DA D2 Research Articles

The dose-dependent effect of the D2R agonist quinpirole microinjected into the ventral pallidum on information flow in the limbic system

The ventral pallidum (VP) receives its primary inputs from the nucleus accumbens (NAC) and the basolateral amygdala (BLA). We demonstrated recently that in the VP, the D2 DA receptor (D2R) agonist quinpirole dose-dependently facilitates memory consolidation in inhibitory avoidance and spatial learning. In the VP, D2R can be found both on NAC and BLA terminals. According to our hypothesis, quinpirole microinjected into the VP can facilitate memory consolidation via modulation of synaptic plasticity on NAC and/or BLA terminals.The effect of intra-VP quinpirole on BLA-VP and NAC shell-VP synapses was investigated via a high frequency stimulation (HFS) protocol. Quinpirole was administered in three doses into the VP of male Sprague-Dawley rats after HFS; controls received vehicle. To examine whether an interaction between the NAC shell and the BLA at the level of the VP was involved, tetrodotoxin (TTX) was microinjected into one of the nuclei while stimulating the other nucleus.Our results showed that quinpirole dose-dependently modulates BLA-VP and NAC shell-VP synapses, similar to those observed in inhibitory avoidance and spatial learning, respectively. The lower dose inhibits BLA inputs, while the larger doses facilitates NAC shell inputs. The experiments with TTX demonstrates that the two nuclei do not influence each others' evoked responses in the VP.Power spectral density analysis demonstrated that independent from the synaptic facilitation, intra-VP quinpirole increases the amplitude of gamma frequency band after NAC HFS, and BLA tonically suppresses the NAC's HFS-induced gamma facilitation. In contrast, HFS of the BLA results in a delayed, transient increase in the amplitude of the gamma frequency band correlating with the LTP of the P1 component of the VP response to BLA stimulation.Furthermore, our results demonstrate that the BLA plays a prominent role in the generation of the delta oscillations: HFS of the BLA leads to a gradually increasing delta frequency band facilitation over time, while BLA inhibition blocks the NAC's HFS induced strong delta facilitation.These findings demonstrate that there is a complex interaction between the NAC shell region and the VP, as well as the BLA and the VP, and support the important role of VP D2Rs in the regulation of limbic information flow.

Effort-related effects of chronic administration of the DA D2 receptor antagonist haloperidol via subcutaneous programmable minipumps: Reversal by co-administration of the adenosine A2A antagonist istradefylline.

Long-acting antipsychotics such as haloperidol decanoate are becoming more commonly used. Long-acting depot formulations have several advantages, but secondary negative effects of prolonged delivery, including motivational dysfunctions, could have debilitating effects. Assessing the behavioral changes that emerge during chronic antipsychotic administration in rats could provide insight regarding the development of motivational dysfunctions and drug tolerance. Acute administration of dopamine D2 antagonists such as haloperidol induce motivational deficits in rats, as marked by a shift towards a low-effort bias during effort-based choice tasks. In the present studies, programmable subcutaneous infusion pumps provided continuous and controlled drug delivery of haloperidol. Animals were assessed using a fixed ratio (FR) 5 lever pressing schedule and the FR5/chow feeding test of effort-based choice. The adenosine A2A antagonist istradefylline was studied for its ability to reverse the effects of chronic haloperidol. Continuous chronic infusions of haloperidol produced significant reductions in FR5 performance and a shift from lever pressing to chow intake in rats tested on FR5/chow feeding choice, with no evidence of tolerance over the 4-week infusion period. Behavior returned to baseline during the vehicle-infusion washout period. Istradefylline significantly reversed the effects of haloperidol, increasing lever pressing and decreasing chow intake in haloperidol-treated rats. These studies provide an important behavioral characterization of the effects of chronically infused haloperidol, and demonstrate that A2A antagonism reverses the effects of chronic haloperidol. This research could contribute to the understanding and treatment of motivational dysfunctions seen in schizophrenia, Parkinson's disease, and other disorders involving dopamine.

Searching for Biomarkers in the Blood of Patients at Risk of Developing Parkinson's Disease at the Prodromal Stage.

Parkinson's disease (PD) is diagnosed many years after its onset, under a significant degradation of the nigrostriatal dopaminergic system, responsible for the regulation of motor function. This explains the low effectiveness of the treatment of patients. Therefore, one of the highest priorities in neurology is the development of the early (preclinical) diagnosis of PD. The aim of this study was to search for changes in the blood of patients at risk of developing PD, which are considered potential diagnostic biomarkers. Out of 1835 patients, 26 patients were included in the risk group and 20 patients in the control group. The primary criteria for inclusion in a risk group were the impairment of sleep behavior disorder and sense of smell, and the secondary criteria were neurological and mental disorders. In patients at risk and in controls, the composition of plasma and the expression of genes of interest in lymphocytes were assessed by 27 indicators. The main changes that we found in plasma include a decrease in the concentrations of l-3,4-dihydroxyphenylalanine (L-DOPA) and urates, as well as the expressions of some types of microRNA, and an increase in the total oxidative status. In turn, in the lymphocytes of patients at risk, an increase in the expression of the DA D3 receptor gene and the lymphocyte activation gene 3 (LAG3), as well as a decrease in the expression of the Protein deglycase DJ-1 gene (PARK7), were observed. The blood changes we found in patients at risk are considered candidates for diagnostic biomarkers at the prodromal stage of PD.

Boosted dopamine and blunted serotonin in Tourette syndrome- evidence from in vivo imaging studies.

The precise cortical and subcortical mechanisms of Tourette syndrome (TS) are still not fully understood. In the present retrospective analysis, adolescent and adult medication-naïve patients showed increased DA transporter (DAT) binding in nucleus caudate (CAUD), putamen (PUT) and/or whole neostriatum (NSTR). D2 receptor (R)binding and DA release were not different from controls throughout the nigrostriatal and mesolimbocortical system. When patients were medication-free (either medication-naïve or under withdrawal), DAT was still increased in PUT, but not different from controls in CAUD, NSTR and ventral striatum (VSTR). SERT was unaltered in midbrain/pons (MP), but decreased in PUT, thalamus (THAL) and hypothalamus. D2R was unaltered throughout the nigrostriatal and mesolimbocortical system, while DA release was not different from controls in PUT, CAUD and NSTR, but elevated in VSTR. 5-HT2AR binding was unaltered in neocortex and cingulate. In acutely medicated adults, DAT was unaltered in PUT, but still increased in CAUD, whereas DA release remained unaltered throughout the nigrostriatal and mesolimbocortical system. When part of the patients was acutely medicated, vesicular monoamine transporter (VMAT2), DAT, SERT and DA synthesis were not different from controls in striatal regions, whereas D2R was decreased in NSTR, THAL, frontal cortex and limbic regions. Conversely, 5-HT2AR binding was unaltered in striatal regions and THAL, but increased in neocortical and limbic areas. It may be hypothesized that both the DA surplus and the 5-HT shortage in key regions of the nigrostriatal and mesolimbic system are relevant for the bouts of motor activity and the deficiencies in inpulse control.

The long-term interaction of diet and dopamine D2 gene expression on brain microglial activation

Dopamine D2 receptors are expressed on microglial in the central nervous system and promote anti-inflammatory responses. Little work has been done on the interaction between the dopamine D2 receptors and diet on activated microglial expression in the brain. To assess this, the current study uses in vitro autoradiography to look at microglial activation in the brain as a marker for neuroinflammation. Mice with different levels of expression of the DA D2 gene were given a chronic diet of either normal diet chow or high fat diet chow for 30 weeks. Mice were then euthanized and their brains were processed for [3H]PK11195 autoradiography. Mice with reductions or lack of the D2 gene showed higher [3H]PK11195 binding in a diet-specific manner within somatosensory and striatal regions, as well as the piriform, frontal, insular, and entorhinal regions compared to mice with normal D2 gene levels. These brain regions are important for sensory processing, habit formation, as well as cognitive function tasks related to learning, motivation, and memory. These results suggest that decreased D2R levels may increase vulnerability to specific inflammatory markers. Future studies will need to examine the implications of these inflammatory changes on brain function and behavior.

Loss of mGluR1-LTD following cocaine exposure accumulates Ca2+-permeable AMPA receptors and facilitates synaptic potentiation in the prefrontal cortex

Addiction results from drug-elicited alterations of synaptic plasticity mechanisms in dopaminergic reward circuits. Impaired metabotropic glutamate receptor (mGluR)-dependent long-term depression (LTD) and accumulation of synaptic Ca2+-permeable AMPA receptors (CP-AMPARs) following drug exposure have emerged as important mechanisms underlying drug craving and relapse. Here we show that repeated cocaine exposure in vivo causes transient but complete loss of mGluR1- and mTOR (mammalian target of rapamycin)-dependent LTD in layer 5 pyramidal neurons of mouse prefrontal cortex (PFC), a major dopaminergic target in the reward circuitry. This mGluR1-LTD impairment was prevented by in vivo administration of an mGluR1 positive allosteric modulator (PAM) and rescued by inhibition of dopamine D1 receptors, suggesting that impaired mGluR1 tone and excessive D1 signaling underlie this LTD deficit. Concurrently, CP-AMPARs were generated, indicated by increased sensitivity to the CP-AMPAR inhibitor Naspm and rectification of synaptic AMPAR currents, which were reversed by PAM in cocaine-exposed mice. Finally, these CP-AMPARs mediate an abnormal spike-timing-dependent long-term potentiation enabled by cocaine exposure. Our findings reveal a mechanism by which cocaine impairs LTD and remodels synaptic AMPARs to influence Hebbian plasticity in the PFC. Failure to undergo LTD may prevent the reversal of drug-potentiated brain circuits to their baseline states, perpetuating addictive behaviors. HIGHLIGHTS A mGluR1- and mTOR-dependent LTD is present in the mouse medial prefrontal cortex. Repeated cocaine exposure in vivo temporally but completely abolishes prefrontal mGluR1-LTD. Impaired mGluR1 function and excessive D1 DA signaling likely underlie cocaine impairment of mGluR1-LTD. Ca2+-permeable AMPA receptors are generated by cocaine exposure, likely resulting from mGluR1-LTD impairment, and contribute to a cocaine-induced extended spike timing LTP.

Blockade of D3 receptor prevents changes in DAT and D3R expression in the mesolimbic dopaminergic circuit produced by social stress- and cocaine prime-induced reinstatement of cocaine-CPP.

Cocaine may cause persistent changes in the brain, which are more apparent in DA transporter (DAT) and DA receptor availability within the nucleus accumbens (NAc). On the other hand, the DA D3 receptor (D3R) has emerged as a promising pharmacotherapeutic target for substance use disorders. This study aims to assess the impact of selective D3R antagonism on DAT and D3R after reinstatement of cocaine preference (CPP) induced by an acute session of social defeat stress (SDS) and a cocaine prime in mice after a period of abstinence. Male mice were conditioned with 25 mg/kg of cocaine for 4 days. After 60 days of extinction training mice were pretreated with the selective D3R antagonist SB-277011A before the re-exposure to a priming dose of cocaine or to a single SDS session. CPP scores were determined and levels of DAT, D3R, phospho Akt (pAkt) and phospho mTOR (pmTOR) were assessed in the NAc shell. An increase in DAT and D3R expression was seen in the NAc after both a cocaine prime- and SDS-induced reinstatement of CPP. Pretreatment with SB-277011A blocked elevated DAT and D3R expression as well as SDS-induced reinstatement. By contrast, the blockade of D3R did not modified the cocaine prime-induced CPP. Changes in DAT and D3R expression do not seem to occur via the canonic pathway involving Akt/mTOR. Our results suggest that the selective D3R antagonist ability to inhibit DAT and D3R up-regulation could represent a possible mechanism for its behavioral effects in cocaine-memories reinstatement induced by social stress.

Preclinical Pharmacology of [2-(3-Fluoro-5-Methanesulfonyl-phenoxy)Ethyl](Propyl)amine (IRL790), a Novel Dopamine Transmission Modulator for the Treatment of Motor and Psychiatric Complications in Parkinson Disease.

IRL790 ([2-(3-fluoro-5-methanesulfonylphenoxy)ethyl](propyl)amine, mesdopetam) is a novel compound in development for the clinical management of motor and psychiatric disabilities in Parkinson disease. The discovery of IRL790 was made applying a systems pharmacology approach based on in vivo response profiling. The chemical design idea was to develop a new type of DA D3/D2 receptor type antagonist built on agonist rather than antagonist structural motifs. We hypothesized that such a dopamine antagonist with physicochemical properties similar to agonists would exert antidyskinetic and antipsychotic effects in states of dysregulated dopaminergic signaling while having little negative impact on physiologic dopamine transmission and, hence, minimal liability for side effects related to dopamine-dependent functions. At the level of in vivo pharmacology, IRL790 displays balancing effects on aberrant motor phenotypes, reducing l-DOPA-induced dyskinesias in the rodent 6-hydroxydopamine lesion model and reducing psychostimulant-induced locomotor hyperactivity elicited by pretreatment with either d-amphetamine or dizocilpine, without negatively impacting normal motor performance. Thus, IRL790 has the ability to normalize the behavioral phenotype in hyperdopaminergic as well as hypoglutamatergic states. Neurochemical and immediate early gene (IEG) response profiles suggest modulation of DA neurotransmission, with some features, such as increased DA metabolites and extracellular DA, shared by atypical antipsychotics and others, such as increased frontal cortex IEGs, unique to IRL790. IRL790 also increases extracellular levels of acetylcholine in the prefrontal cortex and ventral hippocampus. At the receptor level, IRL790 appears to act as a preferential DA D3 receptor antagonist. Computational docking studies support preferential affinity at D3 receptors with an agonist-like binding mode. SIGNIFICANCE STATEMENT: This paper reports preclinical pharmacology along with molecular modeling results on IRL790, a novel compound in clinical development for the treatment of motor and psychiatric complications in advanced Parkinson disease. IRL790 is active in models of perturbed dopaminergic and glutamatergic signaling, including rodent 6-hydroxydopamine l-DOPA-induced dyskinesias and psychostimulant-induced hyperactivity, in a dose range that does not impair normal behavior. This effect profile is attributed to interactions at dopamine D2/D3 receptors, with a 6- to 8-fold preference for the D3 subtype.

A low dosage of the dopamine D2-receptor antagonist sulpiride affects effort allocation for reward regardless of trait extraversion.

Dopamine (DA) is known to be involved in various aspects of reward processing and goal-directed behavior. The present preregistered study aims at directly accessing the causal influence of DA activity on reward motivation in humans, while also accounting for trait extraversion. Therefore, we examined the effect of a single dose of the DA D2 receptor antagonist sulpiride (200 mg) on effort allocation in a modified version of the Effort-Expenditure for Reward Task (EEfRT). Based on its presumably DA increasing action, we expected the low dose of sulpiride to increase participants' willingness to allocate effort during the modified EEfRT relative to placebo, especially in trials with low probability of reward attainment. Further, we expected a moderating effect of trait extraversion on the effects of sulpiride. Two hundred and three healthy male participants were tested in a randomized, double-blind between-subjects design. Contrary to our expectations, sulpiride reduced the average number of clicks within the modified EEfRT and did not interact with reward attributes, suggesting a more global and not reward-specific effect of sulpiride. Furthermore, trait extraversion did not moderate the effect of sulpiride. Our results provide initial support for the validity of the modified version of the EEfRT, suggesting a possible inhibiting effect of a low dose of sulpiride on approach motivation regardless of trait extraversion. However, given the mixed pattern of findings and the possible confounding role of motoric abilities, further studies examining these effects are clearly warranted.

Regulation of stress‐induced gastric ulcers via central oxytocin and a potential mechanism through the VTA‐NAc dopamine pathway

Oxytocin (OT) plays an important role in regulating gastric function. How OT regulates stress-induced gastric ulcers is not understood. We investigated OT's protective role in stress-induced gastric ulcers, with a focus on OT's interaction with the ventral tegmental area (VTA) to nucleus accumbens (NAc) dopamine pathway. Drugs administration into the rats brain nuclei by brain stereotaxic apparatus, to examine related changes in gastric ulcer index, pH of gastric content, and mucus secretion, and to determine complex interactions between OT and DA systems in the regulation of stress and gastric functions. Neurons in the VTA were co-immunoreactive for the OT receptor (OTR) and DA. In a rat model of stress-induced ulcer, water-immersion restricted stress, direct administration of OT into the VTA significantly reduced gastric ulcer index and increased the pH of gastric content and mucus secretion. OT's effects were eliminated by pretreatment with the OTR antagonist atosiban in the VTA and weakened with pretreatment of the DA D2 receptor (DA D2R) antagonist raclopride in the NAc. In OTR gene knockout (Oxtr-/- ) mice, OT's protective effect was lost. OT administered to the VTA of dorsal motor nucleus of the vagus (DMV)-lesioned rats had minimal protective effects on gastric mucosa. This study provides important data necessary for a deeper understanding of the complex interactions between OT and DA systems in the regulation of stress and gastric functions. It provides relevant mechanistic clues into OT's role as a protective factor against stress-induced changes to gastric function.

Влияние острой инъекции этанола на мезолимбическую систему дофамина свободноподвижных крыс

Alcohol is the third leading risk factor for disease in Russia and around the world. According to WHO, as a result of alcohol abuse, 2.5 million people die every year in the world, which is comparable to the population of a large city. Despite the development of science and medicine, the mechanisms for the development of alcohol dependence are not completely clear. Understanding these mechanisms will help create new approaches to the treatment of alcohol dependence. Today it is well known that the mesolimbic system of dopamine plays a key role in the formation of addictive disorders, in particular alcohol dependence. Fast-scan cyclic voltammetry (FSCV) is a widespread electrochemical method for detection of neurotransmitters such as dopamine. The advantages of this technics are a high temporal and spatial resolution that makes FSCV a powerful technique for detecting changing chemical concentrations in vivo. Using FSCV on freely moving animals, we demonstrated that electrical stimulation of the ventral tegmental area (VTA) triggers detectable dopamine release in the nucleus accumbens (NAcc). We showed that acute injection of ethanol (0,5g/kg) on freely moving rats produces a significant decrease in dopamine efflux in NAcc induced by electrical stimulation. Selective D2 DA autoreceptor antagonist raclopride significantly increased measured signal that indicated that the neurotransmitter release measured in the NAcc is dopaminergic but not noradrenergic.

Contribution of monoaminergic mechanisms to the discriminative stimulus effects of 3,4-methylenedioxypyrovalerone (MDPV) in Sprague-Dawley rats.

3,4-Methylenedioxypyrovalerone (MDPV) is a popular synthetic cathinone reported to have a high abuse potential. Recent preclinical research indicates the psychopharmacology of MDPV is comparable to cocaine. Despite a recent influx of research on the psychopharmacology of MDPV, few studies have employed preclinical drug discrimination methods to discern the neurochemical mechanisms involved in its interoceptive stimulus effects. The aim of this study was to evaluate a variety of monoaminergic agents for substitution, potentiation, or antagonism in rats trained to discriminate MDPV. Male Sprague-Dawley rats were trained to discriminate 0.5 (experiment 1) or 1mg/kg MDPV (experiment 2) from saline under an FR 20 schedule of food reinforcement. In experiment 1, MDMA, MDA, and their respective optical isomers (0.75-3mg/kg), cocaine (2.5-20mg/kg), GBR 12909 (5-40mg/kg), and desipramine (3.2-10mg/kg) were assessed for substitution. GBR 12909 (40mg/kg) and desipramine (3.2mg/kg) were subsequently assessed for potentiation of the MDPV cue. In experiment 2, stimulus antagonism tests were conducted with dopamine antagonists (Sch 23390, haloperidol) and serotonin antagonists (pirenperone, MDL100907, WAY 100635). The MDMA and MDA enantiomers produced divergent results, with virtually no substitution by (-)-MDMA or (-)-MDA, partial substitution with (+)-MDA, and full substitution with (+)-MDMA, as well as full substitution by the racemates, (±)-MDMA and (±)-MDA. Consistent with previous findings, cocaine fully substituted for MDPV. Although no dose of GBR 12909 or desipramine substituted for MDPV, these reuptake inhibitors enhanced the discriminative stimulus effects of lower MDPV doses. Both D1 (Sch 23390) and D2 (haloperidol) DA antagonists attenuated 1mg/kg MDPV discrimination, whereas none of the 5-HT antagonists assessed altered MDPV discrimination. These findings indicate MDPV's interoceptive stimulus effects are mediated predominantly by dopaminergic actions, although serotonergic and/or noradrenergic modulation of these effects cannot be ruled out. Further investigations into the neurochemical actions involved in the discriminative stimulus effects of MDPV may serve to inform medication discovery and development for the treatment of MDPV abuse.

Acute anxiety disorder, major depressive disorder, bipolar disorder and schizophrenia are related to different patterns of nigrostriatal and mesolimbic dopamine dysfunction.

Dopamine (DA) receptor and transporter dysfunctions play a major role in the pathophysiology of neuropsychiatric diseases including anxiety disorder (AD), major depressive disorder (MDD), bipolar disorder (BD) in the manic (BDman) or depressive (BDdep) state and schizophrenia (SZ). We performed a PUBMED search, which provided a total of 239 in vivo imaging studies with either positron emission tomography (PET) or single-proton emission computed tomography (SPECT). In these studies, DA transporter binding, D1 receptor (R) binding, D2R binding, DA synthesis and/or DA release in patients with the primary diagnosis of acute AD (n=310), MDD (n=754), BDman (n=15), BDdep (n=49) or SZ (n=1532) were compared to healthy individuals. A retrospective analysis revealed that AD, MDD, BDman, BDdep and SZ differed as to affected brain region(s), affected synaptic constituent(s) and extent as well as direction of dysfunction in terms of either sensitization or desensitization of transporter and/or receptor binding sites. In contrast to AD and SZ, in MDD, BDman and BDdep, neostriatal DA function was normal, whereas MDD, BDman, and BDdep were characterized by the increased availability of prefrontal and frontal DA. In contrast to AD, MDD, BDman and BDdep, DA function in SZ was impaired throughout the nigrostriatal and mesolimbocortical system with an increased availability of DA in the striatothalamocortical and a decreased availability in the mesolimbocortical pathway.

Characterization of Dopaminergic System in the Striatum of Young Adult Park2\u2212/\u2212 Knockout Rats

Mutations in parkin gene (Park2) are linked to early-onset autosomal recessive Parkinson’s disease (PD) and young-onset sporadic PD. Park2 knockout (PKO) rodents; however, do not display neurodegeneration of the nigrostriatal pathway, suggesting age-dependent compensatory changes. Our goal was to examine dopaminergic (DAergic) system in the striatum of 2 month-old PKO rats in order to characterize compensatory mechanisms that may have occurred within the system. The striata form wild type (WT) and PKO Long Evans male rats were assessed for the levels of DAergic markers, for monoamine oxidase (MAO) A and B activities and levels, and for the levels of their respective preferred substrates, serotonin (5-HT) and ß-phenylethylamine (ß-PEA). The PKO rats displayed lower activities of MAOs and higher levels of ß-PEA in the striatum than their WT counterparts. Decreased levels of ß-PEA receptor, trace amine-associated receptor 1 (TAAR-1), and postsynaptic DA D2 (D2L) receptor accompanied these alterations. Drug-naive PKO rats displayed normal locomotor activity; however, they displayed decreased locomotor response to a low dose of psychostimulant methamphetamine, suggesting altered DAergic neurotransmission in the striatum when challenged with an indirect agonist. Altogether, our findings suggest that 2 month-old PKO male rats have altered DAergic and trace aminergic signaling.

Is dopamine transporter-mediated dopaminergic signaling in the retina a noninvasive biomarker for attention-deficit/ hyperactivity disorder? A study in a novel dopamine transporter variant Val559 transgenic mouse model

BackgroundDopamine (DA) is a critical neuromodulator in the retina. Disruption of retinal DA synthesis and signaling significantly attenuates light-adapted, electroretinogram (ERG) responses, as well as contrast sensitivity and acuity. As these measures can be detected noninvasively, they may provide opportunities to detect disease processes linked to perturbed DA signaling. Recently, we identified a rare, functional DA transporter (DAT, SLC6A3) coding substitution, Ala559Val, in subjects with attention-deficit/hyperactivity disorder (ADHD), demonstrating that DAT Val559 imparts anomalous DA efflux (ADE) with attendant physiological, pharmacological, and behavioral phenotypes. To understand the broader impact of ADE on ADHD, noninvasive measures sensitive to DAT reversal are needed.MethodsHere, we explored this question through ERG-based analysis of retinal light responses, as well as HPLC measurements of retinal DA in DAT Val559 mice.ResultsMale mice homozygous (HOM) for the DAT Val559 variant demonstrated increased, light-adapted ERG b-wave amplitudes compared to wild type (WT) and heterozygous (HET) mice, whereas dark-adapted responses were indistinguishable across genotypes. The elevated amplitude of the photopic light responses in HOM mice could be mimicked in WT mice by applying D1 and D4 DA receptor agonists and suppressed in HOM mice by introducing D4 antagonist, supporting elevated retinal DA signaling arising from ADE. Following the challenge with amphetamine, WT exhibited an increase in light-adapted response amplitudes, while HOM did not. Total retinal DA content was similar across genotypes. Interestingly, female DAT Val559 HOM animals revealed no significant difference in photopic ERG responses when compared with WT and HET littermates.ConclusionsThese data reveal that noninvasive, in vivo evaluation of retinal responses to light can reveal physiological signatures of ADE, suggesting a possible approach to the segregation of neurobehavioral disorders based on the DAT-dependent control of DA signaling.

Dopamine-dependent visual attention preference to social stimuli in nonhuman primates

RationaleDopamine (DA) plays a central role in reward processing. Accumulating evidence suggests that social interaction and social stimuli have rewarding properties that activate the DA reward circuits. However, few studies have attempted to investigate how DA is involved in the processing of social stimuli.ObjectivesIn this study, we investigated the effects of pharmacological manipulations of DA D1 and D2 receptors on social vs. nonsocial visual attention preference in macaques.MethodsJapanese macaques were subjected to behavioral tests in which visual attention toward social (monkey faces with and without affective expressions) and nonsocial stimuli was examined, with D1 and D2 antagonist administration.ResultsThe macaques exhibited significantly longer durations of gazing toward the images with social cues than did those with nonsocial cues. Both D1 and D2 antagonist administration decreased duration of gazing toward the social images with and without affective valences. In addition, although D1 antagonist administration increased the duration of gazing toward the nonsocial images, D2 antagonism had no effect.ConclusionsThese results suggest that both D1 and D2 receptors may have roles in the processing of social signals but through separate mechanisms.

1,2,4-Triazolyl octahydropyrrolo[2,3-b]pyrroles: A new series of potent and selective dopamine D3 receptor antagonists

A novel series of 1,2,4-triazolyl octahydropyrrolo[2,3-b]pyrroles showing high affinity and selectivity at the DA D3 receptor is reported here. Compounds endowed with high selectivity over the hERG channel were identified and their pharmacokinetic properties thoroughly analyzed. A few derivatives with appropriate developability characteristics were selected for further studies and progression along the screening cascade. In particular, derivative 60a, (DA D3 pKi=8.4, DA D2 pKi=6.0 and hERG fpKi=5.2) showed a balanced profile and further refinements are in progress around this molecule.

Synthesis and pharmacological evaluation of piperidine (piperazine)-substituted benzoxazole derivatives as multi-target antipsychotics.

The present study describes the optimization of a series of novel benzoxazole-piperidine (piperazine) derivatives combining high dopamine D2 and serotonin 5-HT1A, 5-HT2A receptor affinities. Of these derivatives, the pharmacological features of compound 29 exhibited high affinities for the DA D2, 5-HT1A and 5-HT2A receptors, but low affinities for the 5-HT2C and histamine H1 receptors and human ether-a-go-go-related gene (hERG) channels. Furthermore, compound 29 reduced apomorphine-induced climbing and 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-induced head twitching without observable catalepsy, even at the highest dose tested. Thus, compound 29 is a promising candidate as a multi-target antipsychotic treatment.

Differential effects of the dopamine D3 receptor antagonist PG01037 on cocaine and methamphetamine self‐administration in rhesus monkeys

Within the dopaminergic system, the DA D3 receptor (D3R) has been shown to mediate many of the behavioral effects of psychostimulants associated with high abuse potential. The present study sought to extend the assessment of the highly selective D3R antagonist PG01037 on cocaine and methamphetamine (MA) self‐administration to include a food‐drug choice procedure. Complete cocaine and MA self‐administration dose‐response curves were determined daily in each session for eight male rhesus monkeys (n=4/group). When choice was stable, monkeys received acute and five‐day treatment of PG01037 (1.0‐10 mg/kg, i.v.). Acute administration of PG01037 significantly reallocated choice behavior from cocaine to food and decreased cocaine intake, however, tolerance developed by day 5 of treatment. Up to doses that disrupted responding, MA choice and intake were not decreased following acute or 5‐day PG01037 treatment but the behavioral potency was significantly greater on MA choice compared to cocaine choice. Furthermore, using an unconditioned behavior, yawning elicited by the D3/D2R agonist quinpirole (0.003‐0.3 mg/kg) in these same monkeys, the acute efficacy of PG01037 was negatively correlated with the sensitivity to the behavioral effects of quinpirole. These data suggest (1) that efficacy of D3R compounds to decrease drug choice is greater in subjects with lower D3R, perhaps suggesting that it is percent occupancy that is the critical variable in determining efficacy and (2) differences in D3R activity in chronic cocaine vs. MA users. Supported by DA012460, AA007565, and NIDA‐IRP.

Homeostatic regulation of excitatory synapses on striatal medium spiny neurons expressing the D2 dopamine receptor.

Striatal medium spiny neurons (MSNs) are contacted by glutamatergic axon terminals originating from cortex, thalamus and other regions. The striatum is also innervated by dopaminergic (DAergic) terminals, some of which release glutamate as a co-transmitter. Despite evidence for functional DA release at birth in the striatum, the role of DA in the establishment of striatal circuitry is unclear. In light of recent work suggesting activity-dependent homeostatic regulation of glutamatergic terminals on MSNs expressing the D2 DA receptor (D2-MSNs), we used primary co-cultures to test the hypothesis that stimulation of DA and glutamate receptors regulates the homeostasis of glutamatergic synapses on MSNs. Co-culture of D2-MSNs with mesencephalic DA neurons or with cortical neurons produced an increase in spines and functional glutamate synapses expressing VGLUT2 or VGLUT1, respectively. The density of VGLUT2-positive terminals was reduced by the conditional knockout of this gene from DA neurons. In the presence of both mesencephalic and cortical neurons, the density of synapses reached the same total, compatible with the possibility of a homeostatic mechanism capping excitatory synaptic density. Blockade of D2 receptors increased the density of cortical and mesencephalic glutamatergic terminals, without changing MSN spine density or mEPSC frequency. Combined blockade of AMPA and NMDA glutamate receptors increased the density of cortical terminals and decreased that of mesencephalic VGLUT2-positive terminals, with no net change in total excitatory terminal density or in mEPSC frequency. These results suggest that DA and glutamate signaling regulate excitatory inputs to striatal D2-MSNs at both the pre- and postsynaptic level, under the influence of a homeostatic mechanism controlling functional output of the circuit.