D2 Partial Agonist Research Articles

Counteractive effects of antenatal glucocorticoid treatment on D1 receptor modulation of spatial working memory.

RationaleAntenatal exposure to the glucocorticoid dexamethasone dramatically increases the number of mesencephalic dopaminergic neurons in rat offspring. However, the consequences of this expansion in midbrain dopamine (DA) neurons for behavioural processes in adulthood are poorly understood, including working memory that depends on DA transmission in the prefrontal cortex (PFC).ObjectivesWe therefore investigated the influence of antenatal glucocorticoid treatment (AGT) on the modulation of spatial working memory by a D1 receptor agonist and on D1 receptor binding and DA content in the PFC and striatum.MethodsPregnant rats received AGT on gestational days 16–19 by adding dexamethasone to their drinking water. Male offspring reared to adulthood were trained on a delayed alternation spatial working memory task and administered the partial D1 agonist SKF38393 (0.3–3 mg/kg) by systemic injection. In separate groups of control and AGT animals, D1 receptor binding and DA content were measured post-mortem in the PFC and striatum.ResultsSKF38393 impaired spatial working memory performance in control rats but had no effect in AGT rats. D1 binding was significantly reduced in the anterior cingulate cortex, prelimbic cortex, dorsal striatum and ventral pallidum of AGT rats compared with control animals. However, AGT had no significant effect on brain monoamine levels.ConclusionsThese findings demonstrate that D1 receptors in corticostriatal circuitry down-regulate in response to AGT. This compensatory effect in D1 receptors may result from increased DA-ergic tone in AGT rats and underlie the resilience of these animals to the disruptive effects of D1 receptor activation on spatial working memory.

Update on schizophrenia and bipolar disorder: focus on cariprazine.

Schizophrenia and bipolar disorder are severe psychiatric disorders that are frequently associated with persistent symptoms and significant dysfunction. While there are a multitude of psychopharmacologic agents are available for treatment of these illnesses, suboptimal response and significant adverse consequences limit their utility. Cariprazine is a new, novel antipsychotic medication with dopamine D2 and D3 partial agonist effects. Its safety and efficacy have been investigated in acute psychosis of schizophrenia, bipolar mania, bipolar depression, and unipolar depression. Efficacy has been demonstrated in schizophrenia and mania. It is unclear if cariprazine is effective in depression associated with unipolar or bipolar illness. Adverse consequences include extrapyramidal symptoms including akathisia, and various gastrointestinal symptoms. The US Food and Drug Administration (FDA) has recently approved cariprazine. This review will provide clinicians with basic information regarding the research program of cariprazine.

Review of Clinical Handbook of Psychotropic Drugs for Children and Adolescents, 3rd Ed., edited by Dean Elbe, Kalyna Z. Bezchlibnyk-Butler, Adil S. Virani, and Ric M. Procyshyn

[Author Affiliation]Malgorzata Maria Relja. 1 Department of Psychiatry, Dalhousie University, Fredericton, New Brunswick, Canada.Mira Sachdev. 2 A4 - Private Practice, Titusville, Florida.ISBN: 0.88937.456.2. Boston, MA, Hogrefe Publishing, 2014, 362 pages.Address Correspondence to: Malgorzata Maria Relja, MD, Department of Psychiatry, Dalhousie University, 65 Brunswick Street, Fredericton, NB E3B 1G5, Canada, E-mail: margaret.relja@gnb.caMira Sachdev, MD, Private Practice, 860 Century Medical Drive, Titusville, FL 32796, E-mail: mira.sachdev@gmail.comFor most child and adolescent psychiatrists, psychopharmacology is challenging because of the need to stay current while new information is constantly added. Psychotropic medications are powerful agents that treat many disorders, but also can impose a great risk if not used accordingly. We need to keep dry minutiae in our knowledge base and, therefore, there is a great value of a book to serve as a practical resource guide to quickly access relevant information.Dean Elbe, PharmD, a Canadian clinical pharmacist specialist at British Columbia Children's Hospital and colleagues have written a user-friendly book about prescribing psychotropic medications for children and adolescents. This handbook contains prescribing information for the United States and Canada. It fills a void for Canadian practitioners since most other psychopharmacology books readily available in North America only contain prescribing information for the United States. This book is targeted toward multiple disciplines, including child and adolescent psychiatrists, pediatricians, and nurses. Also this book acknowledges indications for adults and is suitable as an adult reference. FDA-approved indications for children and adolescents are emphasized, but nonapproved indications are also included.This book makes dry material more interesting and is pleasing to the eye. There are several things that make this book different from other psychopharmacology resources as opposed to an online reference. As it is spiral bound with text written in landscape format, it is easy to lay the book flat and read both pages at once. As a book, it can be left open on the table; it does not require toggling between screens as with a computerized medical record. Thus, it is easy to highlight and make notations on paper. There are online resources available, but they do not have the easy digestibility of this color-coded volume.The majority of the book is organized into chapters per class of drugs, such as chapters on antidepressants, antipsychotics, mood stabilizers, anxiolytics, hypnotics/sedatives, and drugs for attention-deficit/hyperactivity disorder (ADHD). There are chapters dedicated to drugs/substances of abuse and its substance abuse treatment, electroconvulsive therapy, unapproved treatments of psychiatric disorders, and natural health products. In each chapter there are color-coded sections such as Indications, Dosing, Pharmacokinetics, Switching Formulations, Adverse Effects, Discontinuation Syndrome, Contraindications, Toxicity, Monitoring, Use in Pregnancy, and Nursing Implications. There is also a set of caregiver information sheets available online.Many of the chapters function as review articles about a class of medications. Basic psychopharmacology is covered well. For example, the chapter on antipsychotics contained an excellent clinical description of dopaminergic rebound in two sentences. If a high D2 affinity medication (e.g., risperidone) is abruptly replaced with a low D2 affinity medication or a rapid on/off fast-dissociating antipsychotic (e.g., quetiapine) or a partial D2 agonist (e.g., aripiprazole), dopaminergic rebound may result. In the mesolimbic tract, this could lead to supersensitivity psychosis; in the nigrostriatal tract, treatment-emergent EPS and TD may materialize (p. 194).The many tables in each chapter are one of the best features. …

Cariprazine for the Treatment of Bipolar Disorder.

To review the data regarding a new antipsychotic, cariprazine. Cariprazine is a dopamine D3, D2 partial agonist, with greater affinity to D3. It has been examined for schizophrenia, bipolar mania, bipolar depression, and unipolar depression. It has demonstrated efficacy in schizophrenia and mania, and has recently been approved by the U.S. Food and Drug Administration. However, it has a more inconsistent effect in depression, both unipolar and bipolar. Adverse effects include extrapyramidal symptoms, akathisia, and gastrointestinal distress. Cariprazine will be a promising addition in the treatment of patients with acute mania and schizophrenia.

Which role for brexpiprazole, a new dopamine D2 partial agonist, in the treatment of schizophrenia?

ABSTRACT FROM: Correll CU, Skuban A, Ouyang J, et al . Efficacy and safety of brexpiprazole for the treatment of acute schizophrenia: a 6-Week Randomized, Double-Blind, Placebo-Controlled Trial. Am J...

Brexpiprazole: A Review in Schizophrenia.

Oral brexpiprazole (Rexulti(®)) is a partial dopamine D2 agonist, which also has activity at several other receptors. This article reviews the pharmacological properties of brexpiprazole and its clinical efficacy and tolerability in patients with schizophrenia; its use in patients with major depressive disorder is beyond the scope of this review. Brexpiprazole 2-4mg/day was generally effective in short-term, phase III studies at improving Positive and Negative Symptom Scale scores and other schizophrenia symptoms in patients with acute schizophrenia. Moreover, maintenance treatment with brexpiprazole 1-4mg/day was associated with a significantly longer time to exacerbation of disease or impending relapse than placebo. The drug was well tolerated in clinical trials, with most serious adverse events in the short term being associated with the underlying disorder. Overall, oral brexpiprazole is a useful treatment option for the treatment of patients with schizophrenia.

An investigation into aripiprazole's partial D₂ agonist effects within the dorsolateral prefrontal cortex during working memory in healthy volunteers.

RationaleWorking memory impairments in schizophrenia have been attributed to dysfunction of the dorsolateral prefrontal cortex (DLPFC) which in turn may be due to low DLPFC dopamine innervation. Conventional antipsychotic drugs block DLPFC D2 receptors, and this may lead to further dysfunction and working memory impairments. Aripiprazole is a D2 receptor partial agonist hypothesised to enhance PFC dopamine functioning, possibly improving working memory.ObjectivesWe probed the implications of the partial D2 receptor agonist actions of aripiprazole within the DLPFC during working memory. Investigations were carried out in healthy volunteers to eliminate confounds of illness or medication status. Aripiprazole’s prefrontal actions were compared with the D2/5-HT2A blocker risperidone to separate aripiprazole’s unique prefrontal D2 agonist actions from its serotinergic and striatal D2 actions that it shares with risperidone.MethodA double-blind, placebo-controlled, parallel design was implemented. Participants received a single dose of either 5 mg aripiprazole, 1 mg risperidone or placebo before performing the n-back task whilst undergoing fMRI scanning.ResultsCompared with placebo, the aripiprazole group demonstrated enhanced DLPFC activation associated with a trend for improved discriminability (d’) and speeded reaction times. In contrast to aripiprazole’s neural effects, the risperidone group demonstrated a trend for reduced DLPFC recruitment. Unexpectedly, the risperidone group demonstrated similar effects to aripiprazole on d’ and additionally had reduced errors of commission compared with placebo.ConclusionAripiprazole has unique DLPFC actions attributed to its prefrontal D2 agonist action. Risperidone’s serotinergic action that results in prefrontal dopamine release may have protected against any impairing effects of its prefrontal D2 blockade.Electronic supplementary materialThe online version of this article (doi:10.1007/s00213-016-4234-9) contains supplementary material, which is available to authorized users.

Aripiprazole once-monthly long-acting injectable for the treatment of schizophrenia

ABSTRACTIntroduction: Patient non-adherence increases the risk for relapse and the long-term care of schizophrenia. Long-acting injectable (LAI) antipsychotics can decrease this risk by ensuring adherence. An extended formulation, aripiprazole 400 mg once-monthly (AOM 400) LAI (AOM LAI), received regulatory approval in the year 2013 for the treatment of schizophrenia. AOM LAI is the first dopamine D2 partial agonist available in a long-acting formulation for the treatment of schizophrenia.Areas covered: This review covers data on the efficacy and tolerability/safety of AOM LAI. AOM LAI is a lyophilized powder of aripiprazole, with an elimination half-life of 29.9 – 46.5 days, allowing for a 4-week injection interval. Antipsychotic efficacy was documented in a 12-week double-blind trial (n = 340) and in two maintenance-of-effect trials: a 38-week trial (n = 662) and a 52-week trial (n = 403). The side effect profile is similar to that of oral aripiprazole. Adverse events (≥5% and at least twice that for placebo) were typically mild or moderate and did not lead to discontinuation: increased weight, akathisia, injection site pain and sedation. The 400 mg dose is tolerated by >90% of patients. Injection does not require additional training of health personnel or post-injection observation.Expert opinion: AOM LAI is an efficacious and well-tolerated antipsychotic treatment for schizophrenia.

Arylpiperazinylalkyl derivatives of 8-amino-1,3-dimethylpurine-2,6-dione as novel multitarget 5-HT/D receptor agents with potential antipsychotic activity

A series of new 7-arylpiperazinylalkyl-1,3-dimethyl-purine-2,6-dione derivatives with diversified 8-amino substituent in 8 position was synthesized and their 5-HT1A, 5-HT2A, 5-HT6, 5-HT7, and D2 receptor affinities were determined. The binding study allowed identifying some potent 5-HT1A/5-HT2A/5-HT7/D2 ligands. The most interesting because of their multireceptor profile were 8-piperidine (30–35) and 8-dipropylamine (45–47) analogs with four and five carbon aliphatic linkers. The selected compounds 24, 31, 34, 39, 41, 43, 45, and 46 in the functional in vitro evaluation for all targeted receptors showed significant partial D2 agonist, partial 5-HT1A agonist, and 5-HT2A antagonist properties. The advantageous in vitro affinity of compound 34 for 5-HT1A and D2 receptors has been explained by means of molecular modeling, taking into consideration its partial agonist activity towards the latter one. In behavioral studies, compounds 32 and 34 revealed antipsychotic-like properties, significantly decreasing d-amphetamine-induced hyperactivity in mice.

C.06.04 Novel dopamine D2 partial agonists in the treatment of schizophrenia

C.06.04 Novel dopamine D2 partial agonists in the treatment of schizophrenia

Identification of 2-aminothiazolobenzazepine metabolites in human, rat, dog, and monkey microsomes by ion-molecule reactions in linear quadrupole ion trap mass spectrometry.

2-Aminothiazolobenzazepine (2-ATBA), 7-[(1-methyl-1H-pyrazol-4-yl)methyl]-6,7,8,9-tetrahydro-5H-[1,3]thiazolo[4,5-h][3]benzazepin-2-amine, is a D2 partial agonist that has demonstrated antipsychotic effects in a rodent in vivo efficacy model. The metabolite profile showed that 2-ATBA is mainly metabolized by oxidation. However, identification of the oxidation site(s) in the 2-aminothiazole group presents a challenge for the traditional metabolite identification methods such as liquid chromatography/mass spectrometry and NMR due to the lack of unique tandem mass spectrometry fragmentation patterns for ions with the 2-aminothiazole group oxidized at different sites and the lack of stability for purification or reference standard synthesis. We describe the characterization of the oxidized heteroatoms of the 2-aminothiazole group via gas-phase ion-molecule reactions (GPIMR) in a modified linear quadrupole ion trap mass spectrometer. The GPIMR reagents used were dimethyl disulfide, tert-butyl peroxide, and tri(dimethylamino)borane. Each reagent was introduced into the ion trap through the helium line and was allowed to react with the protonated metabolites. The ionic ion-molecule reaction products and their fragmentation profiles were compared with the profiles of the ionic ion-molecule reaction products of protonated reference compounds that had specific heteroatom functionalities. The oxidized 2-aminothiazole metabolite of 2-ATBA showed a similar GPIMR profile to that of the reference compounds with a tertiary N-oxide functionality and distinct from the profiles of the reference compounds with N-aryl hydroxylamine, nitroso, or pyridine N-oxide functionalities. This study demonstrates the feasibility of fingerprinting the chemical nature of oxidized nitrogen functional groups via GPIMR profiling for metabolite structure elucidation.

Prolongation of Hyperprolactinemia by Clozapine: A Case Report

Dopamine antagonism by antipsychotic drugs in the mesolimbic pathway leads to their therapeutic effect, while their D2 receptor antagonism in the tuberoinfindibular pathway causes hyperprolactinemia. Atypical (second generation) antipsychotics cause a significantly smaller increase in PRL levels than typical antipsychotics. The main reason for this is that atypical antipsychotics have more affinity for serotonin 2A (5-HT2A) receptors than D2 receptors. Clozapine has weak affinity for D2 receptors in the nigrostriatal and tuberoinfundibular pathways. Thus, clozapine is accepted to have minimal extrapyramidal side effects, to not cause tardive dyskinesia and have little effect on serum prolactin levels. This is the report of a patient who developed galactorrhea and extrapyramidal side effects (EPS) due to amilsulpiride but galactorrhea continued even after amisulpride was switched to clozapine. The serum prolactin level was normalized after stopping clozapine treatment but her psychotic symptoms relapsed. Clozapine was started again but this time it was combined with aripiprazole, a partial D2 agonist agent, which has been emphasized in the literature as a treatment for antipsychotic induced hyperprolactinemia. The patient’s psychiatric symptoms disappeared and her serum prolactin level returned to normal after this combination treatment.

Killing two birds with one stone: The potential role of aripiprazole for patients with comorbid major depressive disorder and nicotine dependence via altering brain activity in the anterior cingulate cortex

The high comorbidity between major depressive disorder (MDD) and nicotine dependence (ND) is well recognized. Patients with comorbid MDD and ND often have increased suicidal risk and poor outcomes. A dysfunctional dopaminergic brain reward system might be a neurobiological link between MDD and ND. Aripiprazole has been considered as a dopamine stabilizer and was the first atypical antipsychotic agent approved by the US Food and Drug Administration as an adjunctive to the treatment of unipolar MDD. Bupropion is well known as a dual norepinephrine and dopamine reuptake inhibitor, and has been shown to be effective in smoking cessation. One reason bupropion is useful in treating ND is that it enhances the level of dopamine in the brain. Aripiprazole might act as a dopamine agonist similar to the way that bupropion does because of its partial dopamine D2 agonist and 30% intrinsic dopaminergic activity. Several recent studies have applied the unique pharmacodynamic characteristics of aripiprazole to treat patients with ND. Based on neuroimaging findings, aripiprazole can reduce substance cravings by altering brain activity, particularly in the brain regions of the anterior cingulate cortex. Therefore, we hypothesize that adjunctive aripiprazole with antidepressant may be an effective treatment for patients with MDD and ND comorbidity. A new drug invention that combines an antidepressant with an adequate dose of aripiprazole thus should be considered. The neurobiological basis for this combination to treat patients with MDD and ND comorbidity deserves further study.

<i>l</i>-Stepholidine Blocks Methamphetamine-Induced Locomotor Sensitization in Mice

Repeating administration of methamphetamine (METH) can result in locomotor sensitization, a progressive increase in their psychomotor activating effects. l-Stepholidine (l-SPD), an alkaloid extract of the Chinese herb Stephania intermedia, is the first compound known to exhibit mixed dopamine D1 receptor agonist/D2 antagonist properties and is a potential medication for the treatment of drug addiction. Therefore, the effects of l-SPD on the hyperactivity, development and expression of METH-induced locomotor sensitization were investigated. The results indicated that l-SPD dose-dependently inhibited hyperlocomotion induced by acute METH and prevented the sensitized motor behavior induced by chronic METH administration. l-SPD likely acts as a D1 partial agonist and a D2 antagonist to produce its in vivo effects and may be a promising agent for treatment of METH addiction.

Brexpiprazole I: In Vitro and In Vivo Characterization of a Novel Serotonin-Dopamine Activity Modulator

Brexpiprazole (OPC-34712, 7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}quinolin-2(1H)-one) is a novel drug candidate in clinical development for psychiatric disorders with high affinity for serotonin, dopamine, and noradrenaline receptors. In particular, it bound with high affinity (Ki < 1 nM) to human serotonin 1A (h5-HT1A)-, h5-HT2A-, long form of human D2 (hD2L)-, hα1B-, and hα2C-adrenergic receptors. It displayed partial agonism at h5-HT1A and hD2 receptors in cloned receptor systems and potent antagonism of h5-HT2A receptors and hα1B/2C-adrenoceptors. Brexpiprazole also had affinity (Ki < 5 nM) for hD3-, h5-HT2B-, h5-HT7-, hα1A-, and hα1D-adrenergic receptors, moderate affinity for hH1 (Ki = 19 nM), and low affinity for hM1 receptors (Ki > 1000 nM). Brexpiprazole potently bound to rat 5-HT2A and D2 receptors in vivo, and ex vivo binding studies further confirmed high 5-HT1A receptor binding potency. Brexpiprazole inhibited DOI (2,5-dimethoxy-4-iodoamphetamine)-induced head twitches in rats, suggestive of 5-HT2A antagonism. Furthermore, in vivo D2 partial agonist activity of brexpiprazole was confirmed by its inhibitory effect on reserpine-induced DOPA accumulation in rats. In rat microdialysis studies, brexpiprazole slightly reduced extracellular dopamine in nucleus accumbens but not in prefrontal cortex, whereas moderate increases of the dopamine metabolites, homovanillic acid and DOPAC (3,4-dihydroxy-phenyl-acetic acid), in these areas also suggested in vivo D2 partial agonist activity. In particular, based on a lower intrinsic activity at D2 receptors and higher binding affinities for 5-HT1A/2A receptors than aripiprazole, brexpiprazole would have a favorable antipsychotic potential without D2 receptor agonist- and antagonist-related adverse effects. In conclusion, brexpiprazole is a serotonin-dopamine activity modulator with a unique pharmacology, which may offer novel treatment options across a broad spectrum of central nervous system disorders.

Efficacy and safety of yokukansan in treatment-resistant schizophrenia: a randomized, double-blind, placebo-controlled trial (a Positive and Negative Syndrome Scale, five-factor analysis).

Treating schizophrenia patients who fail to respond to antipsychotics is a major challenge, and the percentage of treatment-resistant patients is estimated to be 20-25 %. Recent studies indicate that yokukansan (YKS; D2 and 5HT1A partial agonist and 5HT2A and glutamate antagonist) to be safe and useful in treating behavioral and psychological symptoms associated with dementia and other neuropsychiatric conditions. We aimed at evaluating both the efficacy and safety of YKS in patients with treatment-resistant schizophrenia. This randomized, multicenter, double-blind, placebo-controlled study was conducted between May 2010 and August 2012. One hundred twenty antipsychotic-treated inpatients from 34 psychiatric hospitals in Japan were included. Patients were randomized to adjuvant treatment with YKS 7.5 g/day or placebo. During a 4-week follow-up, psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS) with five factors [excitement/hostility (P4, P7, G8, and G14), depression/anxiety (G1, G2, G3, G4, and G6), cognition (P2, N5, N7, G5, G10, G11, G12, G13, and G15], positive (P1, P3, P5, P6, and G9), and negative (N1, N2, N3, N4, N6, G7, and G16]]. Other assessments included, Clinical Global Impression-Severity (CGI-S), Global Assessment of Functioning (GAF), and Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS). The primary efficacy outcome was the change in PANSS five-factor scores. The secondary outcomes were changes in the scores of CGI-S. The analysis was made on a modified intention to treat basis with the help of a last observation carried forward method. YKS showed a tendency of superiority to placebo in reducing total all PANSS five-factor scores in treatment-resistant schizophrenia, but the difference was not statistically significant in total, depression/anxiety, cognition, positive, and negative factors. However, compared to the placebo group, the YKS group showed statistically significant improvements in the PANSS excitement/hostility factor scores (p<0.05). No substantial side effects were recorded. The results of the present study indicate YKS to be a potential adjunctive treatment strategy for treatment-resistant schizophrenia, particularly to improve excitement/hostility symptoms.

Different effects of Bifeprunox, Aripiprazole, and Haloperidol on body weight gain, food and water intake, and locomotor activity in rats

Following on the success of Aripiprazole with its high clinical efficacy and minimal side effects, further antipsychotic drugs (such as Bifeprunox) have been developed based on the same dopamine D2 partial agonist pharmacological profile as Aripiprazole. However clinical trials of Bifeprunox have found differing results to that of its predecessor, without the same significant clinical efficacy. This study has therefore investigated the different effects of 10week treatment with Aripiprazole (0.75mg/kg, 3 times per day), Bifeprunox (0.8mg/kg, 3 times per day) and Haloperidol (0.1mg/kg, 3 times per day) on body weight gain, food and water intake, white fat mass, and 8week treatment on locomotor activity. Treatment with Bifeprunox was found to significantly reduce all of the measured parameters except white fat mass compared to the control group. However, Aripiprazole and Haloperidol treatment reduced water intake compared to the control, without any significant effects on the other measured parameters. These findings further demonstrate the potential pharmacological differences between Aripiprazole and Bifeprunox, and identify potential weight loss side effects and increased anxiety behaviour with Bifeprunox treatment.

The dopaminergic stabilizers pridopidine and ordopidine enhance cortico-striatal Arc gene expression.

The dopaminergic stabilizers pridopidine [4-(3-(methylsulfonyl)phenyl)-1-propylpiperidine] and ordopidine [1-ethyl-4-(2-fluoro-3-(methylsulfonyl)phenyl)piperidine] inhibit psychostimulant-induced hyperactivity, and stimulate behaviour in states of hypoactivity. While both compounds act as dopamine D2 receptor antagonists in vitro, albeit with low affinity, their specific state-dependent behavioural effect profile is not shared by D2 receptor antagonists in general. To further understand the neuropharmacological effects of pridopidine and ordopidine, and how they differ from other dopaminergic compounds in vivo, we assessed the expression of activity-regulated cytoskeleton-associated protein/activity-regulated gene 3.1 (Arc),an immediate early gene marker associated with synaptic activation, in the frontal cortex and striatum. Furthermore, monoamine neurochemistry and locomotor activity were assessed. The effects of pridopidine and ordopidine were compared to reference dopamine D1 and D2 receptor agonists and antagonists, as well as the partial dopamine D2 agonist aripiprazole. Pridopidine and ordopidine induced significant increases in cortical Arc expression, reaching 2.2- and 1.7-fold levels relative to control, respectively. In contrast, none of the reference dopamine D1 and D2 compounds tested increased cortical Arc expression. In the striatum, significant increases in Arc expression were seen with both pridopidine and ordopidine as well as the dopamine D2 receptor antagonists, remoxipride and haloperidol. Interestingly, striatal Arc expression correlated strongly and positively with striatal 3,4-dihydroxyphenylacetic acid, suggesting that antagonism of dopamine D2 receptors increases Arc expression in the striatum. In conclusion, the concurrent increase in cortical and striatal Arc expression induced by pridopidine and ordopidine appears unique for the dopaminergic stabilizers, as it was not shared by the reference compounds tested. The increase in cortical Arc expression is hypothesized to reflect enhanced N-methyl-D-aspartic acid receptor-mediated signalling in the frontal cortex, which could contribute to the state-dependent locomotor effects of pridopidine and ordopidine.

Effects of selective dopamine D3 receptor compounds in nonhuman primate models of cocaine and methamphetamine abuse (661.8)

Within the dopaminergic system, the D3R has been shown to mediate many of the behavioral effects of psychostimulants associated with high abuse potential. The present studies examined the effects of D3‐selective partial agonists and D3/D2R antagonists in three models of cocaine and MA abuse in rhesus monkeys. The highly selective D3 partial agonist PG619 and the D3/D2R antagonists buspirone and eticlopride were administered chronically to monkeys self‐administering cocaine and MA (n=3/group) under a food‐drug choice procedure in which complete cocaine and MA dose‐response curves were determined each session. Neither PG 619 (0.1‐3.0 mg/kg, i.v.), buspirone (0.01‐0.3 mg/kg, i.m.) nor eticlopride (0.001‐0.01 mg/kg, i.v.) significantly decreased cocaine or MA choice and intake while buspirone significantly increased the choice of low drug doses. The ability of buspirone to block reinstatement was also examined. Using the choice procedure in which saline was substituted for the self‐administered drug, buspirone (1.0‐1.7 mg/kg, p.o.) was found to block both cocaine‐ and MA‐induced reinstatement. In relation to this, buspirone (0.03‐0.3 mg/kg, i.m.) was also found to be effective in blocking cocaine and MA discrimination in a separate group of monkeys (n=3/group). Overall, these data indicate that while buspirone did not block the reinforcing effects of stimulants when studied under a food‐drug choice paradigm, it was effective in reducing reinstatement and in attenuating the discriminative stimulus effects of cocaine and MA, supporting a potential use for this compound in drug abuse treatment. DA012460Grant Funding Source: Supported by DA012460

Treatment of Antipsychotic-Induced Hyperprolactinemia: An Update on the Role of the Dopaminergic Receptors D2 Partial Agonist Aripiprazole

Hyperprolactinemia is an unwanted adverse effect present in several typical and atypical antipsychotics. Aripiprazole is a drug with partial agonist activity at the level of dopamine receptors D2, which may be effective for antipsychotic- induced hyperprolactinemia. Therefore, we analyzed the literature concerning the treatment of antipsychoticinduced hyperprolactinemia with aripiprazole by updating a previous paper written on the same topic. More recent studies were reviewed. They showed that there are two options for the treatment of antipsychotic-induced hyperprolactinemia with aripiprazole. The safest strategy may require the addition of aripiprazole to ongoing treatments, in the case patients had previously responded to antipsychotic drugs and then developed hyperprolactinemia. However, it is advisable to monitor the patients in case relapses and/or side effect, although rare, might occur. Switching drugs should be considered when a patient does not appear to be responding to the previous antipsychotic, thus developing hyperprolactinemia. A cross-taper switch should always be considered, but the risk of a relapse in the disorder may occur more frequently and the patients should be closely monitored. However, limitations must be considered and further studies are needed to definitely elucidate this important issue. Some relevant patents are also described in this review.