim, Minjeong; Kim, Hyunji; Kim, Kisok

    2009-08-17

    Although treatment with the essential oil of lavender induces neuroemotional changes, there is a lack of data regarding its specific effects on neurotransduction, especially dopaminergic neurotransduction. We investigated the relationship between altered motor activity and changes in the expression of dopamine receptors (DR), particularly the receptor subtypes D2 and D3, in lavender oil-treated mice. After the administration of lavender oil (intraperitoneal injections of 10-1000 mg/kg lavender oil once per day for 5 days), motor coordination and dopamine receptor expression were examined in the olfactory bulb and the striatum of the mouse brain. After 5 days, mice treated with 1000 mg/kg lavender oil showed significantly increased rotarod activity when compared to controls. Although DRD2 expression showed no change in the olfactory bulb or striatum of lavender-treated mice, DRD3 expression increased significantly in the olfactory bulb; this increase was dose-dependent and was observed at both the mRNA and protein levels. These data indicate that altered dopamine D3 receptor subtype homeostasis in the olfactory bulb may contribute to lavender oil-induced behavioral change.

  19. The neurobiology of glucocerebrosidase-associated parkinsonism: a positron emission tomography study of dopamine synthesis and regional cerebral blood flow

    Science.gov (United States)

    Goker-Alpan, Ozlem; Masdeu, Joseph C.; Kohn, Philip D.; Ianni, Angela; Lopez, Grisel; Groden, Catherine; Chapman, Molly C.; Cropp, Brett; Eisenberg, Daniel P.; Maniwang, Emerson D.; Davis, Joie; Wiggs, Edythe; Berman, Karen F.

    2012-01-01

    Mutations in GBA, the gene encoding glucocerebrosidase, the enzyme deficient in Gaucher disease, are common risk factors for Parkinson disease, as patients with Parkinson disease are over five times more likely to carry GBA mutations than healthy controls. Patients with GBA mutations generally have an earlier onset of Parkinson disease and more cognitive impairment than those without GBA mutations. We investigated whether GBA mutations alter the neurobiology of Parkinson disease, studying brain dopamine synthesis and resting regional cerebral blood flow in 107 subjects (38 women, 69 men). We measured dopamine synthesis with 18F-fluorodopa positron emission tomography, and resting regional cerebral blood flow with H215O positron emission tomography in the wakeful, resting state in four study groups: (i) patients with Parkinson disease and Gaucher disease (n = 7, average age = 56.6 ± 9.2 years); (ii) patients with Parkinson disease without GBA mutations (n = 11, 62.1 ± 7.1 years); (iii) patients with Gaucher disease without parkinsonism, but with a family history of Parkinson disease (n = 14, 52.6 ± 12.4 years); and (iv) healthy GBA-mutation carriers with a family history of Parkinson disease (n = 7, 50.1 ± 18 years). We compared each study group with a matched control group. Data were analysed with region of interest and voxel-based methods. Disease duration and Parkinson disease functional and staging scores were similar in the two groups with parkinsonism, as was striatal dopamine synthesis: both had greatest loss in the caudal striatum (putamen Ki loss: 44 and 42%, respectively), with less reduction in the caudate (20 and 18% loss). However, the group with both Parkinson and Gaucher diseases showed decreased resting regional cerebral blood flow in the lateral parieto-occipital association cortex and precuneus bilaterally. Furthermore, two subjects with Gaucher disease without parkinsonian manifestations showed diminished striatal dopamine. In conclusion, the

  20. The Role of Dopamine in Inflammation-Associated Depression: Mechanisms and Therapeutic Implications.

    Science.gov (United States)

    Felger, Jennifer C

    Studies investigating the impact of a variety of inflammatory stimuli on the brain and behavior have consistently reported evidence that inflammatory cytokines affect the basal ganglia and dopamine to mediate depressive symptoms related to motivation and motor activity. Findings have included inflammation-associated reductions in ventral striatal responses to hedonic reward, decreased dopamine and dopamine metabolites in cerebrospinal fluid, and decreased availability of striatal dopamine, all of which correlate with symptoms of anhedonia, fatigue, and psychomotor retardation. Similar relationships between alterations in dopamine-relevant corticostriatal reward circuitry and symptoms of anhedonia and psychomotor slowing have also been observed in patients with major depression who exhibit increased peripheral cytokines and other inflammatory markers, such as C-reactive protein. Of note, these inflammation-associated depressive symptoms are often difficult to treat in patients with medical illnesses or major depression. Furthermore, a wealth of literature suggests that inflammation can decrease dopamine synthesis, packaging, and release, thus sabotaging or circumventing the efficacy of standard antidepressant treatments. Herein, the mechanisms by which inflammation and cytokines affect dopamine neurotransmission are discussed, which may provide novel insights into treatment of inflammation-related behavioral symptoms that contribute to an inflammatory malaise.

  1. Imaging addiction: D2 receptors and dopamine signaling in the striatum as biomarkers for impulsivity

    Science.gov (United States)

    Trifilieff, Pierre; Martinez, Diana

    2014-01-01

    Dependence to drugs of abuse is closely associated with impulsivity, or the propensity to choose a lower, but immediate, reward over a delayed, but more valuable outcome. Here, we review clinical and preclinical studies showing that striatal dopamine signaling and D2 receptor levels – which have been shown to be decreased in addiction - directly impact impulsivity, which is itself predictive of drug self-administration. Based on these studies, we propose that the alterations in D2 receptor binding and dopamine release seen in imaging studies of addiction constitute neurobiological markers of impulsivity. Recent studies in animals also show that higher striatal dopamine signaling at the D2 receptor is associated with a greater willingness to expend effort to reach goals, and we propose that this same relationship applies to humans, particularly with respect to recovery from addiction. PMID:23851257

  2. DAT genotype modulates striatal processing and long-term memory for items associated with reward and punishment.

    Science.gov (United States)

    Wittmann, Bianca C; Tan, Geoffrey C; Lisman, John E; Dolan, Raymond J; Düzel, Emrah

    2013-09-01

    Previous studies have shown that appetitive motivation enhances episodic memory formation via a network including the substantia nigra/ventral tegmental area (SN/VTA), striatum and hippocampus. This functional magnetic resonance imaging (fMRI) study now contrasted the impact of aversive and appetitive motivation on episodic long-term memory. Cue pictures predicted monetary reward or punishment in alternating experimental blocks. One day later, episodic memory for the cue pictures was tested. We also investigated how the neural processing of appetitive and aversive motivation and episodic memory were modulated by dopaminergic mechanisms. To that end, participants were selected on the basis of their genotype for a variable number of tandem repeat polymorphism of the dopamine transporter (DAT) gene. The resulting groups were carefully matched for the 5-HTTLPR polymorphism of the serotonin transporter gene. Recognition memory for cues from both motivational categories was enhanced in participants homozygous for the 10-repeat allele of the DAT, the functional effects of which are not known yet, but not in heterozygous subjects. In comparison with heterozygous participants, 10-repeat homozygous participants also showed increased striatal activity for anticipation of motivational outcomes compared to neutral outcomes. In a subsequent memory analysis, encoding activity in striatum and hippocampus was found to be higher for later recognized items in 10-repeat homozygotes compared to 9/10-repeat heterozygotes. These findings suggest that processing of appetitive and aversive motivation in the human striatum involve the dopaminergic system and that dopamine plays a role in memory for both types of motivational information. In accordance with animal studies, these data support the idea that encoding of motivational events depends on dopaminergic processes in the hippocampus. © 2013 The Authors. Published by Elsevier Ltd. All rights reserved.

  3. NEUROTRANSMITTERS AND IMMUNITY: 1. DOPAMINE

    Directory of Open Access Journals (Sweden)

    Lucian Hritcu

    2007-08-01

    Full Text Available Dopamine is one of the principal neurotransmitters in the central nervous system (CNC, and its neuronal pathways are involved in several key functions such as behavior (Hefco et al., 2003a,b, control of movement, endocrine regulation, immune response (Fiserova et al., 2002; Levite et al., 2001, Hritcu et al., 2006a,b,c, and cardiovascular function. Dopamine has at least five G-protein, coupled receptor subtypes, D1-D5, each arising from a different gene (Sibley et al., 1993. Traditionally, these receptors have been classified into D1-like (the D1 and D5 and D2-like (D2, D3 and D4 receptors subtypes, primarily according to their ability to stimulate or inhibit adenylate cyclase, respectively, and to their pharmacological characteristics (Seeman et al., 1993. Receptors for dopamine (particularly of D2 subclass are the primary therapeutic target in a number of neuropathological disorders including schizophrenia, Parkinson’s disease and Huntington’s chorea (Seeman et al., 1987. Neither dopamine by itself, nor dopaminergic agonists by themselves, has been shown to activate T cell function. Nevertheless, lymphocytes are most probably exposed to dopamine since the primary and secondary lymphoid organs of various mammals are markedly innervated, and contain nerve fibers which stain for tyrosine hydroxylase (Weihe et al., 1991, the enzyme responsible for dopamine synthesis. Moreover, cathecolamines and their metabolites are present in single lymphocytes and in extracts of T and B cell clones, and pharmacological inhibition of tyrosine hydroxylase reduces catecholamine levels, suggesting catecholamine synthesis by lymphocytes (Bergquist et al., 1994. The existence of putative dopamine receptors of D2, D3, D4 and D5 subtypes on immune cells has been proposed of several authors, primarily on the basis of dopaminergic ligand binding assays and specific mRNA expression as monitored by reverse transcription-PCR. Several experiments evoked the idea of a

  4. A sensitive electrochemical sensor for paracetamole based on a glassy carbon electrode modified with multiwalled carbon nanotubes and dopamine nanospheres functionalized with gold nanoparticles

    International Nuclear Information System (INIS)

    Liu, Xue; Wang, Ling-Ling; Wang, Ya-Ya; Zhang, Xiao-Yan

    2014-01-01

    We describe an electrochemical sensor for paracetamole that is based on a glassy carbon electrode modified with multiwalled carbon nanotubes and dopamine nanospheres functionalized with gold nanoparticles. The functionalized nanospheres were prepared by a chemical route and characterized by scanning electron microscopy. The well-dispersed gold nanoparticles were anchored on the dopamine nanosphere via a chemical reduction of the gold precursor. The stepwise fabrication of the modified electrode and its electrochemical response to paracetamole were evaluated using electrochemical impedance spectroscopy and cyclic voltammetry. The modified electrode displayed improved electrocatalytic activity towards paracetamole, a lower oxidation potential (371 mV), and a larger peak current when compared to a bare electrode or other modified electrodes. The kinetic parameters governing the electro-oxidation of paracetamole were studied, and the analytical conditions were optimized. The peak current was linearly related to the concentration of paracetamole in 0.8–400 μM range, and the detection limit was 50 nM (at an SNR of 3). The method was successfully applied to the determination of paracetamole in spiked human urine samples and gave recoveries between 95.3 and 105.2 %. (author)

  5. The Role of Dopamine in Huntington’s Disease

    Science.gov (United States)

    Cepeda, Carlos; Murphy, Kerry P. S.; Parent, Martin; Levine, Michael S.

    2015-01-01

    Alterations in dopamine (DA) neurotransmission in Parkinson’s disease are well-known and widely studied. Much less is known about DA changes that accompany and underlie some of the symptoms of Huntington’s disease (HD), a dominant inherited neurodegenerative disorder characterized by chorea, cognitive deficits and psychiatric disturbances. The cause is an expansion in CAG (glutamine) repeats in the HTT gene. The principal histopathology of HD is the loss of medium-sized spiny neurons (MSNs) and, to a lesser degree, neuronal loss in cerebral cortex, thalamus, hippocampus and hypothalamus. Neurochemical, electrophysiological and behavioral studies in HD patients and genetic mouse models suggest biphasic changes in DA neurotransmission. In the early stages DA neurotransmission is increased leading to hyperkinetic movements that can be alleviated by depleting DA stores. In contrast, in the late stages DA deficits produce hypokinesia that can be treated by increasing DA function. Alterations in DA neurotransmission affect glutamate receptor modulation and could contribute to excitotoxicity. The mechanisms of DA dysfunction, in particular the increased DA tone in the early stages of the disease, are presently unknown but may include initial upregulation of DA neuron activity caused by the genetic mutation, reduced inhibition resulting from striatal MSN loss, increased excitation from cortical inputs, and DA autoreceptor dysfunction. Targeting both DA and glutamate receptor dysfunction could be the best strategy to treat HD symptoms. PMID:24968783

  6. Neuroinflammation alters voltage-dependent conductance in striatal astrocytes

    Science.gov (United States)

    Karpuk, Nikolay; Burkovetskaya, Maria

    2012-01-01

    Neuroinflammation has the capacity to alter normal central nervous system (CNS) homeostasis and function. The objective of the present study was to examine the effects of an inflammatory milieu on the electrophysiological properties of striatal astrocyte subpopulations with a mouse bacterial brain abscess model. Whole cell patch-clamp recordings were performed in striatal glial fibrillary acidic protein (GFAP)-green fluorescent protein (GFP)+ astrocytes neighboring abscesses at postinfection days 3 or 7 in adult mice. Cell input conductance (Gi) measurements spanning a membrane potential (Vm) surrounding resting membrane potential (RMP) revealed two prevalent astrocyte subsets. A1 and A2 astrocytes were identified by negative and positive Gi increments vs. Vm, respectively. A1 and A2 astrocytes displayed significantly different RMP, Gi, and cell membrane capacitance that were influenced by both time after bacterial exposure and astrocyte proximity to the inflammatory site. Specifically, the percentage of A1 astrocytes was decreased immediately surrounding the inflammatory lesion, whereas A2 cells were increased. These changes were particularly evident at postinfection day 7, revealing increased cell numbers with an outward current component. Furthermore, RMP was inversely modified in A1 and A2 astrocytes during neuroinflammation, and resting Gi was increased from 21 to 30 nS in the latter. In contrast, gap junction communication was significantly decreased in all astrocyte populations associated with inflamed tissues. Collectively, these findings demonstrate the heterogeneity of striatal astrocyte populations, which experience distinct electrophysiological modifications in response to CNS inflammation. PMID:22457466

  7. PET evaluation of the dopamine system of the human brain.

    Science.gov (United States)

    Volkow, N D; Fowler, J S; Gatley, S J; Logan, J; Wang, G J; Ding, Y S; Dewey, S

    1996-07-01

    Dopamine plays a pivotal role in the regulation and control of movement, motivation and cognition. It also is closely linked to reward, reinforcement and addiction. Abnormalities in brain dopamine are associated with many neurological and psychiatric disorders including Parkinson's disease, schizophrenia and substance abuse. This close association between dopamine and neurological and psychiatric diseases and with substance abuse make it an important topic in research in the neurosciences and an important molecular target in drug development. PET enables the direct measurement of components of the dopamine system in the living human brain. It relies on radiotracers which label dopamine receptors, dopamine transporters, precursors of dopamine or compounds which have specificity for the enzymes which degrade dopamine. Additionally, by using tracers that provide information on regional brain metabolism or blood flow as well as neurochemically specific pharmacological interventions, PET can be used to assess the functional consequences of changes in brain dopamine activity. PET dopamine measurements have been used to investigate the normal human brain and its involvement in psychiatric and neurological diseases. It has also been used in psychopharmacological research to investigate dopamine drugs used in the treatment of Parkinson's disease and of schizophrenia as well as to investigate the effects of drugs of abuse on the dopamine system. Since various functional and neurological parameters can be studied in the same subject, PET enables investigation of the functional integrity of the dopamine system in the human brain and investigation of the interactions of dopamine with other neurotransmitters. Through the parallel development of new radiotracers, kinetic models and better instruments, PET technology is enabling investigation of increasingly more complex aspects of the human brain dopamine system. This paper summarizes the different tracers and experimental

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

    International Nuclear Information System (INIS)

    Kujirai, K.; Przedborski, S.; Kostic, V.; Jackson-Lewis, V.; Fahn, S.; Cadet, J.L.

    1990-01-01

    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

  9. 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.

  10. Comparison of nitrogen narcosis and helium pressure effects on striatal amino acids: a microdialysis study in rats.

    Science.gov (United States)

    Vallée, Nicolas; Rostain, Jean-Claude; Boussuges, Alain; Risso, Jean-Jacques

    2009-05-01

    Exposure to nitrogen-oxygen mixture at high pressure induces narcosis, which can be considered as a first step toward general anaesthesia. Narcotic potencies of inert gases are attributed to their lipid solubility. Nitrogen narcosis induces cognitive and motor disturbances that occur from 0.3 MPa in man and from 1 MPa in rats. Neurochemical studies performed in rats up to 3 MPa have shown that nitrogen pressure decreases striatal dopamine release like argon, another inert gas, or nitrous oxide, an anaesthetic gas. Striatal dopamine release is under glutamatergic and other amino acid neurotransmission regulations. The aim of this work was to study the effects of nitrogen at 3 MPa on striatal amino acid levels and to compare to those of 3 MPa of helium which is not narcotic at this pressure, by using a new technique of microdialysis samples extraction under hyperbaric conditions, in freely moving rats. Amino acids were analysed by HPLC coupled to fluorimetric detection in order to appreciate glutamate, aspartate, glutamine and asparagine levels. Nitrogen-oxygen mixture exposure at 3 MPa decreased glutamate, glutamine and asparagine concentrations. In contrast, with helium-oxygen mixture, glutamate and aspartate levels were increased during the compression phase but not during the stay at maximal pressure. Comparison between nitrogen and helium highlighted the narcotic effects of nitrogen at pressure. As a matter of fact, nitrogen induces a reduction in glutamate and in other amino acids that could partly explain the decrease in striatal dopamine level as well as the motor and cognitive disturbances reported in nitrogen narcosis.

  11. Dopamine D2-receptor imaging with 123I-iodobenzamide SPECT in migraine patients abusing ergotamine: does ergotamine cross the blood brain barrier?

    International Nuclear Information System (INIS)

    Verhoeff, N.P.; Visser, W.H.; Ferrari, M.D.; Saxena, P.R.; Royen, E.A. van

    1993-01-01

    Two migraine patients were studied by in vivo SPECT using the dopamine D2-receptor specific radioligand 123 I-3-iodo-6-methoxybenzamide ( 123 I-IBZM) during ergotamine abuse and after withdrawal. Results were compared with 15 healthy controls. Striatum/cerebellum and striatum/occipital cortex ratios of count rate density were calculated as a semiquantitative measurement for striatal dopamine D2-receptor binding potential. No differences were found in striatal uptake of 123 I-IBZM between healthy controls and the patients when on or off ergotamine. Preliminary evidence suggests that ergotamine may not occupy striatal dopamine D2-receptors to a large extent and thus may not cross the blood brain barrier in large quantities. 23 refs., 3 figs

  12. Distinctive Modulation of Dopamine Release in the Nucleus Accumbens Shell Mediated by Dopamine and Acetylcholine Receptors.

    Science.gov (United States)

    Shin, Jung Hoon; Adrover, Martin F; Alvarez, Veronica A

    2017-11-15

    Nucleus accumbens (NAc) shell shows unique dopamine (DA) signals in vivo and plays a unique role in DA-dependent behaviors such as reward-motivated learning and the response to drugs of abuse. A disynaptic mechanism for DA release was reported and shown to require synchronized firing of cholinergic interneurons (CINs) and activation of nicotinic acetylcholine (ACh) receptors (nAChRs) in DA neuron (DAN) axons. The properties of this disynaptic mechanism of DA transmission are not well understood in the NAc shell. In this study, in vitro fast-scan cyclic voltammetry was used to examine the modulation of DA transmission evoked by CINs firing in the shell of mice and compared with other striatal regions. We found that DA signals in the shell displayed significant degree of summation in response to train stimulation of CINs, contrary to core and dorsal striatum. The summation was amplified by a D2-like receptor antagonist and experiments with mice with targeted deletion of D2 receptors to DANs or CINs revealed that D2 receptors in CINs mediate a fast inhibition observed within 100 ms of the first pulse, whereas D2 autoreceptors in DAN terminals are engaged in a slower inhibition that peaks at ∼500 ms. ACh also contributes to the use-dependent inhibition of DA release through muscarinic receptors only in the shell, where higher activity of acetylcholinesterase minimizes nAChR desensitization and promotes summation. These findings show that DA signals are modulated differentially by endogenous DA and ACh in the shell, which may underlie the unique features of shell DA signals in vivo SIGNIFICANCE STATEMENT The present study reports that dopamine (DA) release evoked by activation of cholinergic interneurons displays a high degree of summation in the shell and shows unique modulation by endogenous DA and acetylcholine. Desensitization of nicotinic receptors, which is a prevailing mechanism for use-dependent inhibition in the nucleus accumbens core and dorsal striatum, is

  13. Effects of systemic carbidopa on dopamine synthesis in rat hypothalamus and striatum

    Science.gov (United States)

    Kaakkola, S.; Tuomainen, P.; Wurtman, R. J.; Mannisto, P. T.

    1992-01-01

    Significant concentrations of carbidopa (CD) were found in rat hypothalamus, striatum, and in striatal microdialysis efflux after intraperitoneal administration of the drug. Efflux levels peaked one hour after administration of 100 mg/kg at 0.37 micrograms/ml, or about 2% of serum levels. Concurrent CD levels in hypothalamus and striatum were about 2.5% and 1.5%, respectively, of corresponding serum levels. Levels of dopamine and its principal metabolites in striatal efflux were unaffected. The removal of the brain blood by saline perfusion decreased the striatal and hypothalamic CD concentrations only by 33% and 16%, respectively. In other rats receiving both CD and levodopa (LD), brain L-dopa, dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) levels after one hour tended to be proportionate to LD dose. When the LD dose remained constant, increasing the CD dose dose-dependently enhanced L-dopa levels in the hypothalamus and striatum. However dopamine levels did not increase but, in contrast, decreased dose-dependently (although significantly only in the hypothalamus). CD also caused dose-dependent decrease in striatal 3-O-methyldopa (3-OMD) and in striatal and hypothalamic homovanillic acid (HVA), when the LD dose was 50 mg/kg. We conclude that, at doses exceeding 50 mg/kg, sufficient quantities of CD enter the brain to inhibit dopamine formation, especially in the hypothalamus. Moreover, high doses of LD/CD, both of which are themselves catechols, can inhibit the O-methylation of brain catecholamines formed from the LD.

  14. Behavioral and Neural Manifestations of Reward Memory in Carriers of Low-Expressing versus High-Expressing Genetic Variants of the Dopamine D2 Receptor

    Science.gov (United States)

    Richter, Anni; Barman, Adriana; Wüstenberg, Torsten; Soch, Joram; Schanze, Denny; Deibele, Anna; Behnisch, Gusalija; Assmann, Anne; Klein, Marieke; Zenker, Martin; Seidenbecher, Constanze; Schott, Björn H.

    2017-01-01

    Dopamine is critically important in the neural manifestation of motivated behavior, and alterations in the human dopaminergic system have been implicated in the etiology of motivation-related psychiatric disorders, most prominently addiction. Patients with chronic addiction exhibit reduced dopamine D2 receptor (DRD2) availability in the striatum, and the DRD2 TaqIA (rs1800497) and C957T (rs6277) genetic polymorphisms have previously been linked to individual differences in striatal dopamine metabolism and clinical risk for alcohol and nicotine dependence. Here, we investigated the hypothesis that the variants of these polymorphisms would show increased reward-related memory formation, which has previously been shown to jointly engage the mesolimbic dopaminergic system and the hippocampus, as a potential intermediate phenotype for addiction memory. To this end, we performed functional magnetic resonance imaging (fMRI) in 62 young, healthy individuals genotyped for DRD2 TaqIA and C957T variants. Participants performed an incentive delay task, followed by a recognition memory task 24 h later. We observed effects of both genotypes on the overall recognition performance with carriers of low-expressing variants, namely TaqIA A1 carriers and C957T C homozygotes, showing better performance than the other genotype groups. In addition to the better memory performance, C957T C homozygotes also exhibited a response bias for cues predicting monetary reward. At the neural level, the C957T polymorphism was associated with a genotype-related modulation of right hippocampal and striatal fMRI responses predictive of subsequent recognition confidence for reward-predicting items. Our results indicate that genetic variations associated with DRD2 expression affect explicit memory, specifically for rewarded stimuli. We suggest that the relatively better memory for rewarded stimuli in carriers of low-expressing DRD2 variants may reflect an intermediate phenotype of addiction memory. PMID

  15. Pathological gambling in patients with Parkinson's disease is associated with fronto-striatal disconnection: a path modeling analysis.

    Science.gov (United States)

    Cilia, Roberto; Cho, Sang Soo; van Eimeren, Thilo; Marotta, Giorgio; Siri, Chiara; Ko, Ji Hyun; Pellecchia, Giovanna; Pezzoli, Gianni; Antonini, Angelo; Strafella, Antonio P

    2011-02-01

    Pathological gambling may occur in Parkinson's disease (PD) as a complication of dopaminergic therapy. Neuroimaging studies have suggested an abnormal dopamine transmission within the reward system, but the changes in the neural network characterizing PD patients with pathological gambling have never been investigated. Thirty PD patients (15 with active gambling and 15 matched controls, on-medication) and 15 healthy subjects underwent brain perfusion single photon emission tomography at rest. The severity of gambling was assessed using the South Oaks Gambling Scale. Covariance analysis was applied to identify brain regions whose activity was associated with gambling severity. These regions were used as volume-of-interest to identify functionally interconnected areas using voxel-wise covariance analysis. A path model was defined by means of effective connectivity analysis within the Structural Equation Modeling framework. Gambling severity in PD was associated with a dysfunction of the brain network implicated in decision making, risk processing, and response inhibition, including the ventrolateral prefrontal cortex, anterior (ACC) and posterior cingulate cortex, medial prefrontal cortex, insula and striatum. PD gamblers showed a disconnection between the ACC and the striatum, while this interaction was very robust in both control groups. ACC-striatal disconnection may underlie a specific impairment of shifting behaviors after negative outcomes, possibly explaining why PD gamblers use to perseverate into risktaking behaviors despite self-destructive consequences. Copyright © 2011 Movement Disorder Society.

  16. Structural insight of dopamine β-hydroxylase, a drug target for complex traits, and functional significance of exonic single nucleotide polymorphisms.

    Directory of Open Access Journals (Sweden)

    Abhijeet Kapoor

    Full Text Available Human dopamine β-hydroxylase (DBH is an important therapeutic target for complex traits. Several single nucleotide polymorphisms (SNPs have also been identified in DBH with potential adverse physiological effect. However, difficulty in obtaining diffractable crystals and lack of a suitable template for modeling the protein has ensured that neither crystallographic three-dimensional structure nor computational model for the enzyme is available to aid rational drug design, prediction of functional significance of SNPs or analytical protein engineering.Adequate biochemical information regarding human DBH, structural coordinates for peptidylglycine alpha-hydroxylating monooxygenase and computational data from a partial model of rat DBH were used along with logical manual intervention in a novel way to build an in silico model of human DBH. The model provides structural insight into the active site, metal coordination, subunit interface, substrate recognition and inhibitor binding. It reveals that DOMON domain potentially promotes tetramerization, while substrate dopamine and a potential therapeutic inhibitor nepicastat are stabilized in the active site through multiple hydrogen bonding. Functional significance of several exonic SNPs could be described from a structural analysis of the model. The model confirms that SNP resulting in Ala318Ser or Leu317Pro mutation may not influence enzyme activity, while Gly482Arg might actually do so being in the proximity of the active site. Arg549Cys may cause abnormal oligomerization through non-native disulfide bond formation. Other SNPs like Glu181, Glu250, Lys239 and Asp290 could potentially inhibit tetramerization thus affecting function.The first three-dimensional model of full-length human DBH protein was obtained in a novel manner with a set of experimental data as guideline for consistency of in silico prediction. Preliminary physicochemical tests validated the model. The model confirms, rationalizes and

  17. Dose-dependent and sustained effects of varenicline on dopamine D2/3 receptor availability in rats

    NARCIS (Netherlands)

    Crunelle, C. L.; Schulz, S.; de Bruin, K.; Miller, M. L.; van den Brink, W.; Booij, J.

    2011-01-01

    Imaging studies in drug-dependent subjects show reduced striatal dopamine D-2/3 receptor (DRD2/3) availability, and it is hypothesized that increasing DRD2/3 availability is a promising strategy to treat drug dependence. We recently showed that rats treated for two weeks with 2 mg/kg/day varenicline

  18. Brain dopamine and serotonin transporter binding are associated with visual attention bias for food in lean men

    NARCIS (Netherlands)

    Koopman, K. E.; Roefs, A.; Elbers, D. C. E.; Fliers, E.; Booij, J.; Serlie, M. J.; La Fleur, S. E.

    2016-01-01

    In rodents, the striatal dopamine (DA) system and the (hypo)thalamic serotonin (5-HT) system are involved in the regulation of feeding behavior. In lean humans, little is known about the relationship between these brain neurotransmitter systems and feeding. We studied the relationship between

  19. Amphetamine Elicits Opposing Actions on Readily Releasable and Reserve Pools for Dopamine

    Science.gov (United States)

    Covey, Dan P.; Juliano, Steven A.; Garris, Paul A.

    2013-01-01

    Amphetamine, a highly addictive drug with therapeutic efficacy, exerts paradoxical effects on the fundamental communication modes employed by dopamine neurons in modulating behavior. While amphetamine elevates tonic dopamine signaling by depleting vesicular stores and driving non-exocytotic release through reverse transport, this psychostimulant also activates phasic dopamine signaling by up-regulating vesicular dopamine release. We hypothesized that these seemingly incongruent effects arise from amphetamine depleting the reserve pool and enhancing the readily releasable pool. This novel hypothesis was tested using in vivo voltammetry and stimulus trains of varying duration to access different vesicular stores. We show that amphetamine actions are stimulus dependent in the dorsal striatum. Specifically, amphetamine up-regulated vesicular dopamine release elicited by a short-duration train, which interrogates the readily releasable pool, but depleted release elicited by a long-duration train, which interrogates the reserve pool. These opposing actions of vesicular dopamine release were associated with concurrent increases in tonic and phasic dopamine responses. A link between vesicular depletion and tonic signaling was supported by results obtained for amphetamine in the ventral striatum and cocaine in both striatal sub-regions, which demonstrated augmented vesicular release and phasic signals only. We submit that amphetamine differentially targeting dopamine stores reconciles the paradoxical activation of tonic and phasic dopamine signaling. Overall, these results further highlight the unique and region-distinct cellular mechanisms of amphetamine and may have important implications for its addictive and therapeutic properties. PMID:23671560

  20. Huntington’s Disease and Striatal Signaling

    Science.gov (United States)

    Roze, Emmanuel; Cahill, Emma; Martin, Elodie; Bonnet, Cecilia; Vanhoutte, Peter; Betuing, Sandrine; Caboche, Jocelyne

    2011-01-01

    Huntington’s Disease (HD) is the most frequent neurodegenerative disease caused by an expansion of polyglutamines (CAG). The main clinical manifestations of HD are chorea, cognitive impairment, and psychiatric disorders. The transmission of HD is autosomal dominant with a complete penetrance. HD has a single genetic cause, a well-defined neuropathology, and informative pre-manifest genetic testing of the disease is available. Striatal atrophy begins as early as 15 years before disease onset and continues throughout the period of manifest illness. Therefore, patients could theoretically benefit from therapy at early stages of the disease. One important characteristic of HD is the striatal vulnerability to neurodegeneration, despite similar expression of the protein in other brain areas. Aggregation of the mutated Huntingtin (HTT), impaired axonal transport, excitotoxicity, transcriptional dysregulation as well as mitochondrial dysfunction, and energy deficits, are all part of the cellular events that underlie neuronal dysfunction and striatal death. Among these non-exclusive mechanisms, an alteration of striatal signaling is thought to orchestrate the downstream events involved in the cascade of striatal dysfunction. PMID:22007160