Ventral pallidum DRD3 potentiates a pallido-habenular circuit driving accumbal dopamine release and cocaine seeking.

Drugs of abuse induce persistent remodeling of reward circuit function, a process thought to underlie the emergence of drug craving and relapse to drug use. However, how circuit-specific, drug-induced molecular and cellular plasticity can have distributed effects on the mesolimbic dopamine reward system to facilitate relapse to drug use is not fully elucidated. Here, we demonstrate that dopamine receptor D3 (DRD3)-dependent plasticity in the ventral pallidum (VP) drives potentiation of dopamine release in the nucleus accumbens during relapse to cocaine seeking after abstinence. We show that two distinct VP DRD3+ neuronal populations projecting to either the lateral habenula (LHb) or the ventral tegmental area (VTA) display different patterns of activity during drug seeking following abstinence from cocaine self-administration and that selective suppression of elevated activity or DRD3 signaling in the LHb-projecting population reduces drug seeking. Together, our results uncover how circuit-specific DRD3-mediated plasticity contributes to the process of drug relapse.

Dopamine Receptor D3 Expression Is Altered in CD4+ T-Cells From Parkinson's Disease Patients and Its Pharmacologic Inhibition Attenuates the Motor Impairment in a Mouse Model.

Neuroinflammation constitutes a fundamental process involved in Parkinson's disease (PD). Microglial cells play a central role in the outcome of neuroinflammation and consequent neurodegeneration of dopaminergic neurons in the substantia nigra. Current evidence indicates that CD4+ T-cells infiltrate the brain in PD, where they play a critical role determining the functional phenotype of microglia, thus regulating the progression of the disease. We previously demonstrated that mice bearing dopamine receptor D3 (DRD3)-deficient CD4+ T-cells are completely refractory to neuroinflammation and consequent neurodegeneration induced by the administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In this study we aimed to determine whether DRD3-signalling is altered in peripheral blood CD4+ T-cells obtained from PD patients in comparison to healthy controls (HC). Furthermore, we evaluated the therapeutic potential of targeting DRD3 confined to CD4+ T-cells by inducing the pharmacologic antagonism or the transcriptional inhibition of DRD3-signalling in a mouse model of PD induced by the chronic administration of MPTP and probenecid (MPTPp). In vitro analyses performed in human cells showed that the frequency of peripheral blood Th1 and Th17 cells, two phenotypes favoured by DRD3-signalling, were significantly increased in PD patients. Moreover, naïve CD4+ T-cells obtained from PD patients displayed a significant higher Th1-biased differentiation in comparison with those naïve CD4+ T-cells obtained from HC. Nevertheless, DRD3 expression was selectively reduced in CD4+ T-cells obtained from PD patients. The results obtained from in vivo experiments performed in mice show that the transference of CD4+ T-cells treated ex vivo with the DRD3-selective antagonist PG01037 into MPTPp-mice resulted in a significant reduction of motor impairment, although without significant effect in neurodegeneration. Conversely, the transference of CD4+ T-cells transduced ex vivo with retroviral particles codifying for an shRNA for DRD3 into MPTPp-mice had no effects neither in motor impairment nor in neurodegeneration. Notably, the systemic antagonism of DRD3 significantly reduced both motor impairment and neurodegeneration in MPTPp mice. Our findings show a selective alteration of DRD3-signalling in CD4+ T-cells from PD patients and indicate that the selective DRD3-antagonism in this subset of lymphocytes exerts a therapeutic effect in parkinsonian animals dampening motor impairment.

Dopamine D1 and D3 receptor modulators restore morphine analgesia and prevent opioid preference in a model of neuropathic pain.

A secondary consequence of spinal cord injury (SCI) is debilitating chronic neuropathic pain, which is commonly morphine resistant and inadequately managed by current treatment options. Consequently, new pain management therapies are desperately needed. We previously reported that dopamine D3 receptor (D3R) dysfunction was associated with opioid resistance and increases in D1 receptor (D1R) protein expression in the spinal cord. Here, we demonstrate that in a model of SCI neuropathic pain, adjuvant therapy with a D3R agonist (pramipexole) or D1R antagonist (SCH 39166) can restore the analgesic effects of morphine and reduce reward potential. Prior to surgery thermal and mechanical thresholds were tested in three groups of female rats (naïve, sham, SCI). After surgery, testing was repeated under the following drug conditions: 1) saline, 2) morphine, 3) pramipexole, 4) SCH 39166, 5) morphine + pramipexole, and 6) morphine + SCH 39166. Reward potential of morphine and both combinations was assessed using conditioned place preference. Following SCI, morphine + pramipexole and morphine + SCH 39166 significantly increased both thermal and mechanical thresholds. Morphine alone induced conditioned place preference, but when combined with either the D3R agonist or D1R antagonist preference was not induced. The data suggest that adjunct therapy with receptor-specific dopamine modulators can restore morphine analgesia and decrease reward potential and thus, represents a new target for pain management therapy after SCI.

Increased motor impulsivity in a rat gambling task during chronic ropinirole treatment: potentiation by win-paired audiovisual cues.

RATIONALE: Chronic administration of D2/3 receptor agonists ropinirole or pramipexole can increase the choice of uncertain rewards in rats, theoretically approximating iatrogenic gambling disorder (iGD). OBJECTIVES: We aimed to assess the effect of chronic ropinirole in animal models that attempt to capture critical aspects of commercial gambling, including the risk of losing rather than failing to gain, and the use of win-paired sensory stimuli heavily featured in electronic gambling machines (EGMs). METHODS: Male Long-Evans rats learned the rat gambling task (rGT; n = 24), in which animals sample between four options that differ in the magnitude and probability of rewards and time-out punishments. In the cued rGT (n = 40), reward-concurrent audiovisual cues were added that scaled in complexity with win size. Rats were then implanted with an osmotic pump delivering ropinirole (5 mg/kg/day) or saline for 28 days. RESULTS: Chronic ropinirole did not unequivocally increase preference for more uncertain outcomes in either the cued or uncued rGT. Ropinirole transiently increased premature responses, a measure of motor impulsivity, and this change was larger and more long-lasting in the cued task. CONCLUSIONS: These data suggest that explicitly signaling loss prevents the increase in preference for uncertain rewards caused by D2/3 receptor agonists observed previously. The ability of win-paired cues to amplify ropinirole-induced increases in motor impulsivity may explain why compulsive use of EGMs is particularly common in iGD. These data offer valuable insight into the cognitive-behavioral mechanisms through which chronic dopamine agonist treatments may induce iGD and related impulse control disorders.

Selective activation of Dopamine D3 receptors and norepinephrine transporter blockade enhances sustained attention.

Catecholamine transmitters dopamine (DA) and norepinephrine (NE) regulate prefrontal cortical (PFC) circuit activity and PFC-mediated executive functions. Accordingly, pharmacological agents that influence catecholamine neurotransmission exert prominent effects on cognition. Many such agents are used clinically to treat attention disorders. For example, methylphenidate blocks DA and NE reuptake and is the leading choice for attention deficit hyperactivity disorder (ADHD) treatment. Recently, we have designed SK609 - a selective small molecule agonist of the DA D3 receptor (D3R). In this study, we further characterized SK609's ability to selectively inhibit the reuptake of NE by NE transporters (NET). Our results indicate SK609 selectively inhibits NET with a Ki value of ∼500 nM and behaves as a NET substrate. Systemic dosing of SK609 (4 mg/kg; i.p.) in naïve rats produced a 300% and 160% increase in NE and DA, respectively, in the PFC as measured by microdialysis. Based on these neurochemical results, SK609 was tested in a PFC-dependent, visually-guided sustained attention task in rats. SK609 improved performance in a dose-dependent manner with a classical inverted-U dose response function with a peak effect at 4 mg/kg. SK609's peak effect was blocked by a pre-treatment with either the D2/D3R antagonist raclopride (0.05 mg/kg; i.p) or the alpha-1 adrenergic receptor antagonist prazosin (0.25 mg/kg; i.p), confirming a role for both DA and NE in promoting sustained attention. Additionally, SK609 improved sustained attention more prominently among low-performing animals. Doses of SK609 (2, 4, and 8 mg/kg) associated with cognitive enhancement did not produce an increase in spontaneous locomotor activity, suggesting a lack of side effects mediated by DA transporter (DAT) activity. These results demonstrate that the novel catecholaminergic modulator SK609 has the potential to treat sustained attention deficits without affecting DAT activity, distinguishing it from amphetamines and methylphenidate.

Dopamine D2/3 Binding Potential Modulates Neural Signatures of Working Memory in a Load-Dependent Fashion.

Dopamine (DA) modulates corticostriatal connections. Studies in which imaging of the DA system is integrated with functional imaging during cognitive performance have yielded mixed findings. Some work has shown a link between striatal DA (measured by PET) and fMRI activations, whereas others have failed to observe such a relationship. One possible reason for these discrepant findings is differences in task demands, such that a more demanding task with greater prefrontal activations may yield a stronger association with DA. Moreover, a potential DA-BOLD association may be modulated by task performance. We studied 155 (104 normal-performing and 51 low-performing) healthy older adults (43% females) who underwent fMRI scanning while performing a working memory (WM) n-back task along with DA D2/3 PET assessment using [11C]raclopride. Using multivariate partial-least-squares analysis, we observed a significant pattern revealing positive associations of striatal as well as extrastriatal DA D2/3 receptors to BOLD response in the thalamo-striatal-cortical circuit, which supports WM functioning. Critically, the DA-BOLD association in normal-performing, but not low-performing, individuals was expressed in a load-dependent fashion, with stronger associations during 3-back than 1-/2-back conditions. Moreover, normal-performing adults expressing upregulated BOLD in response to increasing task demands showed a stronger DA-BOLD association during 3-back, whereas low-performing individuals expressed a stronger association during 2-back conditions. This pattern suggests a nonlinear DA-BOLD performance association, with the strongest link at the maximum capacity level. Together, our results suggest that DA may have a stronger impact on functional brain responses during more demanding cognitive tasks.SIGNIFICANCE STATEMENT Dopamine (DA) is a major neuromodulator in the CNS and plays a key role in several cognitive processes via modulating the blood oxygenation level-dependent (BOLD) signal. Some studies have shown a link between DA and BOLD, whereas others have failed to observe such a relationship. A possible reason for the discrepancy is differences in task demands, such that a more demanding task with greater prefrontal activations may yield a stronger association with DA. We examined the relationship of DA to BOLD response during working memory under three load conditions and found that the DA-BOLD association is expressed in a load-dependent fashion. These findings may help explain the disproportionate impairment evident in more effortful cognitive tasks in normal aging and in those suffering dopamine-dependent neurodegenerative diseases (e.g., Parkinson's disease).

Differential involvement of D2 and D3 receptors during reinstatement of cocaine-seeking behavior in the Roman high- and low-avoidance rats.

Roman high- (RHA) and low-avoidance (RLA) rats have been used as a model for drug-addiction, showing, respectively, high- and low-responding to psychostimulants, and low versus high dopamine D2/3 receptors (D2/3R) striatal density. Previous studies indicated a major involvement of D2/3R on reinstatement of cocaine seeking, although the respective role of the two receptor subtypes is not clear. Here, we investigated sensitivity to cocaine self-administration (SA) through a dose-response protocol in RHAs and RLAs, and reinstatement of drug-seeking behavior at 15 days and 5 weeks following withdrawal. Compared to RLAs, RHAs confirmed a higher vulnerability to cocaine SA that was not related to a difference in sensitivity to the drug, as highlighted by the dose-response analysis. Both at early and late withdrawal, RHAs showed higher susceptibility than RLAs to reinstatement of drug-seeking when cocaine was used as a primer, but the two sublines did not differ when primed with the D2/3R agonist quinpirole. Moreover, while the specific D2R antagonist L741,626 blocked, the specific D3R antagonist SB-277011A failed to impair cocaine-primed relapse. The higher vulnerability of RHA versus RLA rats to cocaine-primed relapse, which contrasts with their similar vulnerability to quinpirole-primed relapse, suggests that the different propensity of both sublines to relapse likely relies on presynaptic rather than postsynaptic mechanisms. Moreover, our study challenges the involvement of D3R in the mechanisms underlying relapse to cocaine addiction, at least in conditions that may involve high levels of dopaminergic stimulation, and supports a major role of postsynaptic D2R over D3R in the vulnerability to relapse. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Presynaptic Inhibition of Primary Nociceptive Signals to Dorsal Horn Lamina I Neurons by Dopamine.

The dorsal horn of the spinal cord represents the first relay station in the pain pathway where primary nociceptive inputs are modulated by local circuits and by descending signals before being relayed to supraspinal nuclei. To determine whether dopamine can modulate primary nociceptive Aδ- and C-fiber signals, the effects of dopamine were tested on the excitatory postsynaptic currents (EPSCs) recorded from large lamina I neurons and from retrograde-labeled spinoparabrachial lamina I neurons upon stimulation of the L4/L5 dorsal root in horizontal spinal cord slices in vitro Dopamine inhibited the EPSCs in a dose-dependent manner, with substantial inhibition (33%) at 1 µm and maximum inhibition (∼70%) at 10-20 µm Dopamine reduced the frequency of miniature EPSCs recorded from large lamina I neurons, increased the paired pulse depression ratio of paired EPSCs, and induced similar inhibition of EPSCs after dialysis of large lamina I neurons with GDP-ß-S, consistent with actions at presynaptic sites. Pharmacological experiments suggested that the inhibitory effects of dopamine were largely mediated by D4 receptors (53%). Similar inhibition (66%) by dopamine was observed on EPSCs recorded from ipsilateral large lamina I neurons 6 d after injection of complete Freund's adjuvant in the hindpaw, suggesting that dopamine downregulates primary nociceptive inputs to lamina I neurons during chronic inflammatory pain. We propose that presynaptic inhibition of primary nociceptive inputs to lamina I projection neurons is a mechanism whereby dopamine can inhibit incoming noxious stimuli to the dorsal horn of the spinal cord.SIGNIFICANCE STATEMENT Lamina I projection neurons represent the main output for the pain signals from the dorsal horn of the spinal cord to brainstem and thalamic nuclei. We found that dopamine inhibits the nociceptive Aδ- and C-fiber synaptic inputs to lamina I projection neurons via presynaptic actions. Similar inhibitory effects of dopamine on the EPSCs were observed in rats subjected to complete Freund's adjuvant to induce peripheral inflammation, suggesting that dopamine inhibits the synaptic inputs to lamina I neurons in the setting of injury. A better understanding of how primary nociceptive inputs to the dorsal horn of the spinal cord are modulated by descending monoaminergic signals may help in the development of new pharmacological strategies to selectively downregulate the output from lamina I projection neurons.

DRD3 Gene and ADHD: A Pharmaco-Behavioural Genetic Study.

Results of candidate gene investigations in ADHD have been difficult to replicate. The complexity of the phenotypes and their underlying determinants, and the relatively small effect sizes of genetic variants may, in part, be contributing to these inconsistencies. The objective of this study is to conduct an exploratory analysis using a comprehensive approach to investigate the role of candidate genes. This approach combines a dimensional behavioural approach akin to Research Domain Criteria (RDoC), a pharmaco-dynamic evaluation of behaviours relevant to ADHD, together with association and linkage testing in a large sample of children with ADHD. Parents, teachers, and research staff evaluated children with ADHD under three experimental conditions (EC): 1 week of baseline observation, followed by 1 week of methylphenidate (MPH) and 1 week of placebo, administered in a double-blind crossover order. Several quantitative behavioural and cognitive dimensions relevant for ADHD were also assessed. We combined family-based (FBAT) and quantitative trait genetic analyses (n = 575 probands with members of their nuclear families) to investigate the role of DRD3 (Ser-9-Gly) in ADHD and its relevant behavioural dimensions. Comparing the behaviours of children with different genotypes under the three EC showed a nominal association between the T allele and poorer behavioural scores during the MPH week (as assessed by teachers), particularly in boys. With the family-based analysis, the T allele showed a nominal association with increased risk for ADHD, response to placebo and MPH as assessed by research staff, and the modulation of other behavioural and cognitive dimensions. These results provide convergent, albeit preliminary evidence for the implication of the DRD3 (Ser-9-Gly) polymorphism in the aetiology of ADHD and the modulation of its various behavioural dimensions, including RDoC cognitive constructs and response to pharmacological probes. This illustrative example suggests that this research paradigm might help to reliably uncover the role of other candidate genes in ADHD.

The role of striatal dopamine D2/3 receptors in cognitive performance in drug-free patients with schizophrenia.

OBJECTIVE: A considerable body of research links cognitive function to dopaminergic transmission in the prefrontal cortex, but less is known about cognition in relation to striatal dopamine D2/3 receptors in unmedicated patients with psychosis. METHODS: We investigated this association by obtaining PET recordings with the high-affinity D2/3 antagonist ligand [18F] fallypride in 15 medication-free patients with schizophrenia and 11 healthy controls. On the day of PET scanning, we undertook comprehensive neuropsychological testing and assessment of psychopathology using the Positive and Negative Syndrome Scale (PANSS). RESULTS: The patients' performance in cognitive tests was significantly impaired in almost all domains. Irrespective of medication history, the mean [18F] fallypride binding potential (BPND) in the patient group tended to be globally 5-10% higher than that of the control group, but without reaching significance in any brain region. There were significant positive correlations between individual patient performance in the Trail Making Test (TMT(A) and TMT(B)) and Digit-Symbol-Substitution-Test with regional [18F] fallypride BPND, which remained significant after Bonferroni correction for the TMT(A) in caudate nucleus (CN) and for the TMT(B) in CN and putamen. No such correlations were evident in the control group. DISCUSSION: The association between better cognitive performance and greater BPND in schizophrenia patients may imply that relatively lower receptor occupancy by endogenous dopamine favors better sparing of cognitive function. Absence of comparable correlations in healthy controls could indicate a greater involvement of signaling at dopamine D2/3 receptors in certain cognitive functions in schizophrenia patients than in healthy controls.

Yawning elicited by intravenous ethanol in rhesus monkeys with experience self-administering cocaine and ethanol: Involvement of dopamine D3 receptors.

Characterization of the effects of long-term alcohol consumption on the brain would be aided by the development of behavioral assays that are relatively easy to implement in animal models of alcohol use disorders. Assessing unconditioned behaviors, such as drug-elicited yawning in models that permit long-term alcohol ingestion, may be a valuable complement to more invasive and costly procedures. The present studies investigated previous unexpected findings of ethanol-induced yawning in nonhuman primates. Subjects were adult male rhesus monkeys (n = 8), all of which had experience self-administering intravenous cocaine for several years. Four monkeys also had experience consuming 2.0 g/kg ethanol over 1 h per day, 5 days per week, for 6.8-12.0 months. All monkeys received saline or ethanol (0.25-1.0 g/kg) infused intravenously (i.v.) over 10 min, and the number of yawns elicited during the infusion was counted. A second experiment in the ethanol-experienced monkeys examined whether ethanol-induced yawning could be blocked by PG01037 (1.0, 3.0 mg/kg, i.v.), a selective antagonist at dopamine D3 receptors (D3R). Ethanol significantly and dose-dependently increased yawns in the ethanol-experienced animals, but not the ethanol-naïve animals. In the ethanol-experienced monkeys, this effect of ethanol was blocked by the D3R antagonist. The pharmacology of yawning is complex and a good deal of model development remains to be performed to characterize the potential involvement of other neurotransmitter systems. Nonetheless, drug-elicited yawning may be a useful unconditioned behavioral assay to assess the effects of long-term alcohol consumption in established nonhuman primate models.

The Acute Effects of a Dopamine D3 Receptor Preferring Agonist on Motivation for Cigarettes in Dependent and Occasional Cigarette Smokers.

Background: Dopaminergic functioning is thought to play critical roles in both motivation and addiction. There is preliminary evidence that dopamine agonists reduce the motivation for cigarettes in smokers. However, the effects of pramipexole, a dopamine D3 receptor preferring agonist, have not been investigated. The aim of this study was to examine the effects of an acute dose of pramipexole on the motivation to earn cigarettes and nondrug rewards. Methods: Twenty dependent and 20 occasional smokers received 0.5 mg pramipexole using a double-blind, placebo-controlled crossover design. Motivation for cigarettes and consummatory nondrug rewards was measured using the DReaM-Choice task, in which participants earned, and later "consumed," cigarettes, music, and chocolate. Demand for cigarettes was measured using the Cigarette Purchase Task (CPT). Self-reported craving, withdrawal, and drug effects were also recorded. Results: Dependent smokers chose (p < .001) and button-pressed for (p < .001) cigarettes more, and chose chocolate less (p < .001), than occasional smokers. Pramipexole did not affect the number of choices for or amount of button-pressing for any reward including cigarettes, which was supported by a Bayesian analysis. The dependent smokers had greater demand for cigarettes than occasional smokers across all CPT outcomes (ps < .021), apart from elasticity. Pramipexole did not affect demand for cigarettes, and this was supported by Bayesian analyses. Pramipexole produced greater subjective "feel drug" and "dislike drug" effects than placebo. Conclusions: Dependent and occasional cigarette smokers differed in their motivation for cigarettes but not for the nondrug rewards. Pramipexole did not acutely alter motivation for cigarettes. These findings question the role of dopamine D3 receptors in cigarette-seeking behavior in dependent and occasional smokers. Implications: This study adds to the growing literature about cigarette versus nondrug reward processing in nicotine dependence and the role of dopamine in cigarette-seeking behavior. Our results suggest nicotine dependence is associated with a hypersensitivity to cigarette rewards but not a hyposensitivity to nondrug rewards. Furthermore, our results question the importance of dopamine D3 receptors in motivational processing of cigarettes in occasional and dependent smokers.

The First Negative Allosteric Modulator for Dopamine D2 and D3 Receptors, SB269652 May Lead to a New Generation of Antipsychotic Drugs.

D2 and D3 dopamine receptors belong to the largest family of cell surface proteins in eukaryotes, the G protein-coupled receptors (GPCRs). Considering their crucial physiologic functions and their relatively accessible cellular locations, GPCRs represent one of the most important classes of therapeutic targets. Until recently, the only strategy to develop drugs regulating GPCR activity was through the identification of compounds that directly acted on the orthosteric sites for endogenous ligands. However, many efforts have recently been made to identify small molecules that are able to interact with allosteric sites. These sites are less well-conserved, therefore allosteric ligands have greater selectivity on the specific receptor. Strikingly, the use of allosteric modulators can provide specific advantages, such as an increased selectivity for GPCR subunits and the ability to introduce specific beneficial therapeutic effects without disrupting the integrity of complex physiologically regulated networks. In 2010, our group unexpectedly found that N-[(1r,4r)-4-[2-(7-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-1H-indole-2-carboxamide (SB269652), a compound supposed to interact with the orthosteric binding site of dopamine receptors, was actually a negative allosteric modulator of D2- and D3-receptor dimers, thus identifying the first allosteric small molecule acting on these important therapeutic targets. This review addresses the progress in understanding the molecular mechanisms of interaction between the negative modulator SB269652 and D2 and D3 dopamine receptor monomers and dimers, and surveys the prospects for developing new dopamine receptor allosteric drugs with SB269652 as the leading compound.

Dopamine D1 and D3 Receptors Modulate Heroin-Induced Cognitive Impairment through Opponent Actions in Mice.

Background: Chronic abuse of heroin leads to long-lasting and complicated cognitive impairment. Dopamine receptors are critically involved in the impulsive drug-driven behavior and the altered attention, processing speed, and mental flexibility that are associated with higher relapse rates. However, the effects of the different dopamine receptors and their possible involvement in heroin-induced cognitive impairment remain unclear. Methods: The 5-choice serial reaction time task was used to investigate the profiles of heroin-induced cognitive impairment in mice. The expression levels of dopamine D1- and D2-like receptors in the prefrontal cortex, nucleus accumbens, and caudate-putamen were determined. The effects of dopamine receptors on heroin-induced impulsivity in the 5-choice serial reaction time task were examined by agonist/antagonist treatment on D1 or D3 receptor mutant mice. Results: Systemic heroin administration influences several variables in the 5-choice serial reaction time task, most notably premature responses, a measure of motor impulsivity. These behavioral impairments are associated with increased D1 receptor and decreased D3 receptor mRNA and protein levels in 3 observed brain areas. The heroin-evoked increase in premature responses is mimicked by a D1 agonist and prevented by a D1 antagonist or genetic ablation of the D1 receptor gene. In contrast, a D3 agonist decreases both basal and heroin-evoked premature responses, while genetic ablation of the D3 receptor gene results in increased basal and heroin-evoked premature responses. Conclusions: Heroin-induced impulsive behavior in the 5-choice serial reaction time task is oppositely modulated by D1 and D3 receptor activation. The D1 receptors in the cortical-mesolimbic region play an indispensable role in modulating such behaviors.

Dopamine D1 and D3 receptor interactions in cocaine reward and seeking in rats.

RATIONALE: Animal research has demonstrated a role of dopamine D1 and D3 receptors in cocaine reward and seeking. PURPOSE AND METHODS: Here, we investigated the potential interaction of these two dopamine receptors in cue-induced reinstatement of cocaine seeking, cocaine conditioned place preference (CPP), and cocaine self-administration in rats. RESULTS: The co-administration of a D3 receptor antagonist, NGB 2904 and a D1 partial agonist, SKF 77434, of doses which when administered individually produced no significant effects, prior to reinstatement or CPP tests significantly reduced lever pressing and time spent in the cocaine-paired environment, suggesting synergistic effects of the combined compounds on cocaine seeking. When given to rats self-administering cocaine under a progressive ratio schedule of reinforcement doses of NGB 2904 which were ineffective alone significantly enhanced the break point-reducing effects of SKF 77434. CONCLUSIONS: Our results indicate that the combined treatment with a D1 receptor partial agonist and D3 receptor antagonist produces robust decreases in cocaine seeking and reward. This suggests an interaction between dopamine D1 and D3 receptors in cocaine-related behaviors.

Association between striatal dopamine D2/D3 receptors and brain activation during visual attention: effects of sleep deprivation.

Sleep deprivation (SD) disrupts dopamine (DA) signaling and impairs attention. However, the interpretation of these concomitant effects requires a better understanding of dopamine's role in attention processing. Here we test the hypotheses that D2/D3 receptors (D2/D3R) in dorsal and ventral striatum would distinctly regulate the activation of attention regions and that, by decreasing D2/D3, SD would disrupt these associations. We measured striatal D2/D3R using positron emission tomography with [(11)C]raclopride and brain activation to a visual attention (VA) task using 4-Tesla functional magnetic resonance imaging. Fourteen healthy men were studied during rested wakefulness and also during SD. Increased D2/D3R in striatum (caudate, putamen and ventral striatum) were linearly associated with higher thalamic activation. Subjects with higher D2/D3R in caudate relative to ventral striatum had higher activation in superior parietal cortex and ventral precuneus, and those with higher D2/D3R in putamen relative to ventral striatum had higher activation in anterior cingulate. SD impaired the association between striatal D2/D3R and VA-induced thalamic activation, which is essential for alertness. Findings suggest a robust DAergic modulation of cortical activation during the VA task, such that D2/D3R in dorsal striatum counterbalanced the stimulatory influence of D2/D3R in ventral striatum, which was not significantly disrupted by SD. In contrast, SD disrupted thalamic activation, which did not show counterbalanced DAergic modulation but a positive association with D2/D3R in both dorsal and ventral striatum. The counterbalanced dorsal versus ventral striatal DAergic modulation of VA activation mirrors similar findings during sensorimotor processing (Tomasi et al., 2015) suggesting a bidirectional influence in signaling between the dorsal caudate and putamen and the ventral striatum.

Dopamine D3 Receptors Modulate the Ability of Win-Paired Cues to Increase Risky Choice in a Rat Gambling Task.

Similar to other addiction disorders, the cues inherent in many gambling procedures are thought to play an important role in mediating their addictive nature. Animal models of gambling-related behavior, while capturing dimensions of economic decision making, have yet to address the impact that these salient cues may have in promoting maladaptive choice. Here, we determined whether adding win-associated audiovisual cues to a rat gambling task (rGT) would influence decision making. Thirty-two male Long-Evans rats were tested on either the cued or uncued rGT. In these tasks, animals chose between four options associated with different magnitudes and frequencies of reward and punishing time-out periods. As in the Iowa Gambling Task, favoring options associated with smaller per-trial rewards but smaller losses and avoiding the tempting "high-risk, high-reward" decks maximized profits. Although the reinforcement contingencies were identical in both task versions, rats' choice of the disadvantageous risky options was significantly greater on the cued task. Furthermore, a D3 receptor agonist increased choice of the disadvantageous options, whereas a D3 antagonist had the opposite effects, only on the cued task. These findings are consistent with the reported role of D3 receptors in mediating the facilitatory effects of cues in addiction. Collectively, these results indicate that the cued rGT is a valuable model with which to study the mechanism by which salient cues can invigorate maladaptive decision making, an important and understudied component of both gambling and substance use disorders. Significance statement: We used a rodent analog of the Iowa Gambling Task to determine whether the addition of audiovisual cues would affect choice preferences. Adding reward-concurrent cues significantly increased risky choice. This is the first clear demonstration that reward-paired cues can bias cost/benefit decision making against a subject's best interests in a manner concordant with elevated addiction susceptibility. Choice on the cued task was uniquely sensitive to modulation by D3 receptor ligands, yet these drugs did not alter decision making on the uncued task. The relatively unprecedented sensitivity of choice on the cued task to D3-receptor-mediated neurotransmission data suggest that similar neurobiological processes underlie the ability of cues to both bias animals toward risky options and facilitate drug addiction.

Varenicline-Induced Elevation of Dopamine in Smokers: A Preliminary [(11)C]-(+)-PHNO PET Study.

Varenicline, a nicotinic partial agonist, is the most effective treatment for tobacco use disorder. However, its mechanism of action is still unclear and may involve stimulating dopaminergic transmission. Here we used PET imaging with [(11)C]-(+)-PHNO to explore for the first time the impact of varenicline on dopamine transmission in the D2-rich striatum and D3-rich extra-striatal regions and its relationship with craving, withdrawal and smoking. Eleven treatment-seeking smokers underwent two PET scans with [(11)C]-(+)-PHNO, each following 12-h overnight smoking abstinence both prior to receiving varenicline and following 10-11 days of varenicline treatment (ie, at steady-state drug levels). Subjective measures of craving and urges to smoke were also assessed on the days of the PET scans. Varenicline treatment significantly reduced [(11)C]-(+)-PHNO binding in the dorsal caudate (p=0.008) and reduced some craving measures. These findings provide the first evidence that varenicline is able to increase DA levels in the human brain, a factor that may contribute to its therapeutic efficacy.

In Vitro and In Vivo Identification of Novel Positive Allosteric Modulators of the Human Dopamine D2 and D3 Receptor.

Agonists at dopamine D2 and D3 receptors are important therapeutic agents in the treatment of Parkinson's disease. Compared with the use of agonists, allosteric potentiators offer potential advantages such as temporal, regional, and phasic potentiation of natural signaling, and that of receptor subtype selectivity. We report the identification of a stereoselective interaction of a benzothiazol racemic compound that acts as a positive allosteric modulator (PAM) of the rat and human dopamine D2 and D3 receptors. The R isomer did not directly stimulate the dopamine D2 receptor but potentiated the effects of dopamine. In contrast the S isomer attenuated the effects of the PAM and the effects of dopamine. In radioligand binding studies, these compounds do not compete for binding of orthosteric ligands, but indeed the R isomer increased the number of high-affinity sites for [(3)H]-dopamine without affecting K(d). We went on to identify a more potent PAM for use in native receptor systems. This compound potentiated the effects of D2/D3 signaling in vitro in electrophysiologic studies on dissociated striatal neurons and in vivo on the effects of L-dopa in the 6OHDA (6-hydroxydopamine) contralateral turning model. These PAMs lacked activity at a wide variety of receptors, lacked PAM activity at related Gi-coupled G protein-coupled receptors, and lacked activity at D1 receptors. However, the PAMs did potentiate [(3)H]-dopamine binding at both D2 and D3 receptors. Together, these studies show that we have identified PAMs of the D2 and D3 receptors both in vitro and in vivo. Such compounds may have utility in the treatment of hypodopaminergic function.

The selective dopamine D3 receptor antagonist, SR 21502, reduces cue-induced reinstatement of heroin seeking and heroin conditioned place preference in rats.

BACKGROUND: Because the role of dopamine (DA) D3 receptors has been investigated primarily in relation to cocaine-related behaviors little is known of the role of these receptors in heroin seeking. PURPOSES: To investigate the effect of the selective DA D3 receptor antagonist, SR 21502, on cue-induced reinstatement of heroin seeking and heroin conditioned place preference (CPP). METHODS: In experiment 1, rats were trained to self-administer intravenous heroin for 15 days followed by extinction. Following extinction animals were treated with one of several SR 21502 doses (0, 7.5, 10 or 15mg/kg) and a cue-induced reinstatement test was conducted. In experiment 2, animals were conditioned to experience heroin in one compartment of a CPP apparatus and saline in the other. On the test day animals were treated with 0, 3.75, 7.5, 10 or 15mg/kg of SR 21502 and tested for their CPP. RESULTS: The results from experiment 1 showed a significant dose-related reduction in cue-induced reinstatement of active lever pressing in the 7.5 and 10mg groups and an absence of the reinstatement effect in the 15mg group. In experiment 2, animals treated with vehicle or 3.75mg of SR 21502 showed significant heroin place preferences but those treated with the higher doses showed no CPP. CONCLUSIONS: Our findings suggest that DA D3 receptors play a significant role in heroin approach behaviors driven by conditioned stimuli. As such, we propose that SR 21502 holds potential as an effective pharmacotherapeutic agent for relapse prevention and should be studied further.