Dopamine D2 Receptor Partial Agonist Research Articles

Efficacy and tolerability of brexpiprazole – a new antipsychotic drug from the group of dopamine D2 receptor partial agonists

Efficacy and tolerability of brexpiprazole – a new antipsychotic drug from the group of dopamine D2 receptor partial agonists

Brexpiprazole in patients with schizophrenia with or without substance use disorder: an observational study.

Partial dopamine D2 receptor agonists are used for psychotic symptoms in adults with schizophrenia spectrum disorders. Recently, interest surged for partial dopamine D2 receptor agonists in substance use disorders (SUDs). Since it is believed that SUDs decrease the efficacy of pharmacotherapy of underlying psychiatric disorders, we tested the efficacy of the partial D2 agonist brexpiprazole in patients with schizophrenia who were either comorbid with a SUD (SUD group) or not comorbid (non-SUD) to assess treatment response and the effect of brexpiprazole on substance craving in SUD. We included patients with DSM-5/DSM-5-TR schizophrenia (using SCID-5-CV) aged 18-66 years with either comorbid SUD or non-SUD to treat with brexpiprazole 4 mg/day for 6 months during February-October 2022. Patients were assessed with the Clinical Global Impressions-Severity (CGI-S) scale, the 24-item Brief Psychiatric Rating Scale (BPRS), and the Positive And Negative Syndrome Scale (PANSS) at baseline, weekly for the first 2 months and monthly for the next four. Furthermore, we assessed substance craving in SUD with a visual analog scale for craving (VAScrav) at the same timepoints. The total sample was 86 (85 analysable) 18- to 64-year-old (mean 39.32 ± 14.09) patients with schizophrenia [51 men (59.3%) and 35 women (40.7%)], of whom 48 SUD (55.8%) (37 men and 11 women) and 38 non-SUD (44.2%) (14 men and 24 women). No serious or persistent adverse events developed over the study period, but one patient dropped out for subjective akathisia. Results indicated the main effects of time with improvements over the course of the study for CGI-S, BPRS, and PANSS in both SUD and non-SUD groups and the entire sample, and for VAScrav in SUD. Brexpiprazole was associated with similar significant improvements in both groups at the 6 month endpoint compared to baseline. Treatment with brexpiprazole for 6 months improved psychotic symptoms in patients with schizophrenia, independently from whether they belonged to the SUD or the non-SUD group; hence, SUD comorbidity did not confer treatment resistance to brexpiprazole. Furthermore, in the SUD group, we observed reduced substance craving.

Antipsychotic dose, dopamine D2 receptor occupancy and extrapyramidal side-effects: a systematic review and dose-response meta-analysis.

Antipsychotic drugs differ in their propensity to cause extrapyramidal side-effects (EPS), but their dose-effects are unclear. Therefore, we conducted a systematic review and dose-response meta-analysis. We searched multiple electronic databases up to 20.02.2023 for fixed-dose studies investigating 16 second-generation antipsychotics and haloperidol (all formulations and administration routes) in adults with acute exacerbations of schizophrenia. The primary outcome was the number of participants receiving antiparkinsonian medication, and if not available, the number of participants with extrapyramidal side-effects (EPS) and the mean scores of EPS rating scales were used as proxies. The effect-size was odds ratio (ORs) compared with placebo. One-stage random-effects dose-response meta-analyses with restricted cubic splines were conducted to estimate the dose-response curves. We also examined the relationship between dopamine D2 receptor (D2R) occupancy and ORs by estimating occupancies from administrated doses. We included data from 110 studies with 382 dose arms (37193 participants). Most studies were short-term with median duration of 6 weeks (range 3-26 weeks). Almost all antipsychotics were associated with dose-dependent EPS with varied degrees and the maximum ORs ranged from OR = 1.57 95%CI [0.97, 2.56] for aripiprazole to OR = 7.56 95%CI [3.16, 18.08] for haloperidol at 30 mg/d. Exceptions were quetiapine and sertindole with negligible risks across all doses. There was very low quality of findings for cariprazine, iloperidone, and zotepine, and no data for clozapine. The D2R occupancy curves showed that the risk increased substantially when D2R occupancy exceeded 75-85%, except for D2R partial agonists that had smaller ORs albeit high D2R occupancies. In conclusion, we found that the risk of EPS increases with rising doses and differs substantially in magnitude among antipsychotics, yet exceptions were quetiapine and sertindole with negligible risks. Our data provided additional insights into the current D2R therapeutic window for EPS.

Transformation of a Dopamine D2 Receptor Agonist to Partial Agonists as Novel Antipsychotic Agents.

Designed ligands of G protein-coupled receptors can exert a spectrum of modulating effects, varying from full agonists and partial agonists to antagonists and inverse agonists. For the dopamine D2 receptor (D2R), partial agonist activity is the pharmacological feature of the third-generation antipsychotics, including aripiprazole, brexpiprazole, and cariprazine. Started from a benzofuran-derived D2R full agonist O4LE6 (4), which was identified using a structure-based method by us in previous studies, a series of D2R partial agonists were designed and synthesized by introducing different tail groups. Among them, compound 10b showed excellent activity in D2R pharmacological assays. Further optimizations using a structural rigidification approach led to the discovery of brain-penetrant compounds 29c and 29d, which exhibited potent antipsychotic effects in the mouse hyperlocomotion model. Compound 29c also showed excellent drug-like pharmacokinetic properties in rats and qualifies as an antipsychotic agent that is worth further evaluations.

Application of Antipsychotic Drugs in Mood Disorders.

Since their first application in psychiatry seventy years ago, antipsychotic drugs, besides schizophrenia, have been widely used in the treatment of mood disorders. Such an application of antipsychotics is the subject of this narrative review. Antipsychotic drugs can be arbitrarily classified into three generations. First-generation antipsychotics (FGAs), such as phenothiazines and haloperidol, were mainly applied for the treatment of acute mania, as well as psychotic depression when combined with antidepressants. The second-generation, so-called atypical antipsychotics (SGAs), such as clozapine, risperidone, olanzapine, and quetiapine, have antimanic activity and are also effective for the maintenance treatment of bipolar disorder. Additionally, quetiapine exerts therapeutic action in bipolar depression. Third-generation antipsychotics (TGAs) started with aripiprazole, a partial dopamine D2 receptor agonist, followed by brexpiprazole, lurasidone, cariprazine, and lumateperone. Out of these drugs, aripiprazole and cariprazine have antimanic activity, lurasidone, cariprazine, and lumateperone exert a significant antidepressant effect on bipolar depression, while there is evidence for the efficacy of aripiprazole and lurasidone in the prevention of recurrence in bipolar disorder. Therefore, successive generations of antipsychotic drugs present a diverse spectrum for application in mood disorders. Such a pharmacological overlap in the treatment of schizophrenia and bipolar illness stands in contrast to the dichotomous Kraepelinian division of schizophrenia and mood disorders.

Dopamine D3/D2 Receptor Ligands Based on Cariprazine for the Treatment of Psychostimulant Use Disorders That May Be Dual Diagnosed with Affective Disorders.

Highly selective dopamine D3 receptor (D3R) partial agonists/antagonists have been developed for the treatment of psychostimulant use disorders (PSUD). However, none have reached the clinic due to insufficient potency/efficacy or potential cardiotoxicity. Cariprazine, an FDA-approved drug for the treatment of schizophrenia and bipolar disorder, is a high-affinity D3R partial agonist (Ki = 0.22 nM) with 3.6-fold selectivity over the homologous dopamine D2 receptor (D2R). We hypothesized that compounds that are moderately D3R/D2R-selective partial agonists/antagonists may be effective for the treatment of PSUD. By systematically modifying the parent molecule, we discovered partial agonists/antagonists, as measured in bioluminescence resonance energy transfer (BRET)-based assays, with high D3R affinities (Ki = 0.14-50 nM) and moderate selectivity (<100-fold) over D2R. Cariprazine and two lead analogues, 13a and 13e, decreased cocaine self-administration (FR2; 1-10 mg/kg, i.p.) in rats, suggesting that partial agonists/antagonists with modest D3R/D2R selectivity may be effective in treating PSUD and potentially comorbidities with other affective disorders.

HIV gp120 impairs nucleus accumbens neuroimmune function and dopamine D3 receptor-mediated inhibition of cocaine seeking in male rats

Cocaine Use Disorders (CUDs) are associated with an increased risk of human immunodeficiency virus (HIV) infection. Cocaine and the HIV envelope protein gp120 each induce distinct deficits to mesocorticolimbic circuit function and motivated behavior; however, little is known regarding how they interact to dysregulate these functions or how such interactions impact pharmacotherapeutic efficacy. We have previously shown that the selective, weak partial agonist of the dopamine D3 receptor (D3R), MC-25-41, attenuates cocaine-seeking behavior in male rats. Here, we sought to characterize changes in striatal neuroimmune function in gp120-exposed rats across abstinence from operant access to cocaine (0.75 mg/kg, i.v.) or sucrose (45 mg/pellet), and to examine the impact of gp120 exposure on MC-25-41-reduced cocaine seeking. After establishing a history of cocaine or sucrose self-administration, rats received intracerebroventricular gp120 infusions daily the first 5 days of abstinence and were sacrificed either on day 6 or after 21 days of forced abstinence and a cue-induced cocaine seeking test. We demonstrated that MC-25-41 treatment attenuated cue-induced cocaine seeking among control rats but not gp120-exposed rats. Moreover, postmortem analysis of nucleus accumbens (NAc) core neuroimmune function indicated cocaine abstinence- and gp120-induced impairments, and the expression of several immune factors within the NAc core significantly correlated with cocaine-seeking behavior. We conclude that cocaine abstinence dysregulates striatal neuroimmune function and interacts with gp120 to inhibit the effectiveness of a D3R partial agonist in reducing cocaine seeking. These findings highlight the need to consider comorbidities, such as immune status, when evaluating the efficacy of novel pharmacotherapeutics.

Visualizing classification of drugs used in psychotic disorders: A 'subway map' representing mechanisms, established classes and informal categories.

Drugs used to treat psychotic disorders (‘antipsychotics’) have been widely used in psychiatry since the introduction of chlorpromazine in the mid-1950s. The categorization of these drugs evolved in a piecemeal way, relying initially on grouping by chemical structure (e.g. phenothiazines, butyrophenones), then by epoch of introduction (e.g. first generation (‘conventional’) vs second generation (‘atypical’)). As psychopharmacological expertise has advanced, it has become possible to quantify affinities for each drug in this class for relevant receptors including dopamine D2, 5HT2A, 5HT2C, histamine H1 and others. However, until the recent emergence of a new generation of agents known collectively as dopamine D2 receptor partial agonists (e.g. aripiprazole, brexpiprazole and cariprazine), there had been little reference in drug classification to specific pharmacological properties. An overview of data on receptor affinities across multiple drugs and receptor types would permit categorization according to binding affinities and putative pharmacological mechanisms. In this paper, we have attempted to construct a ‘subway map’ of 32 drugs used for treatment of psychotic disorders. This design allows a visualization of both the historical classifications by structure and epoch of introduction, and of the binding affinities for key receptors based on appraisal of scientific literature. The map represents a step towards categorization by mechanism, allowing prescribers and patients to understand which drugs share common biological features and the extent to which drugs may have similarities and differences in their mechanisms. In addition, this approach may encourage more logical groupings of drugs to be used in systematic reviews and meta-analyses.

A highly D3R-selective and efficacious partial agonist (S)-ABS01-113 compared to its D3R-selective antagonist enantiomer (R)-ABS01-113 as potential treatments for opioid use disorder.

The non-medical use of opioids has become a national crisis in the USA. Developing non-opioid pharmacotherapies for controlling this opioid epidemic is urgent. Dopamine D3 receptor (D3R) antagonists and low efficacy partial agonists have shown promising profiles in animal models of opioid use disorders (OUD). However, to date, advancement to human studies has been limited. Here we report the effects of (S)- and (R)-enantiomers of (±)-ABS01-113, structural analogs of the D3R partial agonist, (±)-VK4-40, in which the 3-OH in the linking chain is replaced by 3-F group. (S)- and (R)-ABS01-113 are identical in chemical structure but with opposite chirality. In vitro receptor binding and functional assays indicate that (S)-ABS01-113 is an efficacious (55%) and potent (EC50 = 7.6 ± 3.9 nM) D3R partial agonist, while the (R)-enantiomer is a potent D3R antagonist (IC50 = 11.4 nM). Both (S)- and (R)-ABS01-113 bind with high affinity to D3R (Ki = 0.84 ± 0.16 and 0.37 ± 0.06 nM, respectively); however, the (S)-enantiomer is more D3/D2-selective (>1000-fold). Pharmacokinetic analyses indicate that both enantiomers display excellent oral bioavailability and high brain penetration. Systemic administration of (S)- or (R)-ABS01-113 alone failed to alter open-field locomotion in male rats and mice. Interestingly, pretreatment with (S)- or (R)-ABS01-113 attenuated heroin-enhanced hyperactivity, heroin self-administration, and (heroin + cue)-induced reinstatement of drug-seeking behavior. Together, these findings reveal that both enantiomers, particularly the highly selective and efficacious D3R partial agonist (S)-ABS01-113, demonstrate promising translational potential for the treatment of OUD.

2-Phenylcyclopropylmethylamine Derivatives as Dopamine D2 Receptor Partial Agonists: Design, Synthesis, and Biological Evaluation.

Partial agonist activity at the dopamine D2 receptor (D2R) is the primary pharmacological feature of the third-generation antipsychotics─aripiprazole, brexpiprazole, and cariprazine. However, all these drugs share a common phenyl-piperazine moiety as the primary pharmacophore. In this study, we designed and synthesized a series of novel compounds based on the 2-phenylcyclopropylmethylamine (PCPMA) scaffold and studied their pharmacological activity at the D2R. A number of potent D2R partial agonists were identified through binding affinity screening and functional activity profiling in both G protein and β-arrestin assays. The structure-functional activity relationship results showed that the spacer group is crucial for fine-tuning the intrinsic activity of these compounds. Compounds (+)-14j and (+)-14l showed good pharmacokinetic properties and an unexpected selectivity against the serotonin 2A (5-HT2A) receptor. Preliminary suppressive effects in a mouse hyperlocomotion model proved that these PCPMA-derived D2R partial agonists are effective as potential novel antipsychotics.

Dopamine D3 receptor ligand suppresses the expression of levodopa-induced dyskinesia in nonhuman primate model of parkinson's disease

Parkinson's disease (PD) is a complex multisystem, chronic and so far incurable disease with significant unmet medical needs. The incidence of PD increases with aging and the expected burden will continue to escalate with our aging population. Since its discovery in the 1961 levodopa has remained the gold standard pharmacotherapy for PD. However, the progressive nature of the neurodegenerative process in and beyond the nigrostriatal system causes a multitude of side effects, including levodopa-induced dyskinesia within 5 years of therapy. Attenuating dyskinesia has been a significant challenge in the clinical management of PD. We report on a small molecule that eliminates the expression of levodopa-induced dyskinesia and significantly improves PD-like symptoms. The lead compound PD13R we discovered is a dopamine D3 receptor partial agonist with high affinity and selectivity, orally active and with desirable drug-like properties. Future studies are aimed at developing this lead compound for treating PD patients with dyskinesia.

Dopaminergic Activity in Antipsychotic-Naïve Patients Assessed With Positron Emission Tomography Before and After Partial Dopamine D2 Receptor Agonist Treatment: Association With Psychotic Symptoms and Treatment Response

BackgroundDopamine activity has been associated with the response to antipsychotic treatment. Our study used a four-parameter model to test the association between the striatal decarboxylation rate of 18F-DOPA to 18F-dopamine (k3) and the effect of treatment on psychotic symptoms in antipsychotic-naïve patients with first-episode psychosis. We further explored the effect of treatment with a partial dopamine D2 receptor agonist (aripiprazole) on k3 and dopamine synthesis capacity (DSC) determined by the four-parameter model and by the conventional tissue reference method. MethodsSixty-two individuals (31 patients and 31 control subjects) underwent 18F-DOPA positron emission tomography at baseline, and 15 patients were re-examined after 6 weeks. Clinical re-examinations were completed after 6 weeks (n = 28) and 6 months (n = 15). Symptoms were evaluated with the Positive and Negative Syndrome Scale. ResultsHigh baseline decarboxylation rates (k3) were associated with more positive symptoms at baseline (p < .001) and with symptom improvement after 6 weeks (p = .006). Subregion analyses showed that baseline k3 for the putamen (p = .003) and nucleus accumbens (p = .013) and DSC values for the nucleus accumbens (p = .003) were associated with psychotic symptoms. The tissue reference method yielded no associations between DSC and symptoms or symptom improvement. Neither method revealed any effects of group or treatment on average magnitudes of k3 or DSC, whereas changes in dopamine synthesis were correlated with higher baseline values, implying a potential effect of treatment. ConclusionsStriatal decarboxylation rate at baseline was associated with psychotic symptoms and treatment response. The strong association between k3 and treatment effect potentially implicate on new treatment strategies.

Discovery research and development history of the dopamine D2 receptor partial agonists, aripiprazole and brexpiprazole.

Otsuka Pharmaceutical Co., Ltd. successfully developed the first dopamine D2 receptor partial agonist approved for schizophrenia, the antipsychotic aripiprazole (Abilify®). The drug was approved for this indication in the United States in 2002 and has received approval in the United States, Europe, Japan, and many other countries for several indications including schizophrenia, acute mania, adjunctive treatment of major depressive disorder (MDD), irritability associated with autistic disorder, and Tourette's disorder. Otsuka next developed brexpiprazole (Rexulti®), another D2 receptor partial agonist, which was granted marketing approval in the United States in 2015 as adjunctive therapy in major depressive disorder and for the treatment of schizophrenia. In Japan, brexpiprazole also received approval as a treatment for schizophrenia in 2018. In this review, we describe Otsuka's research history and achievements over the preceding 40 years in the area of antipsychotic drug discovery for dopamine D2 receptor partial agonists.

M143. REGIONAL CEREBRAL BLOOD FLOW IN INITIALLY ANTIPSYCHOTIC-NAïVE PATIENTS WITH SCHIZOPHRENIA OR PSYCHOSIS: EFFECTS OF PARTIAL D2 RECEPTOR AGONISM AND ASSOCIATION WITH SYMPTOM IMPROVEMENT

BackgroundSchizophrenia is suggested to stem from dysfunction of cortico-striato-thalamo-cortical networks. Supporting this, we have recently found increased glutamate levels in thalamus in antipsychotic-naïve patients with schizophrenia or psychosis. Moreover, higher baseline glutamate levels were related to less improvement of psychotic symptoms after treatment. Other groups have reported that striatal dopaminergic function in patients with psychosis is increased and associated with psychotic symptoms. Regional cerebral blood flow (rCBF) is considered a marker of neuronal activity and can be used to study the cortico-striato-thalamo-cortical networks.Here, we investigated rCBF in a large group of initially antipsychotic-naïve patients with schizophrenia or psychosis before and after treatment and related the findings to changes in psychotic symptoms.MethodsrCBF was acquired in 49 initially antipsychotic-naïve patients and 50 matched healthy controls at baseline, and in 32 patients and 53 healthy controls after 6 weeks with the pseudo-Continuous Arterial Spin Labelling (pCASL) sequence. Patients were treated with a partial dopamine D2 receptor agonist (aripiprazole) as monotherapy (mean dose: 10.6±5.4mg).Primary regions of interest of rCBF were thalamus, limbic- and associative striatum. In explorative analyses, we estimated rCBF in sensorimotor striatum, hippocampus-amygdala, and frontal lobe.Psychopathology was assessed with the positive and negative syndrome scale (PANSS).A linear mixed model was used to test if the change in rCBF was different in patients compared with healthy controls (significant interaction) with adjustment for age, sex, and whole brain rCBF. Post hoc tests evaluated possible group differences at baseline and after 6 weeks.In a general linear model, we investigated associations between baseline rCBF in striatum and thalamus and improvement in psychotic symptoms.ResultsrCBF changed over 6 weeks in all striatal regions (associative striatum: p=0.023; limbic striatum: p=0.004; sensorimotor striatum: p=0.004). Post hoc tests of associative striatum indicated no baseline group differences in rCBF (SCZ/HC: 63.4/65.1 mL/100g/min, p=0.59), however rCBF was higher in patients after 6 weeks (SCZ/HC: 68.8/63.2 mL/100g/min, p=0.049). Post hoc tests of limbic striatum indicated no baseline group differences in rCBF (SCZ/HC: 62.7/65.3 mL/100g/min, p=0.25) and no group differences rCBF after 6 weeks (SCZ/HC: 69.3/63.3 mL/100g/min, p=0.12).Post hoc tests of sensorimotor striatum indicated no baseline group differences in rCBF (SCZ/HC: 72.6/71.2 mL/100g/min, p=0.18), however, rCBF was significantly higher in patients after 6 weeks (SCZ/HC: 80.0/67.2 mL/100g/min, p<0.001).There were no group differences in the rCBF changes in thalamus (p=0.09), hippocampus-amygdala (p=0.24), frontal lobe (p=0.90), and the whole brain (p=0.14).In patients, higher baseline rCBF in limbic striatum was associated with less improvement in PANSS positive symptoms (p=0.025). We found no other associations between rCBF and psychopathy.DiscussionThe findings suggest that treatment with a partial dopamine D2 agonist increases rCBF in associative and sensorimotor striatum in initially antipsychotic-naïve patients and that higher rCBF in limbic striatum at baseline is related to poorer treatment outcome. Future studies should investigate the associations between different neurotransmitters and rCBF in vivo. This could further characterize disturbances in cortico-striato-thalamo-cortical networks in schizophrenia or psychosis as well as the effect of treatment.

Efficacy and Tolerability of Dopamine D2 Receptor Partial Agonists Versus D2 Receptor Antagonists in Early Psychosis: A Systematic Review and Meta-Analysis

Early intervention is fundamental for better treatment response and long-term outcomes in schizophrenia. However, there is little guidance in the scientific literature on how best to choose between dopamine D2 receptor (D2R) partial agonists and D2R antagonists in treating early psychosis. In this meta-analysis, D2R partial agonists were directly compared with D2R antagonists for efficacy and tolerability in early psychosis.

Developing New Dopamine D2 Receptor Agonists and Partial Agonists for Parkinson’s Disease and Schizophrenia

Parkinson’s disease (PD) and schizophrenia are neuropsychiatric disorders that affect millions worldwide. Current medications target the dopamine D2 receptor (D2R). However, adverse side effects associated with these medications significantly reduce quality of life and drug compliance. Thus, new therapeutic strategies are clearly needed. D2R activation by agonists can activate cAMP and ß‐arrestin signaling pathways in neurons. Current evidence suggests that new biased D2R agonists—which preferentially activate one pathway over the other—and new D2R partial agonists could provide greater treatment specificity and avoid side effects. In order to develop new D2R‐selective agonists and partial agonists with potential biased signaling properties, new structural templates are needed. The objective of this project is to identify and investigate new D2R ligands with novel chemical scaffolds, with the long‐term goal of producing more effective medications for neuropsychiatric disorders. An initial virtual screen of a ZINC lead‐like library with &gt;3.6 million molecular structures was performed using models of the D2R crystal structure refined into unbiased agonist and G protein‐biased agonist biding modes via molecular dynamics simulations. Following this in silico screen, 8 potentially novel D2R ligands were purchased and tested in radioligand competition binding screens using [3H]N‐methylspiperone and [3H]7‐OH‐DPAT. 6 of 8 purchased compounds (A01, A02, A03, A08, B03, B06) have detectable affinity for D2R (Ki = 0.75–51 μM), demonstrating the feasibility of our approach. New molecular dynamics simulations have been completed to expand in silico screens to include partial agonist and β‐arrestin‐biased agonist binding modes, and to evaluate a larger ZINC library (&gt;17.9 million structures). Studies are ongoing to determine Ki values at D3R and D4R, and to characterize compound efficacy in cAMP and β‐arrestin signaling pathways for each hit compound. Collaborations are in development to build initial analogue libraries of each compound. Each hit compound is a new structural entity with no previously known dopaminergic activity. The identification of new chemical entities with D2R activity will build the foundation for future research to optimize pharmacological parameters for preclinical medications development.Support or Funding InformationThis research is supported by the Rowan University College of Science &amp; Mathematics SEED Fund and the New Jersey Health Foundation. Travel support is provided by the Dean of the College of Science &amp; Mathematics and the Rowan University Provost’s Office.

Role of the treatment environment in the effects of aripiprazole on ethanol-induced behavioral sensitization and conditioned place preference in female mice

BackgroundEvidence suggests that aripiprazole, a partial dopamine D2 and serotonin 5-HT1A receptor agonist and 5-HT2A receptor antagonist, show significant efficacy in reducing alcohol use. We have previously demonstrated that treatment with aripiprazole blocked the reinstatement of cocaine-induced behavioral sensitization in a context-dependent manner, suggesting that the treatment environment may modulate the therapeutic effects of aripiprazole. The present study aimed to evaluate the effects of treatment with aripiprazole on ethanol-induced behavioral sensitization and conditioned place preference in female mice, and the role of the treatment environment in those effects. MethodsAdult female mice were either sensitized with ethanol injections in the open-field apparatus, or conditioned with ethanol in the conditioned place preference (CPP) apparatus. Animals were then treated with vehicle or 0.1 mg/kg aripiprazole paired to the test environment (open-field or CPP apparatus) or not (home-cage treatments) for 4 alternate days, and the subsequent expression of behavioral sensitization or CPP to ethanol was evaluated during or following an ethanol re-exposure, respectively. ResultsRepeated treatment with aripiprazole attenuated the expression of ethanol-induced behavioral sensitization regardless of the treatment environment. Treatment with aripiprazole was only effective at preventing the reinstatement of ethanol-induced CPP when paired with the ethanol-associated environment, but not when administered in the home-cage. ConclusionsThe present findings corroborate previous studies suggesting the effectiveness of aripiprazole for the treatment of alcohol use disorder. Our results also point to an important role of the treatment environment in the therapeutic effects of aripiprazole in rodent models of ethanol abuse.

Hypersexuality and new sexual orientation following aripiprazole use

Aripiprazole is a dopamine D2 receptor partial agonist infrequently associated with sexual side‐effects. Here the authors present a case of hypersexuality and new‐onset homosexual behaviour, following use of aripiprazole in a male patient, which resulted in discontinuation of aripiprazole and subsequent elimination of the side‐effects.

Chronic unpredictable mild stress-induced behavioral changes are coupled with dopaminergic hyperfunction and serotonergic hypofunction in mouse models of depression

Accumulating evidence shows that stressful events evoke molecular alterations in the brain, considered a pathology in major depressive disorder (MDD). However, the abnormalities of neurotransmissions as well as intracellular signaling pathways affected by chronic stress in brain have not been fully explored. We investigated the effect of chronic unpredictable mild stress (CUMS) on the emotional behaviors, dopaminergic and serotoninergic function, and intracellular signaling in the nucleus accumbens, hippocampus and prefrontal cortex. Male C57BL/6J mice were exposed to CUMS for 4 weeks. CUMS was shown to induce hyperactivity in a novel environment, decrease interaction time in the social interaction test, prolong feeding latency in the novelty suppressed feeding test and enhance immobility in the forced swimming test. The levels of dopamine, its metabolites and turnover, and protein level of tyrosine hydroxylase (TH) were increased by CUMS in the nucleus accumbens (NAc). The level of serotonin and protein levels of tryptophan hydroxylase (TPH) and TH were decreased by CUMS in the hippocampus (HPC) and prefrontal cortex (PFC). Accompanying the increase in dopaminergic function, phosphorylation levels of extracellular signal-regulated kinases (ERK), protein kinase B (Akt) and cAMP response element-binding protein (CREB) were increased by CUMS in the NAc. Administration of fluoxetine (selective serotonin re-uptake inhibitor: 20 mg/kg i.p.) and aripiprazole (dopamine D2 receptor partial agonist: 0.1 mg/kg i.p.) during CUMS, prevented behavioral changes and increase of dopamine level in the NAc. These data suggest that CUMS-induced depression-like behaviors are coupled with dopaminergic hyperfunction in the NAc and serotonergic hypofunction in the HPC and PFC.

Modulation by chronic antipsychotic administration of PKA- and GSK3β-mediated pathways and the NMDA receptor in rat ventral midbrain.

Antipsychotics exert therapeutic effects by modulating various cellular signalling pathways and several types of receptors, including PKA- and GSK3β-mediated signalling pathways, and NMDA receptors. The ventral midbrain, mainly containing the ventral tegmental area (VTA) and substantia nigra (SN), are the nuclei with dopamine origins in the brain, which are also involved in the actions of antipsychotics. Whether antipsychotics can modulate these cellular pathways in the ventral midbrain is unknown. This study aims to investigate the effects of antipsychotics, including aripiprazole (a dopamine D2 receptor (D2R) partial agonist), bifeprunox (a D2R partial agonist), and haloperidol (a D2R antagonist) on the PKA- and GSK3β-mediated pathways and NMDA receptors in the ventral midbrain. Male rats were orally administered aripiprazole (0.75mg/kg, t.i.d. (ter in die)), bifeprunox (0.8mg/kg, t.i.d.), haloperidol (0.1mg/kg, t.i.d.) or vehicle for either 1week or 10weeks. The levels of PKA, p-PKA, Akt, p-Akt, GSK3β, p-GSK3β, Dvl-3, β-catenin, and NMDA receptor subunits in the ventral midbrain were assessed by Western Blots. The results showed that chronic antipsychotic treatment with aripiprazole selectively increased PKA activity in the VTA. Additionally, all three drugs elevated the activity of the Akt-GSK3β signalling pathway in a time-dependent manner, while only aripiprazole stimulated the Dvl-3-GSK3β-β-catenin signalling pathway in the SN. Furthermore, chronic administration with both aripiprazole and haloperidol decreased the expression of NMDA receptors. This study suggests that activating PKA- and GSK3β-mediated pathways and downregulating NMDA receptor expression in the ventral midbrain might contribute to the clinical effects of antipsychotics.