Lateralization and gender differences in the dopaminergic response to unpredictable reward in the human ventral striatum

Electrophysiological studies have shown that mesostriatal dopamine (DA) neurons increase activity in response to unpredicted rewards. With respect to other functions of the mesostriatal dopaminergic system, dopamine’s actions show prominent laterality effects. Whether changes in DA transmission elicited by rewards also are lateralized, however, has not been investigated. Using [¹¹C]raclopride‐PET to assess the striatal DA response to unpredictable monetary rewards, we hypothesized that such rewards would induce an asymmetric reduction in [¹¹C]raclopride binding in the ventral striatum, reflecting lateralization of endogenous dopamine release. In 24 healthy volunteers, differences in the regional D_2/3 receptor binding potential (ΔBP) between an unpredictable reward condition and a sensorimotor control condition were measured using the bolus‐plus‐constant‐infusion [¹¹C]raclopride method. During the reward condition subjects randomly received monetary awards while performing a ‘slot‐machine’ task. The ΔBP between conditions was assessed in striatal regions‐of‐interest and compared between left and right sides. We found a significant condition × lateralization interaction in the ventral striatum. A significant reduction in binding potential (BP_ND) in the reward condition vs. the control condition was found only in the right ventral striatum, and the ΔBP was greater in the right than the left ventral striatum. Unexpectedly, these laterality effects appeared to be partly accounted for by gender differences, as our data showed a significant bilateral BP_ND reduction in women while in men the reduction reached significance only in the right ventral striatum. These data suggest that DA release in response to unpredictable reward is lateralized in the human ventral striatum, particularly in males.     

NMDA antagonist effects on striatal dopamine release: positron emission tomography studies in humans.

Previous brain imaging studies with [(11)C]raclopride have suggested that the psychotogenic effects of the noncompetitive N-methyl-D-aspartate antagonist ketamine in humans might be mediated by increased dopamine (DA) release and increased stimulation of DA D(2) receptors in the striatum. The goal of the present study was to assess the effect of ketamine on D(2) receptor availability in subregions of the striatum (dorsal caudate, DCA; dorsal putamen, DPU; ventral striatum, VST) in humans. Ten healthy subjects were studied twice. In a first group of five subjects, PET scanning was obtained twice for 90 min during bolus plus constant infusion of [(11)C]raclopride. No significant differences were observed in [(11)C]raclopride specific-to-nonspecific activity ratios (V(")(3)) measured during an early interval (30-50 min) and late interval (70-90 min), confirming that a state of sustained equilibrium had been established from 30-90 min (end of infusion). In a second group of five subjects, a similar experiment was performed twice, except that ketamine was administered beginning at 50 min (0.12 mg/kg i.v. bolus followed by 0.65 mg/kg/h i.v. infusion for 70 min). Raclopride V(")(3) measured before ketamine (30-50-min interval) was compared to [(11)C]raclopride V(")(3) measured during ketamine infusion (70-90-min interval). Ketamine induced a robust dissociative state. However, no significant differences were observed in D(2) receptor availability measured before and during the ketamine infusion (n = 10) in any of the regions examined (DCA, DPU, and VST). These data fail to demonstrate an effect of ketamine on [(11)C]raclopride BP and are consistent with microdialysis studies in rodents and nonhuman primates which reported only small effects of acute NMDA receptor blockade on extracellular striatal DA concentration.     

Postpartum and depression status are associated with lower [[11C]raclopride BP(ND) in reproductive-age women

The early postpartum period is associated with increased risk for affective and psychotic disorders. Because maternal dopaminergic reward system function is altered with perinatal status, dopaminergic system dysregulation may be an important mechanism of postpartum psychiatric disorders. Subjects included were non-postpartum healthy (n=13), postpartum healthy (n=13), non-postpartum unipolar depressed (n=10), non-postpartum bipolar depressed (n=7), postpartum unipolar (n=13), and postpartum bipolar depressed (n=7) women. Subjects underwent 60 min of [11C]raclopride-positron emission tomography imaging to determine the nondisplaceable striatal D?/? receptor binding potential (BP(ND)). Postpartum status and unipolar depression were associated with lower striatal D?/? receptor BP(ND) in the whole striatum (p=0.05 and p=0.02, respectively) that reached a maximum of 7-8% in anteroventral striatum for postpartum status (p=0.02). Unipolar depression showed a nonsignificant trend toward being associated with 5% lower BP(ND) in dorsal striatum (p=0.06). D?/? receptor BP(ND) did not differ significantly between unipolar depressed and healthy postpartum women or between bipolar and healthy subjects; however, D?/? receptor BP(ND) was higher in dorsal striatal regions in bipolar relative to unipolar depressives (p=0.02). In conclusion, lower striatal D?/? receptor BP(ND) in postpartum and unipolar depressed women, primarily in ventral striatum, and higher dorsal striatal D?/? receptor BP(ND) in bipolar relative to unipolar depressives reveal a potential role for the dopamine (DA) system in the physiology of these states. Further studies delineating the mechanisms underlying these differences in D?/? receptor BP(ND), including study of DA system responsivity to rewarding stimuli, and increasing power to assess unipolar vs bipolar-related differences, are needed to better understand the affective role of the DA system in postpartum and depressed women.     

Is psychological stress in man associated with increased striatal dopamine levels?: A [11C]raclopride PET study

In rodents, stress causes rapid increases in extracellular dopamine (DA) concentration in cortical and subcortical brain regions, and positron emission tomography (PET) studies in healthy humans have suggested psychological and pharmacological stressors are associated with increased DA concentration in the striatum. In this experiment, we measured the effect of stress, induced by difficult mental arithmetic, on [11C]raclopride binding in order to index striatal DA release. To refine measurements and facilitate interpretation of results a combination of head movement correction, a carefully designed control condition and bolus infusion administration of [11C]raclopride were employed. Fourteen healthy volunteers were scanned using [11C]raclopride PET. Physiological and psychological responses to the task were consistent with a stress response with changes in cardiovascular, hormonal, and subjective state indices. No change of ventral or dorsal striatal [11C]raclopride binding was found in the stress condition compared to nonstress. This negative result suggests that significant DA release does not occur in the striatum in healthy humans after mild, psychological stress.     

Striatal and cortical NMDA receptors are altered by a neurotoxic regimen of methamphetamine

Methamphetamine (m-AMPH) treatment produces long-lasting damage to striatal and cortical monoaminergic terminals and may also injure nonmonoaminergic cortical neurons. Evidence suggests that both dopamine (DA) and glutamate (GLU) play crucial roles in producing this damage. We used quantitative autoradiography to examine [³H]mazindol ([³H]MAZ) binding to striatal DA transporters and [³H]GLU binding to N-methyl-D-aspartate (NMDA) receptors in the striatum and cortex 1 week and 1 month after a neurotoxic regimen of m-AMPH. Rats received m-AMPH (4 mg/kg) or saline (SAL) (1 ml/kg) in four s.c. injections separated by 2 h intervals. One week after m-AMPH, the ventral and lateral sectors of the striatum showed the greatest decreases in both [³H]MAZ and [³H]GLU binding, while the nucleus accumbens (NA) showed no significant decreases. One month after m-AMPH, striatal [³H]MAZ binding was still significantly decreased, while NMDA receptor binding had recovered. Surprisingly, the parietal cortex showed a m-AMPH-induced increase in NMDA receptor binding in layers II/III and IV 1 week after m-AMPH and only in layers II/III 1 month after m-AMPH. The prefrontal cortex showed no m-AMPH-induced changes in NMDA receptor binding at either time point. This is the first demonstration that a regimen of m-AMPH that results in long-lasting damage to DA terminals can alter forebrain NMDA receptor binding. Thus, repeated m-AMPH treatments may produce changes in glutamatergic transmission in selected striatal and cortical regions. © 1996 Wiley-Liss, Inc.     

Differential effects of acute dopaminergic D1 and D2 receptor antagonists on proneurotensin mRNA expression in rat striatum.

The effect of acute dopamine (DA) antagonist treatment on neuronal proneurotensin (NT) mRNA was investigated in the rat striatum using a technique of non-radioactive in situ hybridisation. Adult Wistar rats were given a single intraperitoneal injection of either raclopride (D2 antagonist), SCH 23390 (D1 antagonist) or its inactive isomer SCH 23388 and left to survive for 3 h. Their brains were rapidly removed and striatal sections processed for in situ hybridisation using an alkaline phosphatase (AP) labelled oligonucleotide specific for NT mRNA. Blockade of the DA D2 receptors by a single injection of raclopride resulted in an increase in the number of NT mRNA containing cells in the dorsal lateral rim of the striatum adjacent to the corpus callosum. In contrast, no such increase was observed following blockade of the DA D1 receptors with SCH 23390. These findings demonstrate that NT mRNA expression is differentially regulated in the adult rat striatum by selective D1 and D2 antagonists.     

The effect of nicotine on striatal dopamine release in man: A [11C]raclopride PET study

In common with many addictive substances and behaviors nicotine activates the mesolimbic dopaminergic system. Brain microdialysis studies in rodents have consistently shown increases in extrasynaptic DA levels in the striatum after administration of nicotine but PET experiments in primates have given contradicting results. A recent PET study assessing the effect of smoking in humans showed no change in [(11)C]raclopride binding in the brain, but did find that "hedonia" correlated with a reduction in [(11)C]raclopride binding suggesting that DA may mediate the positive reinforcing effects of nicotine. In this experiment we measured the effect of nicotine, administered via a nasal spray, on DA release using [(11)C]raclopride PET, in 10 regular smokers. There was no overall change in [(11)C]raclopride binding after nicotine administration in any of the striatal regions examined. However, the individual change in [(11)C]raclopride binding correlated with change in subjective measures of "amused" and "happiness" in the associative striatum (AST) and sensorimotor striatum (SMST). Nicotine concentration correlated negatively with change in BP in the limbic striatum. Nicotine had significant effects on cardiovascular measures including pulse rate, systolic blood pressure (BPr), and diastolic BPr. Baseline [(11)C]raclopride binding potential (BP) in the AST correlated negatively with the Fagerstr?m score, an index of nicotine dependence. These results support a role for the DA system in nicotine addiction, but reveal a more complex relationship than suggested by studies in animals.     

Striatal dopamine denervation decreases the GDP binding affinity in rat striatal membranes

The role of G-proteins in D2 receptor supersensitivity was studied in striatal membranes from rats with unilateral 6-hydroxydopamine (6-OHDA) induced lesions of the nigral dopamine (DA) system. Thirteen months after the lesion the number of [3H]raclopride binding sites was increased in the DA denervated striatum, but no changes in ligand binding affinities and in proportion of high-affinity agonist binding sites could be detected. The affinity of [35S]GTPgammaS binding was unaltered after the striatal DA denervation, whereas the binding affinity of GDP was decreased in the DA denervated as compared to the intact striatum. It is proposed that the decrease in GDP binding affinity to D2 DA receptor-coupled G proteins is an important factor in the D2 receptor supersensitivity following degeneration of the striatal DA terminals.     

Dopamine receptor antagonists prevent the d-amphetamine-induced increase in calcitonin gene-related peptide levels in ventral striatum

Microdialysis in conjunction with radioimmunoassay (RIA) were used to study the effects of acute d-amphetamine or dopamine (DA) receptor antagonists administration on extracellular concentrations of calcitonin gene-related peptide (CGRP) in the ventral striatum of the rat. One hour after the subcutaneous (s.c.) injection of saline, the DA-D(1) receptor antagonist SCH 23390 (0.3 mg/kg) or the DA-D(2/3) receptor antagonist raclopride (1.0 mg/kg), one additional s.c. injection of saline or d-amphetamine (1.5 mg/kg) was given. The dialysates were collected at 60-min intervals; CGRP-like immunoreactivities (-LI) were determined by RIA. d-Amphetamine significantly increased extracellular CGRP-LI concentrations compared to the control animals. Administration of either SCH 23390 or raclopride did not significantly affect CGRP-LI concentrations. Pretreatment with either SCH 23390 or raclopride abolished the stimulatory effect of d-amphetamine on CGRP-LI levels. The results show that d-amphetamine administration results in an increase in extracellular concentrations of CGRP in the ventral striatum through a mechanism that appears to involve stimulation of either DA-D(1) or DA-D(2/3) receptors. The results also indicate that changes in dopaminergic neurotransmission affect CGRP outflow in the ventral striatum in a phasic but not tonic manner.     

Spinocerebellar ataxia type 1, 2, and 3 and restless legs syndrome: striatal dopamine D2 receptor status investigated by [11C]raclopride positron emission tomography.

In spinocerebellar ataxias (SCAs), up to 30% of patients complain of restless legs syndrome (RLS). In primary RLS, a putative role of the dopaminergic system has been postulated. To assess dopaminergic function in SCA1, 2, and 3, dopamine D(2) receptor binding potential (BP) was assessed by [(11)C]raclopride positron emission tomography in 10 SCA patients, 4 of whom suffered from RLS as demonstrated by polysomnography. BP was compared to 9 age-matched control subjects. In 2 SCA patients, striatal BP was clearly reduced (<2 SD below the mean of controls). However, there were no significant group differences between SCA and controls, largely owing to a significantly higher variance of striatal BP in SCA. BP was negatively correlated with disease duration. The fit suggests an increased BP in early stages, followed by a moderate decline in all quantified regions (caudate, dorsal putamen, ventral striatum) presumably reflecting a progressive loss of D(2) receptors. RLS in SCA was not accompanied by a significant reduction of D(2) receptor availability in the striatum. This missing correlation may point to an extrastriatal origin of RLS.     

Dopaminergic effects of caffeine in the human striatum and thalamus

Epidemiological studies have provided evidence that caffeine, an adenosine receptor antagonist, reduces the risk for Parkinson's disease. There are indications of specific interactions between striatal adenosine A(2A) and dopamine D(2) receptors, but the in vivo effects of caffeine on human dopamine system have not been investigated. In the present study, the dopaminergic effects of caffeine were examined with [(11)C]raclopride positron emission tomography (PET) in eight healthy habitual coffee drinkers after 24 h caffeine abstinence. Compared to oral placebo, 200 mg oral caffeine induced a 12% decrease in midline thalamic binding potential (p < 0.001). A trend-level increase in ventral striatal [(11)C]raclopride binding potential was seen with a correlation between caffeine-related arousal and putaminal dopamine D(2) receptor binding (r = -0.81, p = 0.03). The findings indicate that caffeine has effects on dopaminergic neurotransmission in the human brain, which may be differential in the striatum and the thalamus.     

Test-retest variability of [¹¹C]raclopride-binding potential in nontreatment-seeking alcoholics

Knowledge of the reproducibility of striatal [11C]raclopride (RAC) binding is important for studies that use RAC PET paradigms to estimate changes in striatal dopamine (DA) during pharmacological and cognitive challenges. To our knowledge, no baseline test-retest data exist for nontreatment-seeking alcoholics (NTS). We determined the test-retest reproducibility of baseline RAC binding potential (BP(ND) ) in 12 male NTS subjects. Subjects were scanned twice with single-bolus RAC PET on separate days. Striatal RAC BP (BP(ND) ) for left and right dorsal caudate, dorsal putamen, and ventral striatum was estimated using the Multilinear Reference Tissue Method (MRTM) and Logan Graphical Analysis (LGA) with a reference region. Test-retest variability (TRV), % change in BP(ND) between scan days, and the intraclass correlation coefficient (ICC) were used as metrics of reproducibility. For MRTM, TRV for striatal RAC binding in NTS subjects was ±6.5% and ±7.1% for LGA. Average striatal ICCs were 0.94 for both methods (P < 0.0001). Striatal BP(ND) values were similar to those reported previously for detoxified alcoholics. The results demonstrate that baseline striatal RAC binding is highly reproducible in NTS subjects, with a low variance similar to that reported for healthy control subjects.     

Concurrent locomotor stimulation and decrease in dopamine release in rats and mice after treatment with the competitive NMDA receptor antagonists D-CPPene and CGS 19755

Summary The present study was aimed at investigating the effects of the competitive N-methyl-D-aspartate (NMDA) receptor antagonists D-CPPene (3-(2-carboxypiperazine-4-yl)-propenyl-1-phosphonic acid) and CGS 19755 (cis-4-(phosphonomethyl)piperidine-2-carboxylic acid) on dopamine (DA) transmission and motor activity in mice and rats. As measures of DA release we used mouse brain 3-methoxytyramine (3-MT) levels, an indirect estimate of DA release, and striatal dialysate measures of DA in conscious and freely moving rats by means of microdialysis. To obtain additional information about monoaminergic neurotransmission, brain tissue levels of DA, DOPAC, HVA, 5-HT and 5-HIAA were measured in both mice and rats. The animals were sacrificed at the time when NMDA antagonist-induced locomotor stimulation was maximal. In mice, D-CPPene and CGS 19755 decreased striatal 3-MT levels, whereas, in general, 3-MT levels in the limbic forebrain were not significantly altered. Treatment with CGS 19755 decreased rat striatal dialysate levels of DA but increased 5-HIAA at time points when locomotor activity was increased. D-CPPene and CGS 19755 have been observed to produce psychotic symptoms in man. The present study suggests that these symptoms are not a result of an increase in central dopamine release.     

Amphetamine-induced dopamine release in human ventral striatum correlates with euphoria.

BACKGROUND: Studies in experimental animals have implicated the mesolimbic dopaminergic projections into the ventral striatum in the neural processes underlying behavioral reinforcement and motivated behavior; however, understanding the relationship between subjective emotional experience and ventral striatal dopamine (DA) release has awaited human studies. Using positron emission tomography (PET), we correlated the change in endogenous dopamine concentrations following dextroamphetamine (AMPH) administration with the associated hedonic response in human subjects and compared the strength of this correlation across striatal subregions. METHODS: We obtained PET measures of [(11)C]raclopride specific binding to DA D2/D3 receptors before and after AMPH injection (0.3 mg/kg IV) in seven healthy subjects. The change in [(11)C]raclopride binding potential (DeltaBP) induced by AMPH pretreatment and the correlation between DeltaBP and the euphoric response to AMPH were compared between the anteroventral striatum (AVS; comprised of accumbens area, ventromedial caudate, and anteroventral putamen) and the dorsal caudate (DCA) using an MRI-based region of interest analysis of the PET data. RESULTS: The mean DeltaBP was greater in the AVS than in the DCA (p <.05). The AMPH-induced changes in euphoria analog scale scores correlated inversely with DeltaBP in the AVS (r = -.95; p <.001), but not in the DCA (r =.30, ns). Post hoc assessments showed that changes in tension-anxiety ratings correlated positively with DeltaBP in the AVS (r =.80; p [uncorrected] <.05) and that similar relationships may exist between DeltaBP and emotion ratings in the ventral putamen (as were found in the AVS). CONCLUSIONS: The preferential sensitivity of the ventral striatum to the DA releasing effects of AMPH previously demonstrated in experimental animals extends to humans. The magnitude of ventral striatal DA release correlates positively with the hedonic response to AMPH.     

Inhibition of striatal dopamine release by glycine and glycyldodecylamide

Phencyclidine (PCP) and other N-methyl-D-aspartate (NMDA) antagonists induce schizophrenia-like symptoms in humans. In rodents, PCP induces a syndrome of stereotypies and hyperactivity that is accompanied by stimulation of striatal dopamine release. Glycine and other NMDA agonists reverse PCP-induced behaviors in rodents and ameliorate PCP psychosis-like symptoms of schizophrenia in clinical trials. Glycine levels in vivo are regulated by the actions of glycine (GLYT1) transporters. The present study investigates effects of glycine and the prototypic glycine transport inhibitor glycyldodecylamide (GDA) on striatal dopamine release in vitro using a mouse striatal assay. Glycine and GDA significantly inhibit NMDA-induced striatal dopamine release, consistent with their ability to enhance local striatal inhibitory neurotransmission in vitro and to reverse PCP-induced hyperactivity in vivo.     

Do NMDA receptor antagonists protect against MPTP-toxicity? Biochemical and immunocytochemical analyses in black mice.

We investigated whether excitatory amino acids acting at the N-methyl-D-aspartate (NMDA) subtype of the L-glutamate receptor contribute to the dopaminergic neurotoxicity induced by systemic administration of the Parkinson's syndrome-inducing toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in C57Bl/6 mice. The MPTP-regimen chosen (30-40 mg/kg body weight subcutaneously) resulted a 60-70% depletion of striatal dopamine (DA) content and a 20% reduction of tyrosine hydroxylase immunoreactive (TH-IR) cells in the substantia nigra pars compacta 20 days after administration. Repeated systemic coadministration of the non-competitive NMDA receptor antagonist MK-801 or of the novel competitive NMDA receptor antagonist CGP 40116 did not protect against MPTP-induced striatal DA depletion 20 days after toxin administration. Additionally, no short-term protective effects of MK-801 on striatal DA content were observed 24, 48, and 96 h, respectively, after exposure to MPTP. A slight and non-significant attenuation (approximately 10%) of the MPTP-induced decrease in the number of nigral TH-IR cells was observed after MK-801- and CGP 40116-treatment. We conclude that neurotoxicity of systemically administered MPTP is not substantially antagonized by NMDA receptor antagonists in mice.     

D1 dopamine receptor-mediated induction of zif268 and c-fos in the dopamine-depleted striatum: Differential regulation and independence from NMDA receptors

Excitatory amino acid afferents from cerebral cortex and dopamine afferents from the substantia nigra synapse on common projection neurons in the striatum. Activation of D1 dopamine receptors increases immediate early gene expression in the striatum and conductance through the N-methyl-d-aspartate (NMDA) receptor. To examine the contribution of NMDA receptor activation to dopamine receptor-mediated responses, we determined the effects of intrastriatal administration of NMDA antagonists on immediate early gene expression in the striatum and rotational behavior induced by stimulation of the D1 receptor in rats with unilateral dopamine depletions. Systemic administration of SKF 38393 increased c-fos and zif268 mRNAs in the striatum and induced contralateral rotation. Intrastriatal infusion of the competitive NMDA receptor antagonist (±)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid caused a dose-dependent attenuation of SKF 38393-induced rotation and partially decreased c-fos mRNA expression. However, D1-mediated increases in zif268 mRNA were not affected, except by the highest concentration of antagonist used (10 mM). Another competitive antagonist, 2-amino-5-phosphonovaleric acid, had similar effects. Like the competitive antagonists, intrastriatal infusion of the non-competitive NMDA antagonist MK-801 partially decreased c-fos, but not zif268, mRNA in the area around the microdialysis probe. However, unlike competitive antagonists, local infusion of 1 mM MK-801 potentiated D1-mediated increases in c-fos and zif268 mRNAs in lateral striatum. These data suggest that 1) some D1 dopamine receptor-mediated effects on striatal function are independent of ongoing NMDA receptor activation, whereas other effects are at least partially mediated by NMDA receptor activity in the striatum, and 2) competitive and non-competitive antagonists of the NMDA receptor differently affect D1-mediated immediate early gene expression in the striatum. © 1996 Wiley-Liss, Inc.     

Quantification and pharmacological characterization of dialysate levels of noradrenaline in the striatum of freely-moving rats: release from adrenergic terminals and modulation by alpha2-autoreceptors

Information concerning striatal levels of noradrenaline (NA) remains inconsistent. Here we have addressed this issue using a sensitive method of HPLC coupled to amperometric detection. The NA reuptake-inhibitor, reboxetine, selectively elevated levels of NA versus dopamine (DA), and NA levels were also selectively elevated by the alpha2-adrenoceptor (AR) antagonist, atipamezole. The actions of atipamezole were mimicked by the preferential alpha2A-AR antagonist, BRL44408, while JO-1 and prazosin, preferential antagonists at alpha2C-ARs, caused less marked elevations in NA levels. In contrast to antagonists, the alpha2-AR agonist, S18616, decreased NA levels and likewise suppressed those of DA. Unilateral lesions of the substantia nigra with 6-hydroxydopamine depleted DA levels without affecting those of NA. Further, the D3/D2 receptor agonist, quinelorane, decreased levels of DA without modifying those of NA. However, the D3/D2 receptor antagonists, haloperidol and raclopride, and the DA reuptake-inhibitor, GBR12935, elevated levels of both DA and NA. Levels of 5-HT (but not of NA or DA) were increased only by the 5-HT reuptake-inhibitor, citalopram. They were decreased by S18616 and prazosin, reflecting the inhibitory and excitatory influence of alpha2- and alpha1-ARs, respectively, upon serotonergic pathways. In conclusion, NA in the striatum is derived from adrenergic terminals. Its release is subject to tonic, inhibitory control by alpha2-ARs, possibly involving both alpha2A- and alpha2C-AR subtypes, though their respective contribution requires clarification. A role of dopaminergic terminals in the reuptake of NA likely explains the elevation in its levels elicited by DA reuptake-inhibitors and D3/D2 receptor antagonists.