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Opioid use disorder (OUD) has become a considerable global public health challenge; however, potential medications for the management of OUD that are effective, safe, and nonaddictive are not available. Accumulating preclinical evidence indicates that antagonists of the dopamine D3 receptor (D3R) have effects on addiction in different animal models. We have previously reported that YQA14, a D3R antagonist, exhibits very high affinity and selectivity for D3Rs over D2Rs, and is able to inhibit cocaine- or methamphetamine-induced reinforcement and reinstatement in self-administration tests. In the present study, our results illustrated that YQA14 dose-dependently reduced infusions under the fixed-ratio 2 procedure and lowered the breakpoint under the progressive-ratio procedure in heroin self-administered rats, also attenuated heroin-induced reinstatement of drug-seeking behavior. On the other hand, YQA14 not only reduced morphine-induced expression of conditioned place preference but also facilitated the extinguishing process in mice. Moreover, we elucidated that YQA14 attenuated opioid-induced reward or reinforcement mainly by inhibiting morphine-induced up-regulation of dopaminergic neuron activity in the ventral tegmental area and decreasing dopamine release in the nucleus accumbens with a fiber photometry recording system. These findings suggest that D3R might play a very important role in opioid addiction, and YQA14 may have pharmacotherapeutic potential in attenuating opioid-induced addictive behaviors dependent on the dopamine system. [ABSTRACT FROM AUTHOR]

Nicotine induces kinetic tremor, which resembles pharmacological features of essential tremors, via activating the inferior olive (IO) neurons. Since nicotine is known to enhance dopamine release by stimulating α4β2 and/or α6 nACh receptors, we examined the effects of various dopamine receptor ligands on nicotine-induced tremor to clarify the role of the dopaminergic system in modulating nicotine tremor. A tremorgenic dose of nicotine increased the dopamine level in the pons and medulla oblongata (P/MO), and the levels of dopamine metabolites in the hippocampus, P/MO, and striatum. Treatment of animals with the D1/5 agonist SKF-38393 inhibited the induction of nicotine tremor, whereas the D3 agonist PD-128,907 facilitated nicotine-induced tremor. The D2 agonist sumanirole showed no effect. In addition, nicotine tremor was significantly enhanced by the D1/5 antagonist SCH-23390 and inhibited by the D3 antagonist U-99194. Neither the D2 (L-741,626) nor D4 (L-745,870) antagonist affected the generation of nicotine tremor. Furthermore, microinjection of U-99194 into the cerebellum significantly inhibited nicotine-induced tremor, whereas its injection into IO or the striatum did not affect tremor generation. Although intrastriatal injection of SCH-23390 showed no effects, its injection into IO tended to enhance nicotine-induced tremor. The present study suggests that dopamine D3 and D1/5 receptors regulate the induction of nicotine tremor in an opposite way, D3 receptors facilitately and D1/5 receptors inhibitorily. In addition, the cerebellar D3 receptors may play an important role in modulating the induction of nicotine tremor mediated by the olivo-cerebellar system. [ABSTRACT FROM AUTHOR]

Nicotine induces kinetic tremor, which resembles pharmacological features of essential tremors, via activating the inferior olive (IO) neurons. Since nicotine is known to enhance dopamine release by stimulating α4β2 and/or α6 nACh receptors, we examined the effects of various dopamine receptor ligands on nicotine-induced tremor to clarify the role of the dopaminergic system in modulating nicotine tremor. A tremorgenic dose of nicotine increased the dopamine level in the pons and medulla oblongata (P/MO), and the levels of dopamine metabolites in the hippocampus, P/MO, and striatum. Treatment of animals with the D1/5 agonist SKF-38393 inhibited the induction of nicotine tremor, whereas the D3 agonist PD-128,907 facilitated nicotine-induced tremor. The D2 agonist sumanirole showed no effect. In addition, nicotine tremor was significantly enhanced by the D1/5 antagonist SCH-23390 and inhibited by the D3 antagonist U-99194. Neither the D2 (L-741,626) nor D4 (L-745,870) antagonist affected the generation of nicotine tremor. Furthermore, microinjection of U-99194 into the cerebellum significantly inhibited nicotine-induced tremor, whereas its injection into IO or the striatum did not affect tremor generation. Although intrastriatal injection of SCH-23390 showed no effects, its injection into IO tended to enhance nicotine-induced tremor. The present study suggests that dopamine D3 and D1/5 receptors regulate the induction of nicotine tremor in an opposite way, D3 receptors facilitately and D1/5 receptors inhibitorily. In addition, the cerebellar D3 receptors may play an important role in modulating the induction of nicotine tremor mediated by the olivo-cerebellar system.

Social dysfunction is one of the most debilitating aspects of schizophrenia. Treatment of this complex phenomenon, constituted by negative, cognitive, and affective symptoms, has been difficult with the available pharmacological agents, hence it represents an unmet medical need. Cariprazine, a novel, third-generation antipsychotic with a unique mechanism of action has been proven to sufficiently alleviate negative, cognitive, and affective symptoms of schizophrenia. These characteristics make this compound a valid candidate for addressing social dysfunction too. In this perspective, we argue that cariprazine can be viewed as a "socializing drug" that has the ability to improve the patient's functionality and ultimately their quality of life. Data from animal research, clinical trials, an observational study, and patient cases are provided. [ABSTRACT FROM AUTHOR]

Social dysfunction is one of the most debilitating aspects of schizophrenia. Treatment of this complex phenomenon, constituted by negative, cognitive, and affective symptoms, has been difficult with the available pharmacological agents, hence it represents an unmet medical need. Cariprazine, a novel, third-generation antipsychotic with a unique mechanism of action has been proven to sufficiently alleviate negative, cognitive, and affective symptoms of schizophrenia. These characteristics make this compound a valid candidate for addressing social dysfunction too. In this perspective, we argue that cariprazine can be viewed as a “socializing drug” that has the ability to improve the patient's functionality and ultimately their quality of life. Data from animal research, clinical trials, an observational study, and patient cases are provided.

Autism spectrum disorders (ASD) are a group of disorders characterized by impairment in social communication and repetitive and stereotyped behaviors. ASD etiology is very complex, including the effect of both genetic and environmental factors. So far, no specific treatment for the core symptoms of ASD has been developed, although attempts have been made for the treatment of repetitive behavior. The pharmacological treatment is aimed at treating non-specific symptoms such as irritability and aggression. Recent studies pointed out to the possible role of altered dopamine signaling in mesocorticolimbic and nigrostriatal circuits in ASD. In addition, several research pointed out to the association of dopamine receptors polymorphism and ASD, specifically repetitive and stereotyped behavior. In this paper, we will provide a review of the studies regarding dopamine signaling in ASD, existing data on the effects of D2/D3 partial agonists in ASD, possible implications regarding their individual receptor profiles, and future perspectives of their possible use in ASD treatment. [ABSTRACT FROM AUTHOR]

Autism spectrum disorders (ASD) are a group of disorders characterized by impairment in social communication and repetitive and stereotyped behaviors. ASD etiology is very complex, including the effect of both genetic and environmental factors. So far, no specific treatment for the core symptoms of ASD has been developed, although attempts have been made for the treatment of repetitive behavior. The pharmacological treatment is aimed at treating non-specific symptoms such as irritability and aggression. Recent studies pointed out to the possible role of altered dopamine signaling in mesocorticolimbic and nigrostriatal circuits in ASD. In addition, several research pointed out to the association of dopamine receptors polymorphism and ASD, specifically repetitive and stereotyped behavior. In this paper, we will provide a review of the studies regarding dopamine signaling in ASD, existing data on the effects of D2/D3 partial agonists in ASD, possible implications regarding their individual receptor profiles, and future perspectives of their possible use in ASD treatment.

Development of medications selective for dopamine D2 or D3 receptors is an active area of research in numerous neuropsychiatric disorders including addiction and Parkinson’s disease. The positron emission tomography (PET) radiotracer [11C]-(+)-PHNO, an agonist that binds with high affinity to both D2 and D3 receptors, has been used to estimate relative receptor subtype occupancy by drugs based on a priori knowledge of regional variation in the expression of D2 and D3 receptors. The objective of this work was to use a data-driven independent component analysis (ICA) of receptor blocking scans to separate D2-and D3-related signal in [11C]-(+)-PHNO binding data in order to improve the precision of subtype specific measurements of binding and occupancy. Eight healthy volunteers underwent [11C]-(+)-PHNO PET scans at baseline and at two time points following administration of the D3-preferring antagonist ABT-728 (150–1000 ​mg). Parametric binding potential (BPND) images were analyzed as four-dimensional image series using ICA to extract two independent sources of variation in [11C]-(+)-PHNO BPND. Spatial source maps for each component were consistent with respective regional patterns of D2-and D3-related binding. ICA-derived occupancy estimates from each component were similar to D2-and D3-specific occupancy estimated from a region-based approach (intraclass correlation coefficients ​> ​0.95). ICA-derived estimates of D3 receptor occupancy improved quality of fit to a single site binding model. Furthermore, ICA-derived estimates of the regional fraction of [11C]-(+)-PHNO binding related to D3 receptors was generated for each subject and values showed good agreement with region-based model estimates and prior literature values. In summary, ICA successfully separated D2-and D3-related components of the [11C]-(+)-PHNO binding signal, establishing this approach as a powerful data-driven method to quantify distinct biological features from PET data composed of mixed data sources. Editor highlights: • ICA of [11C]-(+)-PHNO PET competition binding data with a D3-selective drug. • Produced individual maps of D2-and D3-receptor binding patterns. • More precise D3 occupancy and EC50 estimates compared to conventional methods. • ICA offers a data-driven method to separate signals from multi-target PET tracers.

Background: We recently showed that striatal overexpression of brain derived neurotrophic factor (BDNF) by adeno-associated viral (AAV) vector exacerbated L-DOPA-induced dyskinesia (LID) in 6-OHDA-lesioned rats. An extensive sprouting of striatal serotonergic terminals accompanied this effect, accounting for the increased susceptibility to LID. Objective: We set to investigate whether the BDNF effect was restricted to LID, or extended to dyskinesia induced by direct D1 receptor agonists. Methods: Unilaterally 6-OHDA-lesioned rats received a striatal injection of an AAV vector to induce BDNF or GFP overexpression. Eight weeks later, animals received daily treatments with a low dose of SKF82958 (0.02 mg/kg s.c.) and development of dyskinesia was evaluated. At the end of the experiment, D1 and D3 receptors expression levels and D1 receptor-dependent signaling pathways were measured in the striatum. Results: BDNF overexpression induced significant worsening of dyskinesia induced by SKF82958 compared to the GFP group and increased the expression of D3 receptor at striatal level, even in absence of pharmacological treatment; by contrast, D1 receptor levels were not affected. In BDNF-overexpressing striata, SKF82958 administration resulted in increased levels of D1–D3 receptors co-immunoprecipitation and increased phosphorylation levels of Thr34 DARPP-32 and ERK1/2. Conclusion: Here we provide evidence for a functional link between BDNF, D3 receptors and D1–D3 receptor close interaction in the augmented susceptibility to dyskinesia in 6-OHDA-lesioned rats. We suggest that D1–D3 receptors interaction may be instrumental in driving the molecular alterations underlying the appearance of dyskinesia; its disruption may be a therapeutic strategy for treating dyskinesia in PD patients. [ABSTRACT FROM AUTHOR]

Dopamine D3R are widely expressed in basal ganglia where interact with D1R. D3R potentiate cAMP accumulation and GABA release stimulated by D1R in striatonigral neurons through "atypical" signaling. During dopaminergic denervation, D3R signaling changes to a "typical" in which antagonizes the effects of D1R, the mechanisms of this switching are unknown. D3nf splice variant regulates membrane anchorage and function of D3R and decreases in denervation; thus, it is possible that D3R signaling switching correlates with changes in D3nf expression and increases of membranal D3R that mask D3R atypical effects. We performed experiments in unilaterally 6‐hydroxydopamine lesioned rats and found a decrease in mRNA and protein of D3nf, but not of D3R in the denervated striatum. Proximity ligation assay showed that D3R‐D3nf interaction decreased after denervation, whereas binding revealed an increased Bmax in D3R. The new D3R antagonized cAMP accumulation and GABA release stimulated by D1R; however, in the presence of N‐Ethylmaleimide (NEM), to block Gi protein signaling, activation of D3R produced its atypical signaling stimulating D1R effects. Finally, we investigated if the typical and atypical effects of D3R modulating GABA release are capable of influencing motor behavior. Injections of D3R agonist into denervated nigra decreased D1R agonist‐induced turning behavior but potentiated it in the presence of NEM. Our data indicate the coexistence of D3R typical and atypical signaling in striatonigral neurons during denervation that correlated with changes in the ratio of expression of D3nf and D3R isoforms. The coexistence of both atypical and typical signaling during denervation influences motor behavior. [ABSTRACT FROM AUTHOR]

Dopamine (DA) modulates basal ganglia (BG) activity for initiation and execution of goal-directed movements and habits. While most studies are aimed to striatal function, the cellular and molecular mechanisms underlying dopaminergic regulation in other nuclei of the BG are not well understood. Therefore, we set to analyze the dopaminergic modulation occurring in subthalamo-nigral synapse, in both pars compacta (SNc) and pars reticulata (SNr) neurons, because these synapses are important for the integration of information previously processed in striatum and globus pallidus. In this study, electrophysiological and pharmacological evidence of dopaminergic modulation on glutamate release through calcium channels is presented. Using paired pulse ratio (PPR) measurements and selective blockers of these ionic channels, together with agonists and antagonists of DA D2-like receptors, we found that blockade of the CaV3 family occludes the presynaptic inhibition produced by the activation of DA receptors pharmacologically profiled as D3-type in the STh-SNc synapses. On the contrast, the blockade of CaV2 channels, but not CaV3, occlude with the effect of the D3 agonist, PD 128907, in the STh-SNr synapse. The functional role of this differential distribution of calcium channels that modulate the release of glutamate in the SN implies a fine adjustment of firing for both classes of neurons. Dopaminergic neurons of the SNc establish a DA tone within the SN based on the excitatory/inhibitory inputs; such tone may contribute to processing information from subthalamic nucleus and could also be involved in pathological DA depletion that drives hyperexcitation of SNr neurons. [ABSTRACT FROM AUTHOR]

Rationale: Nucleus accumbens (NAc) dopamine (DA) plays an integral role in overcoming effort costs, as blockade of D1 and D2 receptors reduces the choice of larger, more-costly rewards. Similarly, the stress neuropeptide corticotropin-releasing factor (CRF) modulates DA transmission and mediates stress-induced alterations in effort-related choice. Objectives: The current study explored how excessive stimulation of different DA receptors within the NAc core and shell alters effort-related decision-making and compared these effects to those induced by CRF stimulation. Methods: Male Long Evans rats were well-trained on an effort-discounting task wherein they choose between a low-effort/low-reward and a high-effort/high-reward lever where the effort requirement increased over blocks (2–20 presses). Dopamine D1 (SKF 81297, 0.2–2 μg), D2/3 (quinpirole, 1–10 μg), or D3 (PD 128,907, 1.5–3 μg) receptor agonists, or CRF (0.5 μg), were infused into the NAc core or shell prior to testing. Results: Stimulation of D2/3 receptors with quinpirole in the NAc core or shell markedly reduced the choice of high-effort option and increase choice latencies, without altering preference for larger vs smaller rewards. Stimulation of D1 or D3 receptors did not alter choice, although SKF 81297 infusions into the shell reduced response vigor. In comparison, core infusions of CRF flattened the discounting curve, reducing effortful choice when costs were low and increasing it when costs were high. Conclusions: Excessive stimulation of NAc D2 receptors has detrimental effects on effort-related decision-making. Furthermore, CRF stimulation induces dissociable effects on decision-making compared with those induced the effects of stimulation of different DA receptors. [ABSTRACT FROM AUTHOR]

Substantia nigra pars reticulata is the output station in basal ganglia; its GABAergic neurons control the activity of thalamo-cortical premotor nuclei, thus controlling motor behavior. D1-like and D2-like presynaptic dopamine receptors on subthalamo-nigral afferents by modulation of glutamate release change the firing rate of nigral neurons; however, their relative contribution to the control of glutamate release and their pharmacological properties have not been studied. This is important since the prevalence of the inhibition or stimulation of release determines the firing rate of nigral neurons, therefore motor activity. Here we used depolarization induced [3H]-glutamate release in slices of rat substantia nigra from reserpinized and non-reserpinized rats to explore the relative contribution of the D1-like and D2-like receptor subtypes to the control of glutamate release. We found a significant control of release by D1-like and D3R, and a modest effect of D2R. D4R exerted no effect. Dopamine showed more potency for D3R than for D1-like receptors; however, these latter enhanced release to a greater degree, as shown by the E max. We also co-activated these to test their interaction; an antagonist interaction of D1-like with D2 and D3R, and an additive between D2 and D3R were found. Pharmacological receptor antagonist effects in release from reserpinized vs. non-reserpinized slices were similar, suggesting that endogenous dopamine stimulates receptors in the same way. These findings suggest differences in the control of glutamate release by different dopamine receptors in the substantia nigra, which could contribute to explaining the effect of dopamine and its agonists on motor behavior. Unlabelled Image • D1-like, D2 and D3 but not D4 dopamine receptors modulate glutamate release in the substantia nigra pars reticulata. • The main control is exerted by D1-like receptors and D3Rs. • D1-like receptors and D3Rs have an antagonist interaction in the control of glutamate release. • Dopamine has higher EC 50 for D3 receptors than for D1-like receptors, but D1-like receptors have higher effect on glutamate release. [ABSTRACT FROM AUTHOR]

Highlights • Method to assess in vivo selectivity of ligands targeting dopamine D3 receptors. • Understanding differences between D3 and D2 circuitry is important. • D3 receptor probe development has been challenging due to similarities with D2. Abstract Dopamine D3 receptors have key roles in behavioral reward, addiction, Parkinson's disease, and schizophrenia, and there is interest in studying their role in these disorders using PET. However, current PET radiotracers for studying D3 receptors in humans all bind to both D2 and D3 due to similarities between the two receptors. Selective D2 and D3 radioligands would aid investigation of the differences between D2 and D3 circuitry in the central nervous system. While there are currently in vitro measures of ligand D3/D2 selectivity, there is a need for an in vivo PET measure of D3/D2 selectivity. This review discusses current PET imaging of dopamine D2/D3 receptors and proposes methodology for quantitating in vivo selectivity of probes for PET imaging of dopamine D3 receptors. [ABSTRACT FROM AUTHOR]

Abstract Despite extensive research, the neurobiological risk factors that convey vulnerability to opioid abuse are still unknown. Recent studies suggest that the dopamine D3 receptor (D3R) is involved in opioid self-administration, but it remains unclear whether altered D3R availability is a risk factor for the development of opioid abuse and addiction. Here we used dopamine D3 receptor-knockout (D3-KO) mice to investigate the role of this receptor in the different phases of opioid addiction. D3-KO mice learned to self-administer heroin faster and took more heroin than wild-type mice during acquisition and maintenance of self-administration. D3R-KO mice also displayed higher motivation to work to obtain heroin reward during self-administration under progressive-ratio reinforcement, as well as elevated heroin-seeking during extinction and reinstatement testing. In addition, deletion of the D3R induced higher baseline levels of extracellular dopamine (DA) in the nucleus accumbens (NAc), higher basal levels of locomotion, and reduced NAc DA and locomotor responses to lower doses of heroin. These findings suggest that the D3R is critically involved in regulatory processes that normally limit opioid intake via DA-related mechanisms. Deletion of D3R augments opioid-taking and opioid-seeking behaviors. Therefore, low D3R availability in the brain may represent a risk factor for the development of opioid abuse and addiction. Highlights • Deletion of D3Rs increased heroin self-administration and heroin intake. • Deletion of D3Rs increased motivation for heroin during PR self-administration. • Deletion of D3Rs increased basal levels of NAc extracellular DA and decreased DA responses to heroin. • Deletion of D3Rs increased basal levels of locomotion and decreased locomotor responses to heroin. • Reduced D3R availability in the brain may facilitate opioid abuse and addiction. [ABSTRACT FROM AUTHOR]

In the search for efficacious pharmacotherapies to treat cocaine addiction much attention has been given to agents targeting dopamine D1 or D3 receptors because of the involvement of these receptors in drug-related behaviors. D1-like and D3 receptor partial agonists and antagonists have been shown to reduce drug reward, reinstatement of drug seeking and conditioned place preference in rodents and non-human primates. However, translation of these encouraging results to clinical settings has been limited due to a number of factors including toxicity, poor pharmacokinetic properties and extrapyramidal and sedative side effects. This review highlights the role of D1 and D3 receptors in drug reward and seeking, the discovery of D1-D3 heteromers and their potential as targets in the treatment of addiction. [ABSTRACT FROM AUTHOR]

The dopamine D2‐like receptors (ie, D2/3 receptors) have been the most extensively studied CNS receptor with Positron Emission Tomography (PET). The 3 different radiotracers that have been used in these studies are [11C]raclopride, [18F]fallypride, and [11C]PHNO. Because these radiotracers have a high affinity for both dopamine D2 and D3 receptors, the density of dopamine receptors in the CNS is reported as the D2/3 binding potential, which reflects a measure of the density of both receptor subtypes. Although the development of D2‐ and D3‐selective PET radiotracers has been an active area of research for many years, this by and large presents an unmet need in the area of translational PET imaging studies. This article discusses some of the challenges that have inhibited progress in this area of research and the current status of the development of subtype selective radiotracers for imaging D3 and D2 dopamine receptors with PET. [ABSTRACT FROM AUTHOR]

In vivo activation of dopamine D3 receptors (D3Rs) depresses motor activity. D3Rs are widely expressed in subthalamic, striatal, and dendritic dopaminergic inputs into the substantia nigra pars reticulata (SNr). In vitro studies showed that nigral D3Rs modulate their neurotransmitter release; thus, it could be that these changes in neurotransmitter levels modify the discharge of nigro-thalamic neurons and, therefore, motor behavior. To determine how the in vitro responses correspond to the in vivo responses, we examined the effect of intra-nigral and systemic blockade of D3Rs in the interstitial content of glutamate, dopamine, and GABA within the SNr using microdialysis coupled to motor activity determinations in freely moving rats. Intranigral unilateral blockade of D3R with GR 103,691 increased glutamate, dopamine, and GABA. Increments correlated with increased ambulatory distance, non-ambulatory activity, and induced contralateral turning. Concomitant blockade of D3R with D1R by perfusion of SCH 23390 reduced the increase of glutamate; prevented the increment of GABA, but not of dopamine; and abolished behavioral effects. Glutamate stimulates dopamine release by NMDA receptors, while blockade with kynurenic acid prevented the increase in dopamine and, in turn, of GABA and glutamate. Finally, systemic administration of D3R selective antagonist U 99194A increased glutamate, dopamine, and GABA in SNr and stimulated motor activity. Blockade of intra-nigral D1R with SCH 23390 prior to systemic U 99194A diminished increases in neurotransmitter levels and locomotor activity. These data highlight the pivotal role of presynaptic nigral D3 and D1R in the control of motor activity and help to explain part of the effects of the in vivo administration of D3R agents.

Cognitive deficits in depression can be modelled using the novel object recognition (NOR) test, performance in which is impaired by chronic mild stress (CMS). We aimed to examine the involvement of mesocorticolimbic DA terminal regions, and to establish the substrate for CMS-induced impairment of NOR and its reversal by chronic antidepressant treatment. In experiments 1 and 2, we examined the effect of infusions into medial PFC, dorsal hippocampus (HPC), and nucleus accumbens (NAc) shell of D1 and D2 antagonists and D3 agonist, which were predicted to impair NOR with a short (1 h) delay, and of D1 and D2 agonists and D3 antagonist, which were predicted to facilitate NOR with a long (24 h) delay. Using optimal doses identified in experiment 2, in experiments 3 and 4, we examined effects on drug-stimulated NOR of CMS and chronic treatment with venlafaxine (VFX) or risperidone (RSP). We found a wide involvement of DA systems in memory for NOR: D1 receptors in PFC, HPC, and NAc; D3 receptors in PFC and HPC; and D2 receptors in PFC. CMS impaired D2- and D3-mediated effects in PFC and HPC; antidepressants rescued those effects in PFC but not HPC. The involvement of DA in NOR is multifaceted, but the effects of CMS and antidepressants are more discrete, involving D2 and D3 receptors in PFC specifically. While raising many difficult questions, these results suggest that the D2 and D3 receptors in the medial PFC may be an important substrate for cognitive deficits in depression and their remediation. [ABSTRACT FROM AUTHOR]

Dopamine and the endocannabinoids, anandamide and 2-arachidonoylglycerol, interact at several levels in the brain, with the involvement of both cannabinoid CB1 receptors and transient receptor potential vanilloid type-1 (TRPV1) channels (which are alternative anandamide receptors). Using pharmacological, immunohistochemical and analytical approaches, we investigated the response of dopamine D3 receptor null (D3R(−/−)) mice in models of epilepsy and anxiety, in relation to their brain endocannabinoid and endovanilloid tone. Compared to wild-type mice, D3R(−/−) mice exhibited a delayed onset of clonic seizures, enhanced survival time, reduced mortality rate and more sensitivity to anticonvulsant effects of diazepam after intraperitoneal administration of picrotoxin (7 mg/kg), and a less anxious-like behaviour in the elevated plus maze test. D3R(−/−) mice also exhibited different endocannabinoid and TRPV1, but not CB1, levels in the hippocampus, nucleus accumbens, amygdala and striatum. Given the role played by CB1 and TRPV1 in neuroprotection and anxiety, and based on data obtained here with pharmacological tools, we suggest that the alterations of endocannabinoid and endovanilloid tone found in D3R(−/−) mice might account for part of their altered responses to excitotoxic and anxiogenic stimuli.

Chronic exposure to cannabinoids during adolescence results in long-lasting behavioral deficits that match some symptomatologic aspects of schizophrenia. The aim of this study was to investigate the reversibility of the emotional and the cognitive effects of chronic exposure to cannabinoids during adolescence, via subsequent modulation of the serotoninergic 5-HT4 and dopaminergic D3 receptors. RS67333 as a 5-HT4 agonist and U-99194A as a D3 antagonist were administered separately at 1 mg/kg and 20 mg/kg, and in combination at 0.5 mg/kg and 10 mg/kg to adult animals undergoing chronic treatment with the synthetic cannabinoid receptor agonist WIN55,212-2 (1 mg/kg) during adolescence. Animals were tested for anxiety-like behavior and episodic-like memory in the open field and novel object recognition tests respectively 30 minutes after the last drug administration. Chronic WIN55,212-2 treated animals exhibited a lasting disruption of episodic memory and increased anxiety levels. The effect on episodic-like memory were partially restored by acute administration of RS67333 and U-99194A and completely by administration of both drugs in combination at lower doses. However, only RS67333 (20 mg/kg) improved the anxiogenic-like effect of WIN55,212-2. These findings give further support that chronic exposure to cannabinoids during adolescence may be used as an animal model for schizophrenia, and highlight D3 and 5-HT4 receptors as potential targets for an enhanced treatment of the cognitive aspect of this disease. [ABSTRACT FROM AUTHOR]

Abstract: Preclinical studies suggest that dopamine D3 receptor (D3R) antagonists are promising for the treatment of drug abuse and addiction. However, few D3R antagonists have potential to be tested in humans due to short half-life, toxicity or limited preclinical research into pharmacotherapeutic efficacy. Here, we report on a novel D3R antagonist YQA14, which has improved half-life and pharmacokinetic profile and which displays potent pharmacotherapeutic efficacy in attenuating cocaine reward and relapse to drug-seeking behavior. Electrical brain-stimulation reward (BSR) in laboratory animals is a highly sensitive experimental approach to evaluate a drug's rewarding effects. We found that cocaine (2 mg/kg) significantly enhanced electrical BSR in rats (i.e., decreased stimulation threshold for BSR), while YQA14 alone had no effect on BSR. Pretreatment with YQA14 significantly and dose-dependently attenuated cocaine-enhanced BSR. YQA14 also facilitated extinction from drug-seeking behavior in rats during early behavioral extinction, and attenuated cocaine- or contextual cue-induced relapse to drug-seeking behavior. YQA14 alone did not maintain self-administration in either naïve rats or in rats experienced at cocaine self-administration. YQA14 also inhibited expression of repeated cocaine-induced behavioral sensitization. These findings suggest that YQA14 may have pharmacotherapeutic potential in attenuating cocaine-taking and cocaine-seeking behavior. Thus, YQA14 deserves further investigation as a promising agent for treatment of cocaine addiction. [Copyright &y& Elsevier]

BACKGROUND AND PURPOSE Disturbed cortical gamma band oscillations (30-80 Hz) have been observed in schizophrenia: positive symptoms of the disease correlate with an increase in gamma oscillation power, whereas negative symptoms are associated with a decrease. EXPERIMENTAL APPROACH Here we investigated the effects of first and second generation antipsychotics (FGAs and SGAs, respectively) on gamma oscillations. The FGAs haloperidol, flupenthixol, chlorpromazine, chlorprothixene and the SGAs clozapine, risperidone, ziprasidone, amisulpride were applied on gamma oscillations induced by acetylcholine and physostigmine in the CA3 region of rat hippocampal slices. KEY RESULTS Antipsychotics inhibited the power of gamma oscillations and increased the bandwidth of the gamma band. Haloperidol and clozapine had the highest inhibitory effects. To determine which receptor is responsible for the alterations in gamma oscillations, the effects of the antipsychotics were plotted against their p Ki values for 19 receptors and analysed for correlation. Our results indicated that 5-HT3 receptors have an enhancing effect on gamma oscillations whereas dopamine D3 receptors inhibit them. To test this prediction, m-chlorophenylbiguanide, PD 128907 and CP 809101, selective agonists at 5-HT3, D3 and 5-HT2C receptors were applied and revealed that 5-HT3 receptors indeed enhanced the gamma power whereas D3 receptors reduced it. As predicted, 5-HT2C receptors had no effects on gamma oscillations. CONCLUSION AND IMPLICATIONS Our data suggest that antipsychotics alter hippocampal gamma oscillations by interacting with 5-HT3 and dopamine D3 receptors. Moreover, a correlation of receptor affinities with the biological effects can be used to predict targets for the pharmacological effects of multi-target drugs. [ABSTRACT FROM AUTHOR]

Dopamine D3 receptors are densely expressed in mesolimbic projection areas, and selective antagonists enhance cognition, consistent with their potential therapeutic use in the treatment of schizophrenia. This study examines the effect of dopamine D3vs. D2 receptor antagonists on the cognitive impairment and hyperactivity produced by social isolation of rat pups, in a neurodevelopmental model of certain deficits of schizophrenia. Three separate groups of male Lister hooded rats were group-housed or isolation-reared from weaning. Six weeks later rats received either vehicle or the dopamine D3 selective antagonist, S33084 (0.04 and 0.16 mg/kg), the preferential D3 antagonist, S33138 (0.16 and 0.63 mg/kg) or the preferential D2 antagonist, L-741,626 (0.63 mg/kg) s.c. 30 min prior to recording; horizontal locomotor activity in a novel arena for 60 min and, the following day, novel object discrimination using a 2-h inter-trial interval. Isolation rearing induced locomotor hyperactivity in a novel arena and impaired novel object discrimination compared to that in group-housed littermates. Both S33084 and S33138 restored novel object discrimination deficits in isolation-reared rats without affecting discrimination in group-housed controls. By contrast, L-741,626 impaired novel object discrimination in group-housed rats, without affecting impairment in isolates. S33084 (0.16 mg/kg), S33138 and, less markedly, L741,626 reduced the locomotor hyperactivity in isolates without attenuating activity in group-housed controls. Selective blockade of dopamine D3 receptors reverses the visual recognition memory deficit and hyperactivity produced by isolation rearing. These data support further investigation of the potential use of dopamine D3 receptor antagonists to treat schizophrenia. [ABSTRACT FROM AUTHOR]

Abstract: Most antipsychotics are thought to have an effect on D2 and D3 receptors, although their D3, versus D2 binding has not been clearly established in vivo in humans. However, the development of [11C]-(+)-PHNO now permits the differentiation of antipsychotic activity on these two receptor subtypes. In this study we examined the effects of antipsychotics on D2 and D3 receptors by comparing [11C]-(+)-PHNO in D2-rich (caudate, CAU and putamen, PUT), mixed (ventral striatum) and D3-rich (globus-pallidus, GP and substantia nigra, SN) regions before and after the initiation of antipsychotic medication. The investigation therefore represents a longitudinal within-subject follow-up design wherein antipsychotic-naive patients with schizophrenia spectrum disorders were first scanned in a drug-naïve state and then again after ~2.5weeks of antipsychotic treatment (risperidone or olanzapine). Binding potential (non displaceable or BPND) was obtained to derive estimates of drug occupancy in the identified brain regions. Antipsychotic treatment was associated with the expected occupancies in the D2-rich regions; unexpectedly though, patients showed a higher, rather than the expected lower, [11C]-(+)-PHNO BPND in the GP and SN despite simultaneous evidence for ongoing D2 blockade in the other regions (CAU and PUT). In conclusion, patients treated with atypical antipsychotics demonstrated no evidence of D3 receptor occupancy, but instead possible D3 up-regulation following short-term treatment. The present findings add to a very limited body of evidence related to D3 binding in vivo. [11C]-(+)-PHNO offer new opportunities for exploring the potential therapeutic significance of the D3 receptor in schizophrenia and the action of antipsychotics. [Copyright &y& Elsevier]

Abstract: Introduction: Four benzamide analogs having a high affinity and selectivity for D3 versus D2 receptors were radiolabeled with 11C or 18F for in vivo evaluation. Methods: Precursors were synthesized, and the four D3 selective benzamide analogs were radiolabeled. The tissue distribution and brain uptake of the four compounds were evaluated in control rats and rats pretreated with cyclosporin A, a modulator of P-glycoprotein and an inhibitor of other ABC efflux transporters that contribute to the blood brain barrier. Micro-positron emission tomographic (PET) imaging was carried out for [11C]6 in a control and a cyclosporin A pretreated rat. Results: All four compounds showed low brain uptake in control rats at 5 and 30 min post-injection; despite recently reported rat behavioral studies conducted on analogs 6 (WC-10) and 7 (WC-44). Following administration of cyclosporin A, increased brain uptake was observed with all four PET radiotracers at both 5 and 30 min post-intravenous injection. An increase in brain uptake following modulation/inhibition of the ABC transporters was also observed in the microPET study. Conclusions: These data suggest that D3 selective conformationally-flexible benzamide analogs which contain a N-2-methoxyphenylpiperazine moiety are substrates for P-glycoprotein or other adenosine triphosphate (ATP)-binding cassette transporters expressed at the blood-brain barrier, and that PET radiotracers containing this pharmacophore may display low brain uptake in rodents due to the action of these efflux transporters. [Copyright &y& Elsevier]

Abstract: Memories of learned associations between the rewarding properties of drugs and environmental cues contribute to craving and relapse in humans. The mesocorticolimbic dopamine (DA) system is involved in reward-related learning induced by drugs of abuse. DA D3 receptors are preferentially expressed in mesocorticolimbic DA projection areas. Genetic and pharmacological studies have shown that DA D3 receptors suppress locomotor-stimulant effects of cocaine and reinstatement of cocaine-seeking behaviors. Activation of the extracellular signal-regulated kinase (ERK) induced by acute cocaine administration is also inhibited by D3 receptors. How D3 receptors modulate cocaine-induced reward-related learning and associated changes in cell signaling in reward circuits in the brain, however, have not been fully investigated. In the present study, we show that D3 receptor mutant mice exhibit potentiated acquisition of conditioned place preference (CPP) at low doses of cocaine compared to wild-type mice. Activation of ERK and CaMKIIα, but not the c-Jun N-terminal kinase and p38, in the nucleus accumbens, amygdala and prefrontal cortex is also potentiated in D3 receptor mutant mice compared to that in wild-type mice following CPP expression. These results support a model in which D3 receptors modulate reward-related learning induced by low doses of cocaine by inhibiting activation of ERK and CaMKIIα in reward circuits in the brain. [Copyright &y& Elsevier]

Abstract: Dopamine and the endocannabinoids, anandamide and 2-arachidonoylglycerol, interact at several levels in the brain, with the involvement of both cannabinoid CB1 receptors and transient receptor potential vanilloid type-1 (TRPV1) channels (which are alternative anandamide receptors). Using pharmacological, immunohistochemical and analytical approaches, we investigated the response of dopamine D3 receptor null (D3R(−/−)) mice in models of epilepsy and anxiety, in relation to their brain endocannabinoid and endovanilloid tone. Compared to wild-type mice, D3R(−/−) mice exhibited a delayed onset of clonic seizures, enhanced survival time, reduced mortality rate and more sensitivity to anticonvulsant effects of diazepam after intraperitoneal administration of picrotoxin (7 mg/kg), and a less anxious-like behaviour in the elevated plus maze test. D3R(−/−) mice also exhibited different endocannabinoid and TRPV1, but not CB1, levels in the hippocampus, nucleus accumbens, amygdala and striatum. Given the role played by CB1 and TRPV1 in neuroprotection and anxiety, and based on data obtained here with pharmacological tools, we suggest that the alterations of endocannabinoid and endovanilloid tone found in D3R(−/−) mice might account for part of their altered responses to excitotoxic and anxiogenic stimuli. [Copyright &y& Elsevier]

Abstract: Bifeprunox and aripiprazole are two novel antipsychotics presenting partial agonistic activity for the D2 and D3 dopamine (DA) receptors. Using in vivo electrophysiological paradigms in anaesthetized rats, we have previously shown that both drugs independently inhibit the spontaneous firing and bursting activity of ventral tegmental area (VTA) dopaminergic neurons and partially reverse the suppressing effect of the full DA receptor agonist apomorphine. Moreover, we have also shown that the D2/3 receptor antagonist haloperidol prevents the inhibitory effects of these antipsychotics, confirming their partial D2-like agonistic activities [L. Dahan, H. Husum, O. Mnie-Filali, J. Arnt, P. Hertel, N. Haddjeri, Effects of bifeprunox and aripiprazole on rat serotonin and dopamine neuronal activity and anxiolytic behaviour, J. Psychopharmacol. (2009)]. In the present electrophysiological study, selective antagonists of D2 and D3 receptors were used to further characterize the inhibitory role of bifeprunox and aripiprazole on the D2 and D3 receptors in vivo. Administration of bifeprunox (250μg/kg, i.v.) or aripiprazole (300μg/kg, i.v.) reduced the firing activity of VTA DA neurons by 40–50%. The bursting activity was reduced by 95% and 77% by bifeprunox and aripiprazole, respectively. Systemic administration of the preferential D3 receptor antagonist GR218,231 (200μg/kg, i.v.) did not modify the inhibitory effect of bifeprunox or aripiprazole, either on the firing or on the bursting activity. On the other hand, the preferential D2 receptor antagonist L741,626 (500μg/kg, i.v.) completely blocked the inhibitory effect of both bifeprunox and aripiprazole on the VTA DA neuronal activity. The present study shows that bifeprunox and aripiprazole behave as partial D2, but not D3, receptor agonists in vivo, inhibiting the firing activity (preferentially the phasic activity) of VTA DA cells. [Copyright &y& Elsevier]

Abstract: Starting with the preferential dopamine (DA) D3 agonist S32504, we prepared two series of derivatives of the general formula I-A and I-B, in an effort to improve both potency and selectivity. For the first set of derivatives, where the primary amide function of S32504 was replaced by either secondary and tertiary amide or ester, acid, nitrile and ketone, no improvement was obtained. Conversely, when the primary amide function was integrated in a lactam ring, an enhancement of affinity and selectivity was attained for the five-membered ring lactam but also for its five-membered ring lactone analogue. [Copyright &y& Elsevier]

Abstract: In the search for compounds with potential for development as positron emission tomography radioligands for brain D3 receptor imaging, a series of N-[4-(4-arylpiperazin-1-yl)butyl]arylcarboxamides with appropriate lipophilicity (2

A solid phase parallel synthesis using SynPhase™ technology was used to couple a series of 21 carboxylic with three different 4-(4-arylpiperazinyl)butanamines. The resulting library was evaluated as dopamine D3 receptor ligands giving rise to several compounds with affinities in the low nanomolar concentration range (9e and 9n with binding affinities at D3 receptors of 0.10 and 0.35 nM respectively). [ABSTRACT FROM AUTHOR]

Abstract: There has been considerable interest in the role of dopamine D3 receptors in appetitive conditioning but few studies have examined their role in aversive conditioning. The present study examined the effect of the dopamine D3 receptor-preferring partial agonist BP 897 (1-(4-(2-naphthoyl-amino)butyl)-4-(2-methoxyhenyl)-1A-piperazine hydrochloride) and the selective dopamine D3 receptor antagonist SB-277011A (trans-N-[4-[2-(6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]syclohexyl]4-quinolininecarboxamide]) on the expression and acquisition of fear conditioning. Rats (N =143) received 3 conditioned stimulus–shock pairings and then received 15 conditioned stimulus-alone presentations (3 per day) while lever pressing for food. Response suppression was taken as the behavioral measure of fear. Rats showed strong suppression to the conditioned stimulus after it had been paired with shock and suppression progressively weakened over conditioned stimulus-alone presentations. In experiment 1, rats that received BP 897 (1.0, 2.0 mg/kg i.p.) or SB-277011A (10.0 mg/kg i.p.) prior to conditioned stimulus-alone presentation sessions showed reduced suppression to the conditioned stimulus as compared to rats that received vehicle or lower doses of drug (0, 0.1 mg/kg BP 897; 0, 0.5, 5.0 mg/kg SB-277011A). Injections of BP 897 (1.0, 2.0 mg/kg) or SB-277011A (10.0 mg/kg) prior to conditioned stimulus–shock pairings did not significantly affect subsequent response suppression. Thus, BP 897 and SB-277011A dose-dependently attenuated the expression but not the acquisition of conditioned fear. These findings suggest that BP 897 and SB-277011A reduce the control of responding by aversively conditioned stimuli. [Copyright &y& Elsevier]

The inbred Roman high- (RHA-I) and low-avoidance (RLA-I) rats, differing in dopaminergic activity and novelty/substance-seeking profiles, may be a suitable model to study the implication of the dopaminergic system in vulnerability to drug abuse. Differences in D3 receptor binding recently described between the two strains (Guitart-Masip M, Johansson B, Fernández-Teruel A, Cañete T, Tobeña A, Terenius L, Giménez-Llort L, Neuroscience 142:1231–1243, 2006b) may be important in shaping the aforementioned differences in novelty seeking. The aim of the present work was to study the effect of D3 receptor activation on novelty-induced locomotor activity in these two strains of rats. We administered saline and PD-128,907 (0.01 and 0.1 mg/kg), a putative D3 receptor agonist, to the Roman rats and studied the locomotor activity when animals were placed in a novel environment. Thereafter, by means of in situ hybridization, nerve growth factor inducible clone A (NGFI-A) mRNA was measured in the striatum and the Calleja islands of these animals. We found that RLA-I rats showed stronger locomotor inhibition than RHA-I rats after PD-128,907 administration. Moreover, RLA-I rats showed stronger reduction of NGFI-A mRNA in the Calleja islands than RHA-I rats. These results, together with previous findings, suggest that differences in D3 receptor expression in the Calleja islands may contribute to the divergent behavioral effect of PD-128,907 administration in the two strains of Roman rats. [ABSTRACT FROM AUTHOR]

Previous studies have demonstrated that paradoxical sleep deprivation (PSD) potentiates cocaine-induced genital reflexes in male rats and both D1 and D2 receptors may play a role in those effects, and to examine the possibility that such might involve other dopaminergic receptors, we investigated the effects of D3 and D4 receptor subtype antagonists on cocaine-induced reflexes in sleep-deprived rats. Separate groups of PSD rats received saline, D3 (U9919A; 0.75, 1.5 and 3 mg/kg) or D4 (L745870; 0.75, 1.5 and 3 mg/kg) antagonists prior to acute cocaine challenge. Results demonstrated that U9919A induced significant reduction in the number of animals that displayed erection and the frequency of erection at two smaller doses, while no significant difference was reported for the D4 receptor antagonist. Although our studies indicate that there is a relevant participation of D3 receptors in male sexual function, D4 receptors seem not to exert an essential role in this model. [ABSTRACT FROM AUTHOR]

Emerging evidence from agonist–antagonist studies suggests a role for the dopamine D3 receptor subtype in the regulation of PPI in animals, but such evidence is lacking for human subjects. This study examines the effect of the preferential D3 agonist ropinirole on PPI in humans. PPI was tested in 12 healthy men in three sessions associated with ropinirole 0.25 mg, ropinirole 0.5 mg, or placebo according to a balanced, crossover, double-blind design. Two prepulses (75- and 85-dB white noise bursts) and two lead intervals (50 and 80 ms) were employed. Ropinirole 0.5 mg significantly reduced prepulse inhibition (PPI) with both prepulses at the 80-ms lead intervals. There was no effect of treatment on startle amplitude and habituation. These results suggest a role for the dopamine D3 receptor in the mediation of human PPI, although a contribution from ropinirole’s agonistic activity at the D2 receptor cannot be entirely excluded. Firm conclusions on the role of the D3 receptor in the modulation of human PPI can only be drawn with the use of genetic approaches or more selective ligands for this receptor. [ABSTRACT FROM AUTHOR]

Maternal deprivation and handling can lead to a vulnerability to opiate dependence. However, the involvement of the dopamine D3 receptors has not been investigated. This study analysed the effects of a selective partial D3 receptor agonist, BP 897, on morphine-conditioned place preference (CPP) in deprived and handled rats. The effects of BP 897 were studied on the expression and the extinction of morphine CPP. Quantitative autoradiography of D2, D3 receptors and immunoautoradiography of dopamine transporter were performed in some saline- and morphine-treated rats 24 h after the place preference test. Morphine (5 mg/kg) induced a more prolonged morphine CPP in deprived and handled rats than in control animals. BP 897 (0.5 or 2 mg/kg) enhanced the expression of morphine conditioning in control rats. Same doses did not change morphine conditioning in deprived rats. BP 897 (2 mg/kg) suppressed morphine CPP in handled rats. An increase in basal D2 receptor density in the mesencephalon of handled rats, which was suppressed after morphine CPP, was observed. A decrease in D2 receptor levels in morphine-treated deprived rats occurred in the nucleus accumbens. This study shows that maternal deprivation and handling induced a prolonged morphine CPP, and different changes of D2/D3 receptor functioning revealed after morphine CPP. Early manipulations of infant–mother relationships may have different consequences on the balance of opioidergic and dopaminergic neurotransmission and may be of interest to reveal pharmacological properties of dopamine receptor partial agonists or antagonists potentially useful for therapeutic applications. [ABSTRACT FROM AUTHOR]

Identification of behaviors specifically mediated by the dopamine D2 and D3 receptors would allow for the determination of in vivo receptor selectivity and aide the development of novel therapeutics for dopamine-related diseases. These studies were aimed at evaluating the specific receptors involved in the mediation of D2/D3 agonist-induced yawning and hypothermia. The relative potencies of a series of D2-like agonists to produce yawning and hypothermia were determined. The ability of D3-selective and D2-selective antagonists to inhibit the induction of yawning and hypothermia were assessed and a series of D2/D3 antagonists were characterized with respect to their ability to alter yawning induced by a low and high dose of PD-128,907 and sumanirole-induced hypothermia. D3-preferring agonists induced yawning at lower doses than those required to induce hypothermia and the D2-preferring agonist, sumanirole, induced hypothermia at lower doses than were necessary to induce yawning. The rank order of D3 selectivity was pramipexole > PD-128,907 = 7-OH-DPAT = quinpirole = quinelorane > apomorphine = U91356A. Sumanirole had only D2 agonist effects. PG01037, SB-277011A, and U99194 were all D3-selective antagonists, whereas haloperidol and L-741,626 were D2-selective antagonists and nafadotride’s profile of action was more similar to the D2 antagonists than to the D3 antagonists. D3 and D2 receptors have specific roles in the mediation of yawning and hypothermia, respectively, and the analysis of these effects allow inferences to be made regarding the selectivity of D2/D3 agonists and antagonists with respect to their actions at D2 and D3 receptors. [ABSTRACT FROM AUTHOR]

As a continuation of our work with SB-277011A, we have examined the effects of another highly elective dopamine (DA) D3 receptor antagonist, N-(4-[4-{2,3-dichlorophenyl}-1-piperazinyl]butyl)-2-fluorenylcarboxamide (NGB 2904), in animal models of addiction. Our results indicate that by systemic administration, NGB 2904 inhibits intravenous cocaine self-administration maintained under a progressive-ratio (PR) reinforcement schedule, cocaine- or cocaine cue–induced reinstatement of cocaine-seeking behavior, and cocaine- or other addictive drug-enhanced brain stimulation reward (BSR). The action of NGB 2904 on PR cocaine self-administration was long-lasting (1–2 days) after a single injection, supporting its potential use in treatment of cocaine addiction. The effects of NGB 2904 in the BSR paradigm were dose-dependent for both NGB 2904 and cocaine; that is, only lower doses of NGB 2904 were effective, and their putative antiaddiction effect could be overcome by increasing the doses of cocaine or other addictive drugs. A dopamine-dependent mechanism is proposed to explain the effects of NGB 2904 on cocaine's actions in these animal models of drug addiction. The data reviewed in this paper suggest that NGB 2904 or other D3-selective antagonists may have potential in controlling motivation for drug-taking behavior or relapse to drug-seeking behavior, but may have a limited role in antagonizing the acute rewarding effects produced by cocaine or other addictive drugs. In addition, NGB 2904 may also act as a useful tool to study the role of D3 receptors in drug addiction. [ABSTRACT FROM AUTHOR]

Drug-discrimination studies have proven instructive in the characterization of psychotropic agents, a procedure applied herein to the novel antiparkinson agent, S32504. This highly selective agonist at dopamine D3 and (less potently) D2 receptors displays potent antiparkinson, neuroprotective and antidepressant properties (Millan et al., J Pharmacol Exp Ther 309:936–950, ; Millan et al., J Pharmacol Exp Ther 309:903–920, ; Millan et al., J Pharmacol Exp Ther 309:921–935, ). To generate a discriminative stimulus (DS) with S32504 and undertake substitution/antagonism studies with diverse antiparkinson and antipsychotic agents. Using a two-lever, fixed-ratio 10 schedule, rats were trained to recognize S32504 (0.04 mg/kg, s.c.) from saline. S32504 displayed dose-dependent and stereospecific substitution in comparison to its less active racemic form, (±) S31411, and to its inactive (−) distomer, S32601. Apomorphine, and the selective D3/D2 receptor agonists, ropinirole, PD128,907, 7-OH-DPAT and CGS15855A, fully (=80%) substituted for S32504, whereas D4 and D1/D5 receptor agonists were ineffective. The selective D3 vs D2 receptor partial agonist, BP897, did not substitute for S32504 and the selective D3 receptor antagonists, S33084, SB277,011, GR218,231, PNU99194A and S14297, did not block its DS properties. By contrast, S32504 lever selection was blocked by the preferential D2 vs D3 receptor antagonists, L741,626 and S23199, and by the D2/D3 antagonists, raclopride and haloperidol. The D2/D3 receptor partial agonists and antipsychotics, aripiprazole, bifeprunox, N-desmethylclozapine and preclamol did not substitute for S32504: indeed, they dose-dependently attenuated its DS properties. The antiparkinson agent, S32504, displays DS properties principally mediated by high-efficacy activation of D2 receptors Antipsychotics known to act as partial agonists at D2/D3 receptors attenuate DS properties of S32504, actions reflecting their low efficacy at these sites. [ABSTRACT FROM AUTHOR]

The serine/threonine kinase Akt is a downstream target of dopamine receptor signaling that is inhibited/dephosphorylated in response to direct and indirect dopamine receptor agonists. Although pharmacological studies uncovered the involvement of D2-class dopamine receptors in Akt regulation, they did not identify the role of individual receptor subtypes in this process. Here we used knock-out mice lacking the D1, D2, D2 long, or D3 dopamine receptors as well as a D4 receptor-selective antagonist to address the function of each of these receptors in the regulation of Akt in vivo. Under basal conditions, D2, D2 long, and D3 knock-out mice display enhanced striatal Akt activation, whereas D1 knock-out mice and mice treated with the D4 receptor antagonist L745870 (3-[[4-(4-chlorophenyl)piperazin-1-yl]methyl]-1H-pyrrolo[2,3-b]pyridine trihydrochloride) have phospho-Akt levels comparable with those of normal control animals. Furthermore, both amphetamine and apomorphine lose their ability to inhibit Akt in D2 knock-out mice but retain their normal effect on this signaling molecule in D1 knock-out animals. Finally, D3 knock-out mice show a reduced sensitivity of Akt-mediated signaling to dopaminergic drugs but retain the action of these drugs on Akt at high dose regimens. These results indicate that D2 receptors are essential for the inhibition of Akt by dopamine and that D3 receptors also participate in this signaling potentially by enhancing D2 receptor response. Identification of the functions of individual dopamine receptor subtypes in Akt regulation may help the development of new pharmaceutical approaches for mental disorders related to abnormal dopamine transmission such as bipolar disorder and schizophrenia. [ABSTRACT FROM AUTHOR]

Abstract: FAUC346 (N-[4-[4-(2-methoxyphenyl)piperazin-1-yl]butyl]benzo[b]thiophene-2-carboxamide), an in vitro D3-selective ligand, and its normethyl derivative have been synthesized from commercially available 1-(2-substituted-phenyl)piperazines. FAUC346 has been labeled using [11C]methyl triflate in acetone containing aqueous NaOH (5 Eq) at −10 °C for 1 min, purified on semipreparative reverse-phase high-performance liquid chromatography (HPLC) and formulated as an intravenous injectable solution using a Sep-Pak Plus C18 device. Up to 5.5 GBq of [11C]FAUC346 (N-[4-[4-(2-[methyl-11C]methoxyphenyl)piperazin-1-yl]butyl]benzo[b]thiophene-2-carboxamide), with a specific radioactivity of 45–75 GBq/μmol, could be obtained in 30–35 min, including HPLC purification and formulation starting from 44.4 GBq of [11C]carbon dioxide. Preliminary pharmacological evaluation of [11C]FAUC346 in rat brain clearly demonstrated in vivo selectivity for D3 receptors and the absence of radiolabeled metabolite within the brain. These encouraging results, however, could not be confirmed in nonhuman primates; therefore, this radioligand does not appear to have the required pharmacological profile for a positron emission tomography probe for imaging D3 receptors. [Copyright &y& Elsevier]

Abstract: A variety of studies indicate that CART in the nucleus accumbens (NAcc) is involved in the action of psychostimulants. In order to understand in more detail if and how dopamine is involved in the regulation of CART mRNA in the NAcc, the present studies of individual receptors were performed. The D1 agonist, dihydrexidine, and the D1 antagonist, SCH23,390, were administered separately and in combination to adult male rats; however, no changes were found in CART mRNA as measured by in situ hybridization. The D2/3 agonist, quinpirole, was administered either separately or in combination with the D2 selective antagonist, L741,626, or the D3 selective antagonist, GR103,691. Quinpirole produced a decrease in CART mRNA of up to 43%. This effect was blocked by pretreatment with the D3 antagonist GR103, 691, but not by the D2 antagonist, L741,626. CART peptide levels showed a similar decrement after acute quinpirole. CART mRNA levels in the NAcc of D3 mutant mice were found to be higher than that in wild-type animals, but treating the mutants with quinpirole failed to produce a decrease in CART expression like that observed in wild-type rodents. These findings demonstrate that CART is regulated by dopamine in the NAcc, at least partly by D3 dopamine receptors. [Copyright &y& Elsevier]

Abstract: D3 receptor radioligands (E)-4,3,2-[11C]methoxy-N-4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl-cinnamoylamides (4-[11C]MMC, [11C]1a; 3-[11C]MMC, [11C]1b; and 2-[11C]MMC, [11C]1c) were synthesized for evaluation as novel potential positron emission tomography (PET) imaging agents for brain D3 receptors. The new tracers 4,3,2-[11C]MMCs were prepared by O-[11C]methylation of corresponding precursors (E)-4,3,2-hydroxy-N-4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl-cinnamoylamides (4,3,2-HMCs) using [11C]methyl triflate and isolated by the solid-phase extraction (SPE) purification procedure with 40–65% radiochemical yields, decay corrected to end of bombardment (EOB), and a synthesis time of 15–20min. The PET dynamic studies of the tracers [11C]1a–c in rats were performed using an animal PET scanner, IndyPET-II, developed in our laboratory. The results show that the brain uptake sequence was 4-[11C]MMC>3-[11C]MMC>2-[11C]MMC, which is consistent with their in vitro biological properties. The initial PET blocking studies of the tracers 4,3,2-[11C]MMCs with corresponding pretreatment drugs (E)-4,3,2-methoxy-N-4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl-cinnamoylamides (4,3,2-MMCs, 1a–c) had no effect on 4,3,2-[11C]MMCs-PET rat brain imaging. These results suggest that the localization of 4,3,2-[11C]MMCs in rat brain is mediated by nonspecific processes, and the visualization of 4,3,2-[11C]MMCs-PET in rat brain is related to nonspecific binding. [Copyright &y& Elsevier]

Repeat dose oral toxicity studies were conducted in rat and dog to assess the safety for human clinical testing of the potent dopamine D3 receptor antagonist, PNU-177864. Systemic phospholipidosis was the principal treatment-related change with epididymal epithelial cell phospholipidosis being the most prominent finding in rats and dogs. Epididymal epithelial cells had no histologic evidence of degeneration; sperm density and morphology were normal histologically in both species; and sperm concentration, morphology, and motility in the dog were comparable to dogs given vehicle. Other sites with phospholipidosis included lymphoid tissues (lymph nodes, Peyer's patches, and/or spleen), pulmonary alveolar macrophages, and peripheral blood lymphocytes in rats and dogs and adrenal cortex, liver, pituitary, hair follicles, bone marrow lymphocytes and plasma cells, and skeletal muscle in rats only. The phospholipidosis was resolved after a 6-week recovery period in all tissues but epididymis. There was no evidence of cell injury in tissues that had phospholipid accumulations except in rat skeletal muscle that had multifocal myofiber degeneration and necrosis. For clinical trials, serum AST and CK and peripheral blood lymphocyte vacuolation were considered potential safety biomarkers for skeletal muscle degeneration and phospholipidosis, respectively. [ABSTRACT FROM AUTHOR]

While many experiment with drugs, relatively few individuals develop a true addiction. We hypothesized that, in rats, such individual differences in the actions of addictive drugs might be determined by postnatal rearing conditions. To test this idea, we investigated whether stimulant- and stress-induced activation of nucleus accumbens dopamine transmission and dopamine-dependent behaviours might differ among adults rats that had been either repeatedly subjected to prolonged maternal separation or a brief handling procedure or left undisturbed (non-handled) during the first 14 days of life. We found that, in comparison with their handled counterparts, maternally separated and non-handled animals are hyperactive when placed in a novel setting, display a dose-dependent higher sensitivity to cocaine-induced locomotor activity and respond to a mild stressor (tail-pinch) with significantly greater increases in nucleus accumbens dopamine levels. In addition, maternally separated animals were found to sensitize to the locomotor stimulant action of amphetamine when repeatedly stressed under conditions that failed to sensitize handled and non-handled animals. Finally, quantitative receptor autoradiography revealed a lower density of nucleus accumbens-core and striatal dopamine transporter sites in maternally separated animals. Interestingly, we also found greatly reduced D3 dopamine receptor binding and mRNA levels in the nucleus accumbens-shell of handled animals. Together, these findings provide compelling evidence that disruptions in early postnatal rearing conditions can lead to profound and lasting changes in the responsiveness of mesocorticolimbic dopamine neurons to stress and psychostimulants, and suggest a neurobiological basis for individual differences in vulnerability to compulsive drug taking. [ABSTRACT FROM AUTHOR]

ABSTRACT BP 897 is a potent ( Ki= 0.92 nM) dopamine D3 receptor compound developed for the treatment of cocaine abuse and craving. BP 897 has a high selectivity for the dopamine D3 versus D2 receptors (70-fold) and a moderate affinity for 5-HT1A receptors, ( Ki= 84 nM), adrenergic-α1 ( Ki= 60 nM) and -α2 adrenoceptors ( Ki= 83 nM). BP 897 displays significant intrinsic activity at the human dopamine D3 receptor by decreasing forskolin-stimulated cAMP levels and by stimulating mitogenesis of dopamine D3-expressing NG108-15 cells. Although these findings suggest that BP 897 is a partial agonist, recent studies in Chinese Hamster Ovary (CHO) cells with expressed dopamine D3 receptors demonstrated that BP 897 is devoid of any intrinsic activity but potently inhibits dopamine agonist effects (pIC50= 9.43 and 9.51) in agonist-induced acidification rate or increase of GTPγS binding, respectively. In addition, BP 897 inhibits in vivo (EC50= 1.1 mg/kg, i.v.) agonist-induced decrease of firing rate of dopaminergic neurons in the substantia nigra. It has been clearly shown that BP 897, 1 mg/kg, i.p., reduces cocaine-seeking behavior in rats, without producing reinforcement on its own. In rhesus monkeys, BP 897 is not self-administered (up to 30 μg/kg, i.v.) but reduces cocaine self-administration. The potential usefulness of BP 897 in the treatment of drug-seeking behavior is further supported by its effects in drug conditioning models. Although BP 897 reduces L-DOPA-induced dyskinesia in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys, it provokes a return of parkinsonian symptoms. At high doses BP 897 has been reported to produce catalepsy in rats. Pharmacokinetic and toxicological data have not yet been published. These interesting preclinical findings with BP 897 provide additional validation for dopamine D3 receptor as a therapeutic target for the treatment of cocaine abuse and its associated central nervous system (CNS) disorders. BP 897 recently entered phase II clinical studies. [ABSTRACT FROM AUTHOR]