Dopamine D2 receptor partial agonists in the treatment of schizophrenia -example of brexpiprazole. / Czesciowi agonisci receptora dopaminowego D2 w leczeniu schizofrenii -przyklad brekspiprazolu.

Since the 1950s, there have been rapid developments in psychiatric pharmacotherapy, resulting not only in more effective treatment of patients, but also in improvements in minimizing adverse effects of therapy. Modern third-generation antipsychotics, in addition to antagonism toward D2 receptors, also exhibit partial agonism toward dopamine receptors. Such a mechanism of action is intended to regulate dopaminergic transmission - inhibit (antagonism) it in pathways where it is excessive (excessive transmission in the mesolimbic pathway in psychotic patients, excessive transmission in the tuberoinfundibular pathway in patients with hyperprolactinemia) and stimulate (agonism) it in pathways where it is too low (mesocortical pathway). This has a beneficial effect on both the reduction of adverse symptoms and the negative, affective and cognitive symptoms of patients suffering from schizophrenia. The purpose of this review article is to present the most important clinical aspects of the use of dopamine D2 receptor partial agonists in the treatment of schizophrenia, using brexpiprazole as an example, and to define the profile of patients to whom this drug could be dedicated - based on recent studies.

Dopamine D2 receptors in the accumbal core region mediates the effects of fentanyl on sleep-wakefulness.

Fentanyl, a potent analgesic and addictive substance, significantly impacts sleep-wakefulness (S-W). Acutely, it promotes wake, whereas chronic abuse leads to severe sleep disruptions, including insomnia, which contributes to opioid use disorders (OUD), a chronic brain disease characterized by compulsive opioid use and harmful consequences. Although the critical association between sleep disruptions and fentanyl addiction is acknowledged, the precise mechanisms through which fentanyl influences sleep remain elusive. Recent studies highlight the role of the dopaminergic system of the nucleus accumbens (NAc) in S-W regulation, but its specific involvement in mediating fentanyl's effects on S-W remains unexplored. We hypothesized that dopamine D2 receptors mediate fentanyl-induced effects on S-W. To test this hypothesis, male C57BL/6J mice, instrumented with sleep recording electrodes and bilateral guide cannulas above the accumbal core region (NAcC), were utilized in this study. At dark onset, animals were bilaterally administered sulpiride (D2 receptors antagonist; 250 ng/side) in the NAcC followed by an intraperitoneal injection of fentanyl (1.2 mg/Kg). S-W was examined for the next 12 h. We found that systemic administration of fentanyl significantly increased wakefulness during the first 6 h of the dark which was followed by a significant increase in NREM and REM sleep during the second 6 h of the dark period. D2-receptor blockade significantly reduced this effect as evidenced by a significant reduction in fentanyl-induced wakefulness during first 6 h of dark period and sleep rebound during the second 6 h. Our findings suggest that D2 receptors in the NAcC plays a vital role in mediating the fentanyl-induced changes in S-W.

Early-life risperidone alters locomotor responses to apomorphine and quinpirole in adulthood.

An escalating trend of antipsychotic drug use in children with ADHD, disruptive behavior disorder, or mood disorders has raised concerns about the impact of these drugs on brain development. Since antipsychotics chiefly target dopamine receptors, it is important to assay the function of these receptors after early-life antipsychotic administration. Using rats as a model, we examined the effects of early-life risperidone, the most prescribed antipsychotic drug in children, on locomotor responses to the dopamine D1/D2 receptor agonist, apomorphine, and the D2/D3 receptor agonist, quinpirole. Female and male Long-Evans rats received daily subcutaneous injections of risperidone (1.0 and 3.0 mg/kg) or vehicle from postnatal day 14-42. Locomotor responses to one of three doses (0.03, 0.1, and 0.3 mg/kg) of apomorphine or quinpirole were tested once a week for four weeks beginning on postnatal day 76 and 147 for each respective drug. The locomotor activity elicited by the two lower doses of apomorphine was significantly greater in adult rats, especially females, administered risperidone early in life. Adult rats administered risperidone early in life also showed more locomotor activity after the low dose of quinpirole. Overall, female rats were more sensitive to the locomotor effects of each agonist. In a separate group of rats administered risperidone early in life, autoradiography of forebrain D2 receptors at postnatal day 62 revealed a modest increase in D2 receptor density in the medial caudate. These results provide evidence that early-life risperidone administration can produce long-lasting changes in dopamine receptor function and density.

Sustained fentanyl exposure inhibits neuronal activity in dissociated striatal neuronal-glial cocultures through actions independent of opioid receptors.

Besides having high potency and efficacy at the µ-opioid (MOR) and other opioid receptor types, fentanyl has some affinity for some adrenergic receptor types, which may underlie its unique pathophysiological differences from typical opioids. To better understand the unique actions of fentanyl, we assessed the extent to which fentanyl alters striatal medium spiny neuron (MSN) activity via opioid receptors or α1-adrenoceptors in dopamine type 1 or type 2 receptor (D1 or D2)-expressing MSNs. In neuronal and mixed-glial cocultures from the striatum, acute fentanyl (100 nM) exposure decreased the frequency of spontaneous action potentials. Overnight exposure of cocultures to 100 nM fentanyl severely reduced the proportion of MSNs with spontaneous action potentials, which was unaffected by coexposure to the opioid receptor antagonist naloxone (10 µM) but fully negated by coadministering the pan-α1-adrenoceptor inverse agonist prazosin (100 nM) and partially reversed by the selective α1A-adrenoceptor antagonist RS 100329 (300 nM). Acute fentanyl (100 nM) exposure modestly reduced the frequency of action potentials and caused firing rate adaptations in D2, but not D1, MSNs. Prolonged (2-5 h) fentanyl (100 nM) application dramatically attenuated firing rates in both D1 and D2 MSNs. To identify possible cellular sites of α1-adrenoceptor action, α1-adrenoceptors were localized in subpopulations of striatal astroglia and neurons by immunocytochemistry and Adra1a mRNA by in situ hybridization in astrocytes. Thus, sustained fentanyl exposure can inhibit striatal MSN activity via a nonopioid receptor-dependent pathway, which may be modulated via complex actions in α1-adrenoceptor-expressing striatal neurons and/or glia.NEW & NOTEWORTHY Acute fentanyl exposure attenuated the activity of striatal medium spiny neurons (MSNs) in vitro and in dopamine D2, but not D1, receptor-expressing MSNs in ex vivo slices. By contrast, sustained fentanyl exposure suppressed the spontaneous activity of MSNs cocultured with glia through a nonopioid receptor-dependent mechanism modulated, in part, by α1-adrenoceptors. Fentanyl exposure can affect striatal function via a nonopioid receptor mechanism of action that appears mediated by α1-adrenoreceptor-expressing striatal neurons and/or astroglia.

Three paradoxes related to the mode of action of pramipexole: The path from D2/D3 dopamine receptor stimulation to modification of dopamine-modulated functions.

Pramipexole, a D2/D3 dopamine receptor agonist, is used to treat the motor symptoms of Parkinson's disease, caused by degeneration of the dopaminergic nigrostriatal pathway. There are three paradoxes associated with its mode of action. Firstly, stimulation of D2/D3 receptors leads to neuronal inhibition, although pramipexole does not inhibit but promotes some dopamine-modulated functions, such as locomotion and reinforcement. Secondly, another dopamine-modulated function, arousal, is not promoted but inhibited by pramipexole, leading to sedation. Thirdly, pramipexole-evoked sedation is associated with an increase in pupil diameter, although sedation is expected to cause pupil constriction. To resolve these paradoxes, the path from stimulation of D2/D3 receptors to the modification of dopamine-modulated functions has been tracked. The functions considered are modulated by midbrain dopaminergic nuclei: locomotion - substantia nigra pars compacta (SNc), reinforcement/motivation - ventral tegmental area (VTA), sympathetic activity (as reflected in pupil function) - VTA; arousal - ventral periaqueductal grey (vPAG), with contributions from VTA and SNc. The application of genetics-based molecular techniques (optogenetics and chemogenetics) has enabled tracing the chains of neurones from the dopaminergic nuclei to their final targets executing the functions. The functional neuronal circuits linked to the D2/D3 receptors in the dorsal and ventral striata, stimulated by inputs from SNc and VTA, respectively, may explain how neuronal inhibition induced by pramipexole is translated into the promotion of locomotion, reinforcement/motivation and sympathetic activity. As the vPAG may increase arousal mainly by stimulating cortical D1 dopamine receptors, pramipexole would stimulate only presynaptic D2/D3 receptors on vPAG neurones, curtailing their activity and leading to sedation.

Efficacy and tolerability of brexpiprazole - a new antipsychotic drug from the group of dopamine D2 receptor partial agonists. / Skutecznosc i tolerancja brekspiprazolu ­ nowego leku przeciwpsychotycznego z grupy czesciowych agonistów receptorów dopaminowych D2.

Brexpiprazole is a new antipsychotic drug from the group of dopamine D2/D3 receptor partial agonists. It represents a development of the second-generation antipsychotics and is an important addition to the pharmacological treatment options for schizophrenia. The purpose of this article is to present, illustrated by the case of brexpiprazole, how advances in the pharmacological properties of new antipsychotics translate into improved results in the treatment of schizophrenia, not only in terms of symptom reduction, but also in terms of functional improvement. The ratio of activation to blocking of the D2/D3 receptor is lower for brexpiprazole than for aripiprazole and cariprazine, which may translate into a lower risk of akathisia. Brexpiprazole has also stronger antihistaminic activity, which is likely to be associated with a stronger sedative effect, a lower risk of akathisia, excessive agitation and insomnia. Brexpiprazole meets the traditional requirements for an antipsychotic drug's efficacy, i.e., compared to placebo, it brings a greater reduction in schizophrenia symptoms in short-term studies and prevents schizophrenia relapses in long-term follow-up. The highest antipsychotic efficacy was found with the highest registered dose (4 mg/day). In addition to reducing positive symptoms, brexpiprazole treatment also leads to a reduction in negative and depressive symptoms, as well as anxiety. It has also a positive effect on patients' social and personal functioning and quality of life. This action of the drug is in line with the expectations of patients and their families regarding effective treatment. It should not only reduce symptoms, but also enable a return to health, i.e., a state that, in addition to optimal health and a sense of psychological well-being, also makes it possible to maintain proper social relations.

Dopamine D2-like receptors on conditioned and unconditioned fear: A systematic review of rodent pharmacological studies.

Growing evidence supports dopamine's role in aversive states, yet systematic reviews focusing on dopamine receptors in defensive behaviors are lacking. This study presents a systematic review of the literature examining the influence of drugs acting on dopamine D2-like receptors on unconditioned and conditioned fear in rodents. The review reveals a predominant use of adult male rats in the studies, with limited inclusion of female rodents. Commonly employed tests include the elevated plus maze and auditory-cued fear conditioning. The findings indicate that systemic administration of D2-like drugs has a notable impact on both innate and learned aversive states. Generally, antagonists tend to increase unconditioned fear, while agonists decrease it. Moreover, both agonists and antagonists typically reduce conditioned fear. These effects are attributed to the involvement of distinct neural circuits in these states. The observed increase in unconditioned fear induced by D2-like antagonists aligns with dopamine's role in suppressing midbrain-mediated responses. Conversely, the reduction in conditioned fear is likely a result of blocking dopamine activity in the mesolimbic pathway. The study highlights the need for future research to delve into sex differences, explore alternative testing paradigms, and identify specific neural substrates. Such investigations have the potential to advance our understanding of the neurobiology of aversive states and enhance the therapeutic application of dopaminergic agents.

Parental Exposure to Morphine Before Conception Decreases Morphine and Cocaine-Induced Locomotor Sensitization in Male Offspring.

Repeated exposure to abused drugs leads to reorganizing synaptic connections in the brain, playing a pivotal role in the relapse process. Additionally, recent research has highlighted the impact of parental drug exposure before gestation on subsequent generations. This study aimed to explore the influence of parental morphine exposure 10 days prior to pregnancy on drug-induced locomotor sensitization. Adult male and female Wistar rats were categorized into morphine-exposed and control groups. Ten days after their last treatment, they were mated, and their male offspring underwent morphine, methamphetamine, cocaine, and nicotine-induced locomotor sensitization tests. The results indicated increased locomotor activity in both groups after drug exposure, although the changes were attenuated in morphine and cocaine sensitization among the offspring of morphine-exposed parents (MEPs). Western blotting analysis revealed altered levels of D2 dopamine receptors (D2DRs) in the prefrontal cortex and nucleus accumbens of the offspring from MEPs. Remarkably, despite not having direct in utero drug exposure, these offspring exhibited molecular alterations affecting morphine and cocaine-induced sensitization. The diminished sensitization to morphine and cocaine suggested the development of a tolerance phenotype in these offspring. The changes in D2DR levels in the brain might play a role in these adaptations.

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.

Dopamine, activation of ingestion and evaluation of response efficacy: a focus on the within-session time-course of licking burst number.

RATIONALE: Evidence on the effect of dopamine D1-like and D2-like receptor antagonists on licking microstructure and the forced swimming response led us to suggest that (i) dopamine on D1-like receptors plays a role in activating reward-directed responses and (ii) the level of response activation is reboosted based on a process of evaluation of response efficacy requiring dopamine on D2-like receptors. A main piece of evidence in support of this hypothesis is the observation that the dopamine D2-like receptor antagonist raclopride induces a within-session decrement of burst number occurring after the contact with the reward. The few published studies with a detailed analysis of the time-course of this measure were conducted in our laboratory. OBJECTIVES: The aim of this review is to recapitulate and discuss the evidence in support of the analysis of the within-session burst number as a behavioural substrate for the study of the mechanisms governing ingestion, behavioural activation and the related evaluation processes, and its relevance in the analysis of drug effects on ingestion. CONCLUSIONS: The evidence gathered so far suggests that the analysis of the within-session time-course of burst number provides an important behavioural substrate for the study of the mechanisms governing ingestion, behavioural activation and the related evaluation processes, and might provide decisive evidence in the analysis of the effects of drugs on ingestion. However, further evidence from independent sources is necessary to validate the use and the proposed interpretation of this measure.

The trace amine-associated receptor 1 agonists - non-dopaminergic antipsychotics or covert modulators of D2 receptors?

A major effort of the pharmaceutical industry has been to identify and market drug treatments that are effective in ameliorating the symptoms of psychotic illness but without the limitations of the current treatments acting at dopamine D2 receptors. These limitations include the induction of a range of adverse effects, the inadequate treatment response of a substantial proportion of people with schizophrenia, and the generally poor response to negative and cognitive features of the disease. Recently introduced drug treatments have gone some way to avoiding the first of these, with a reduced propensity for weight gain, cardiovascular risk and extrapyramidal motor effects. Despite claims of some small improvements in negative symptoms, these drugs have not demonstrated substantial increases in efficacy. Of the drugs currently in development as antipsychotic agents, several are misleadingly described as having novel 'non-dopaminergic' mechanisms that may offer improvements in addressing the limitations of adverse effects and efficacy. It will be argued, using the trace amine-associated receptor 1 agonist as an example, that several of these new drugs still act primarily through modulation of dopaminergic neurotransmission and, in not addressing the primary pathology of schizophrenia, are therefore unlikely to have the much-needed improvements in efficacy required to address the unmet need associated with resistance to current treatments.

Brain antioxidant status and gene expressions of nicotinic and dopamine receptors are improved by black seed oil administration in cigarette smoke or nicotine vapour-exposed rats.

BACKGROUND: Smoking is associated with dysregulation of the antioxidant system and addiction. AIM: This study sought to ascertain the effect of Nigella Sativa (NS) oil on the antioxidant system, nicotine/tobacco addiction as well as the expressions of α4ß2 nicotinic (nAChR) and dopamine type-2 (DRD2) receptors in selected brain regions of the rat. METHODS: Thirty male Sprague-Dawley rats were divided into 6 groups comprising of vehicle-treated control, NS oil only, Smoke only, Smoke + NS oil, Nicotine only and Nicotine + NS oil. Animals were passively exposed to cigarette smoke or nicotine vapour for 12 weeks, however, NS oil treatment commenced from 9th-12th week of the experimental duration. RESULTS: Nicotine vapour and cigarette smoke-induced increase in cotinine level were significantly ameliorated by NS treatment. Cigarette smoke or nicotine vapour exposure significantly (p<0.05) decreased the level of antioxidant enzymes while increasing malondialdehyde level in the brain homogenates of the rats.  Administration of NS oil significantly (p<0.05) reversed the reduced antioxidant level. Cigarette-smoke also significantly increased α4-nAChR expression in the frontal cortex and olfactory bulb compared to control. Nicotine vapour significantly increased DRD2 expression only in the olfactory cortex. NS oil administration reduced both the cigarette-smoke-induced increase in α4-nAChR and nicotine vapour-induced increase in DRD2 gene expression only in the olfactory cortex. CONCLUSION: Findings from this study suggest that NS oil improves brain antioxidant status while ameliorating nicotine vapour and cigarette smoke addiction through down-regulation of α4-nAChR and DRD2 gene expressions in discrete brain regions in Sprague-Dawley rats.

Dopamine D2L receptor density influences the recruitment of ß-arrestin2 and Gi1 induced by antiparkinsonian drugs.

INTRODUCTION: Brain imaging studies have highlighted that the density of dopamine D2 receptors markedly fluctuates across the stages of Parkinson's disease and in response to pharmacological treatment. Moreover, receptor density constitutes a molecular determinant for the signaling profile of D2 receptor ligands. We therefore hypothesized that variations in receptor expression could influence D2 receptor response to antiparkinsonian drugs, most notably with respect to the recruitment bias between Gi1 and ß-arrestin2. METHODS: The recruitment bias of dopamine, pramipexole, ropinirole, and rotigotine was examined using a nanoluciferase-based biosensor for probing the interactions of the D2L receptor with either Gi1 or ß-arrestin2. The characterization of the functional selectivity of these D2 receptor agonists was performed at two distinct D2L receptor densities by taking advantage of a cell model carrying an inducible system that enables the overexpression of the D2L receptor when exposed to doxycycline. RESULTS: A high receptor density oriented the balanced signaling profile of dopamine towards a preferential recruitment of Gi1. It also moderated the marked Gi1 and ß-arrestin2 biases of pramipexole and rotigotine, respectively. At variance, the Gi1 bias of ropinirole appeared as not being influenced by D2L receptor density. CONCLUSIONS: Taken together, these observations highlight receptor density as a key driver of the signaling transducer recruitment triggered by antiparkinsonian agents. Moreover, given the putative beneficial properties of ß-arrestin2 in promoting locomotion, this study provides molecular insights that position the arrestin-biased ligand rotigotine as a putatively more beneficial D2 receptor agonist for the treatment of early and late Parkinson's disease.

Activation of dopamine D2 receptors in the shell of nucleus accumbens triggers conditioned avoidance responses in rats.

Conditioned avoidance responses (CAR) behavior is a classical instrumental response paradigm, which is widely used to study aversive conditioning and defensive motivation behavior. Previous studies have shown that dopamine D1 and D2 receptors are involved in CAR behavior; however, it is unclear in which brain regions that dopamine evokes CAR behavior. The aim of the study is to investigate whether dopamine triggers CAR behavior via activating dopamine D1 or D2 receptors in the shell of nucleus accumbens or dorsolateral striatum. The present study found that infusion of the dopamine D2 receptor agonist quinpirole, but not D1 receptor agonist SKF38393, into the shell of nucleus accumbens evoked CAR behavior in reserpine-treated rats. Whereas, infusion of neither SKF38393 nor quinpirole into the dorsolateral striatum evoked CAR behavior. In addition, infusion of quinpirole into the shell of nucleus accumbens enhanced CAR behavior in the unsuccessful trained rats without affecting the motor function in the balance beam and locomotor tests. In conclusion, activation of dopamine D2, but not D1 receptors in the shell of nucleus accumbens evokes CAR behavior. However, activation of dopamine D1 and D2 receptors in the dorsolateral striatum does not evoke CAR behavior. It is suggested that the shell of nucleus accumbens is the critical brain region for dopamine to invoke CAR behavior, and activation of dopamine D2 receptors in the shell of nucleus accumbens is sufficient and necessary to evoke CAR behavior.

Heterobivalent Ligand for the Adenosine A2A-Dopamine D2 Receptor Heteromer.

A G protein-coupled receptor heteromer that fulfills the established criteria for its existence in vivo is the complex between adenosine A2A (A2AR) and dopamine D2 (D2R) receptors. Here, we have designed and synthesized heterobivalent ligands for the A2AR-D2R heteromer with various spacer lengths. The indispensable simultaneous binding of these ligands to the two different orthosteric sites of the heteromer has been evaluated by radioligand competition-binding assays in the absence and presence of specific peptides that disrupt the formation of the heteromer, label-free dynamic mass redistribution assays in living cells, and molecular dynamic simulations. This combination of techniques has permitted us to identify compound 26 [KDB1 (A2AR) = 2.1 nM, KDB1 (D2R) = 0.13 nM], with a spacer length of 43-atoms, as a true bivalent ligand that simultaneously binds to the two different orthosteric sites. Moreover, bioluminescence resonance energy transfer experiments indicate that 26 favors the stabilization of the A2AR-D2R heteromer.

Beta band modulation by dopamine D2 receptors in the primary motor cortex and pedunculopontine nucleus in a rat model of Parkinson's disease.

Beta band (12-30 Hz) hypersynchrony within the basal ganglia-thalamocortical network has been suggested as a hallmark of Parkinson's disease (PD) pathophysiology. Abnormal beta band oscillations are found in the pedunculopontine nucleus (PPN) and primary motor cortex (M1) and are correlated with dopamine depletion. Dopamine acts locomotion and motor performance mainly through dopamine receptors (D1 and D2). However, the precise mechanism by which dopamine receptors regulate beta band electrophysiological activities between the PPN and M1 is still unknown. Here, we recorded the neuronal activity of the PPN and M1 simultaneously by the administration of the drug (SCH23390 and raclopride), selectively blocking the dopamine D1 receptor and D2 receptor. We discovered that the increased coherent activity of the beta band (12-30 Hz) between M1 and PPN in the lesioned group could be reduced and restored by injecting raclopride in the resting and wheel running states. Our studies revealed the unique role of D2 dopamine receptor signaling in regulating ß band oscillatory activity in M1 and PPN and their relationship after the loss of dopamine, which contributes to elucidating the underlying mechanism of the pathophysiology of PD.

Cannabidiol impairs the rewarding effects of methamphetamine: Involvement of dopaminergic receptors in the nucleus accumbens.

Cannabidiol, as component of cannabis, can potentially hinder the rewarding impact of drug abuse; however, its mechanism is ambiguous. Moreover, the nucleus accumbens (NAc), as a key area in the reward circuit, extensively receives dopaminergic projections from the ventral tegmentum area. To elucidate the role of accumbal D1 and D2 dopamine receptor families in Cannabidiol's inhibitory impact on the acquisition and expression phases of methamphetamine (MET), the conditioned place preference (CPP) procedure as a common method to assay reward characteristics of drugs was carried out. Six groups of rats were treated by various doses of SCH23390 or Sulpiride (0.25, 1, and 4 µg/0.5 µL) in the NAc as D1 or D2 dopamine receptor family antagonists, respectively, prior to infusion of Cannabidiol (10 µg/5 µL) in the lateral ventricle (LV) over conditioning phase in the acquisition experiments. In the second step of the study, animals received SCH23390 or Sulpiride in the NAc before Cannabidiol (50 µg/5 µL) infusion into the LV in the expression phase of MET to illuminate the influence of SCH23390 or Sulpiride on the inhibitory impact of Cannabidiol on the expression of MET-induced CPP. Intra-NAc administration of either SCH23390 or Sulpiride impaired Cannabidiol's suppressive impact on the expression phase, while just Sulpiride could suppress the Cannabidiol's impact on the acquisition phase of the MET-induced CPP. Also, the inhibitory impact of Sulpiride was stranger in both phases of MET reward. It seems that Cannabidiol prevents the expression and acquisition phases of MET-induced CPP partly through the dopaminergic system in the NAc.

Pharmacological perturbation reveals deficits in D2 receptor responses in Thap1 null mice.

The primary dystonia DYT6 is caused by mutations in the transcription factor Thanatos-associated protein 1 (THAP1). To understand THAP1's functions, we generated mice lacking THAP1 in the nervous system. THAP1 loss causes locomotor deficits associated with transcriptional changes. Since many of the genes misregulated involve dopaminergic signaling, we pharmacologically challenged the two striatal canonical dopamine pathways: the direct, regulated by the D1 receptor, and the indirect, regulated by the D2 receptor. We discovered that depleting THAP1 specifically interferes with the D2 receptor responses, pointing to a selective misregulation of the indirect pathway in DYT6 with implications for pathogenesis and treatment.

Chiral Cyclic Aliphatic Linkers as Building Blocks for Selective Dopamine D2 or D3 Receptor Agonists.

Linkers are emerging as a key component in regulating the pharmacology of bitopic ligands directed toward G-protein coupled receptors (GPCRs). In this study, the role of regio- and stereochemistry in cyclic aliphatic linkers tethering well-characterized primary and secondary pharmacophores targeting dopamine D2 and D3 receptor subtypes (D2R and D3R, respectively) is described. We introduce several potent and selective D2R (rel-trans-16b; D2R Ki = 4.58 nM) and D3R (rel-cis-14a; D3R Ki = 5.72 nM) agonists while modulating subtype selectivity in a stereospecific fashion, transferring D2R selectivity toward D3R via inversion of the stereochemistry around these cyclic aliphatic linkers [e.g., (-)-(1S,2R)-43 and (+)-(1R,2S)-42]. Pharmacological observations were supported with extensive molecular docking studies. Thus, not only is it an innovative approach to modulate the pharmacology of dopaminergic ligands described, but a new class of optically active cyclic linkers are also introduced, which can be used to expand the bitopic drug design approach toward other GPCRs.

Early life exposure to poly I:C impairs striatal DA-D2 receptor binding, myelination and associated behavioural abilities in rats.

Early-life viral infections critically influence the brain development and have been variously reported to cause neuropsychiatric diseases such as Schizophrenia, Parkinson's diseases, demyelinating diseases, etc. To investigate the alterations in the dopaminergic system, myelination and associated behavioral impairments following neonatal viral infection, the viral immune activation model was created by an intraperitoneal injection of Poly I:C (5 mg/kg bw/ip) to neonatal rat pups on PND-7. The DA-D2 receptor binding was assessed in corpus striatum by using 3H-Spiperone at 3, 6 and 12 weeks of age. MOG immunolabelling was performed to check myelination stature and myelin integrity, while corpus callosum calibre was assessed by Luxol fast blue staining. Relative behavioral tasks i.e., motor activity, motor coordination and neuromuscular strength were assessed by open field, rotarod and grip strength meter respectively at 3, 6 and 12 weeks of age. Following Poly I:C exposure, a significant decrease in DA-D2 receptor binding, reduction in corpus callosum calibre and MOG immunolabelling indicating demyelination and a significant decrease in locomotor activity, neuromuscular strength and motor coordination signify motor deficits and hypokinetic influence of early life viral infection. Thus, the findings suggest that early life poly I:C exposure may cause demyelination and motor deficits by decreasing DA-D2 receptor binding affinity.