卡利拉嗪:抗精神分裂症新药、多巴胺D3/D2受体部分激动剂

多巴胺D3受体(D3R)是一种G蛋白偶联的D2样受体,多表达于与认知、情绪等脑机能密切相关的边缘区域。以D3R为靶标治疗帕金森病、精神分裂症及药物成瘾等中枢神经系统疾病具有潜在的应用价值,因此高选择性及亲和性的D3R配体的设计合成、结构优化及活性筛选成为研究热点。阿特维斯公司和匈牙利吉瑞大药厂开发的口服新药卡利拉嗪于2015年9月被FDA批准上市,作为一种对D3受体表现出更高亲和力的多巴胺D3/D2受体部分激动剂,用于治疗精神分裂症及双向躁郁症。介绍卡利拉嗪的研发背景、合成方法、临床药理学、临床评价、安全性和耐受性等研究概况。     

Cariprazine (RGH-188), a D3-preferring dopamine D3/D2 receptor partial agonist antipsychotic candidate demonstrates anti-abuse potential in rats

Rationale

Cariprazine (RGH-188) is a D₃-preferring dopamine D₃/D₂ receptor partial agonist antipsychotic candidate for the treatment of schizophrenia and bipolar mania. Substance abuse is a frequent comorbidity of both disorders and is associated with serious health issues. Based on preclinical efficacy, dopamine D₂ and D₃ receptor partial agonists and antagonists are assumed to have relapse-preventing potential in human cocaine addiction.

Objectives

We investigated the anti-abuse potential of cariprazine in cocaine self-administration paradigms. Aripiprazole and bifeprunox were used as comparators because of their pharmacological similarity to cariprazine.

Methods

The effects of compounds on cocaine's rewarding effect were investigated in a continuous self-administration regimen. The relapse-preventing potential of drugs was studied in rats with a history of cocaine self-administration after a period of complete abstinence in a relapse to cocaine-seeking paradigm.

Results

Cariprazine, as well as aripiprazole and bifeprunox, were able to reduce the rewarding effect of cocaine (minimum effective doses were 0.17, 1, and 0.1 mg/kg, respectively) and attenuated relapse to cocaine seeking with half maximal effective dose [ED₅₀] values of 0.2, 4.2, and 0.17 mg/kg, respectively.

Conclusions

These results may predict a relapse-preventing action for cariprazine in humans in addition to its already established antipsychotic and antimanic efficacy.     

多巴胺D3受体部分激动剂BP897的合成

目的：合成多巴胺D3受体部分激动剂BP897。方法：以二羟乙基胺为起始原料，经过氯化、环合、取代、肼解、缩合等反应合成BP897。结果：以总产率为40．2％合成了多巴胺D3受体部分激动剂BP897，结构经核磁氢谱（^1HNMR）、质谱（MS）和红外（IR）确证。结论：该法原料价廉易得，反应条件温和，收率较文献有所提高。     

Evidence for antagonist activity of the dopamine D3 receptor partial agonist, BP 897, at human dopamine D3 receptor

The dopaminergic system has long been implicated in the mechanisms of reward and addiction. 1-(4-(2-Naphthoylamino)butyl)-4-(2-methoxyphenyl)-1A-piperazine HCl (BP 897) has been claimed to be a selective dopamine D3 receptor partial agonist and has recently been shown to inhibit cocaine-seeking behaviour, suggesting a role for dopamine D3 receptor agonists in the treatment of addiction. We have previously characterised the pharmacological profile of the human dopamine D3 and D2(long) receptors using microphysiometry and radioligand binding and we have now studied the interaction of BP 897 with the dopamine D2 and D3 receptors using these methods. At both human dopamine D3 and D2 receptors, BP 897 lacked agonist activity but was a potent and selective antagonist with pK(b) values of 8.05+/-0.16 (4) and 9.43+/-0.22 (4) at human dopamine D2 and D3 receptors, respectively. These results, therefore, suggest that it may be the dopamine D3 receptor antagonist properties of BP 897 which have potential in the treatment of addiction and withdrawal.     

The dopamine D3 receptor partial agonist, BP 897, is an antagonist at human dopamine D3 receptors and at rat somatodendritic dopamine D3 receptors

Recent studies have fueled the interest in dopamine D3 receptor antagonists and partial agonist for the treatment of psychosis and drug abuse, respectively. N-[4-[4-(2-methoxyphenyl)-1-piperazinyl]butyl]naphthalene-2-carboxamide (BP 897) is a dopamine D3 receptor selective ligand recently described as partial agonist with potential effects on drug-dependence. The aim of the present study was to determine both the functional activity of BP 897 at human dopamine D3 receptors expressed in Chinese hamster ovary (CHO) cells and in an electrophysiological in vivo model of dopaminergic activity. BP 897 failed to stimulate the human dopamine D3 receptor and showed antagonistic effects (cpIC(50)=9.51) in a [(35)S]GTPgammaS binding assay in cells expressing the human dopamine D3 receptor. In vivo, BP 897 up to 8.2 mg/kg, i.v., had no agonistic effects on firing rate of substantia nigra dopaminergic neurons and antagonized the quinpirole-induced inhibition of firing (DID(50)=1.1 mg/kg). Our data demonstrate that BP 897 acts, in vivo and in vitro, as a dopamine D3 receptor antagonist.     

Aripiprazole ameliorates phencyclidine-induced impairment of recognition memory through dopamine D1 and serotonin 5-HT1A receptors

Rationale

Cognitive deficits, including memory impairment, are regarded as a core feature of schizophrenia. Aripiprazole, an atypical antipsychotic drug, has been shown to improve disruption of prepulse inhibition and social interaction in an animal model of schizophrenia induced by phencyclidine (PCP); however, the effects of aripiprazole on recognition memory remain to be investigated.

Objectives

In this study, we examined the effect of aripiprazole on cognitive impairment in mice treated with PCP repeatedly.

Materials and methods

Mice were repeatedly administered PCP at a dose of 10mg/kg for 14days, and their cognitive function was assessed using a novel-object recognition task. We investigated the therapeutic effects of aripiprazole (0.01–1.0mg/kg) and haloperidol (0.3 and 1.0mg/kg) on cognitive impairment in mice treated with PCP repeatedly.

Results

Single (1.0mg/kg) and repeated (0.03 and 0.1mg/kg, for 7days) treatment with aripiprazole ameliorated PCP-induced impairment of recognition memory, although single treatment significantly decreased the total exploration time during the training session. In contrast, both single and repeated treatment with haloperidol (0.3 and 1.0mg/kg) failed to attenuate PCP-induced cognitive impairment. The ameliorating effect of aripiprazole on recognition memory in PCP-treated mice was blocked by co-treatment with a dopamine D₁ receptor antagonist, SCH23390, and a serotonin 5-HT_1A receptor antagonist, WAY100635; however, co-treatment with a D₂ receptor antagonist raclopride had no effect on the ameliorating effect of aripiprazole.

Conclusions

These results suggest that the ameliorative effect of aripiprazole on PCP-induced memory impairment is associated with dopamine D₁ and serotonin 5-HT_1A receptors.     

Impaired set-shifting and dissociable effects on tests of spatial working memory following the dopamine D2 receptor antagonist sulpiride in human volunteers

Rationale Dopamine (DA) D₂ receptor antagonists have been shown to produce similar impairments to those seen in Parkinsons disease. These include working memory and set-shifting deficits. Theories of DA function have predicted that distraction or impaired switching may be important determinants of such deficits.Objectives In order to test these hypotheses, we have followed up our previous findings with more refined tests (1) that allow measurement of spatial working memory (SWM) and distraction, (2) that allow separation of executive and mnemonic components of SWM and (3) that allow isolation of set-shifting from learning deficits.Methods Thirty-six young healthy male volunteers were tested on two occasions after oral administration of either 400 mg sulpiride or placebo. All participants performed the delayed response task. Sixteen participants received task-irrelevant distractors during this task, and were also given a self-ordered SWM test. The remaining participants were given delayed response tasks with task-relevant distractors, and tests of attentional and task set-shifting.Results Sulpiride impaired performance of the delayed-response task both without distraction and with task-relevant distraction. By contrast, the drug protected against deficits from task-irrelevant distraction seen in the placebo group. Task set-switching was also impaired by sulpiride, with participants being slower to respond on switch trials compared with non-switch trials. There was also a trend for attentional set-shifting to be impaired following sulpiride. In contrast, self-ordered SWM performance was enhanced by sulpiride on the second test session only.Conclusions These results support models of central DA function that postulate a role in switching behaviour, and in certain aspects of working memory.     

Characterization of aripiprazole partial agonist activity at human dopamine D3 receptors

Aripiprazole is the first dopamine D2/D3 receptor partial agonist approved for use in the treatment of psychiatric disorders, including schizophrenia, bipolar disorder, and unipolar depression in the US. To explore the functional activity of aripiprazole at dopamine D3 receptors, we established Chinese hamster ovary (CHO) cell lines stably expressing high and low densities of Ser-9 and Gly-9 variants of human dopamine D3 receptors and compared aripiprazole's dopamine D3 pharmacological properties with other marketed and non-approved dopamine D3 receptor modulating agents on inhibition of forskolin-stimulated cAMP accumulation. Maximal cell responses for dopamine were dependent on receptor expression levels, and all cells had similar potency for dopamine responses. Aripiprazole, terguride, bifeprunox, OPC-4392 (7-(3-[4-(2,3-dimethylphenyl)piperazinyl]propoxy)-2(1H)-quinolinone), (-)-3-PPP ((-)-3-(3-hydroxyphenyl)-N-n-propylpiperidine), SDZ 208-912 (N-[(8 alpha)-2-chloro-6-methylergolin-8-yl]-2,2-dimethylpropanamide), BP897 (N-[4-[4-(2-Methoxyphenyl)-1-piperazinyl]butyl]naphthalene-2-carboxamide) and GR103691 (4'-Acetyl-N-[4-[4-(2-methoxyphenyl)piperazin-1-yl]butyl]biphenyl-4-carboxamide) behaved as partial agonists. Aripiprazole's intrinsic activity was similar to that of BP897 and GR103691, lower than that of terguride, bifeprunox, OPC-4392, and (-)-3-PPP, and higher than that of SDZ 208-912. The Gly-9 variant did not differ from the Ser-9 variant with respect to those agonist potencies and intrinsic activities. These compounds blocked the action of dopamine with a maximum effect equal to that of each compound alone. ACR16 (4-(3-Methanesulfonyl-phenyl)-1-propyl-piperidine), quetiapine, clozapine, olanzapine, ziprasidone, risperidone, and haloperidol acted as antagonists. Aripiprazole's unique activity at dopamine D3 receptors may translate into clinically relevant outcomes in patients with a variety of neuropsychiatric disorders.     

Terguride, a dopamine D(2) partial agonist, as a discriminative stimulus in rats

Drug discrimination training with terguride, a 9, 10-transdihydrogenated derivative of lisuride, was carried out using a two-lever food-reinforced procedure (FR 10) in rats, to investigate its influence on central dopaminergic (DA) and serotonergic (5-HT) functions. The terguride (0.05mg/kg, i.p.) discrimination was established within 64 +/- 5 training sessions (mean +/- S.E.) and was stably maintained thereafter. Higher doses of terguride could not be used for discriminative training due to response disruption. In generalization tests with terguride, drug-appropriate responding increased dose-dependently and reached levels of 45 and 99% at 0.01 and 0.05mg/kg i.p. The D(2) agonist lisuride at low doses and the DA autoreceptor agonist (-)-3-PPP substituted for terguride. The DA agonist apomorphine and the 5-HT agonist 5-MeO-DMT produced dose-dependent but incomplete substitution. The D(1) agonist SKF38393, the DA antagonist haloperidol, the D(2) antagonist sulpiride, the D(1) antagonist SCH23390, the 5-HT(1A) agonist 8-OH-DPAT, the 5-HT(1B) agonist m-CPP and the 5-HT(2) agonist DOI were not generalized. In antagonism tests, sulpride completely blocked the terguride-appropriate response, but SCH23390 and the 5-HT antagonist methysergide did not. These results indicate that discriminative stimulus properties of terguride in rats are mediated primarily by activation of receptors with characteristics similar to those of presynaptic D(2) autoreceptors.     

Unusual interactions between the neuroleptic haloperidol, and the dopamine D2 partial agonist, terguride

Terguride is an ergoline derivative which has been reported to act as a partial agonist at central dopamine D2 receptors. Depending on the state of the receptor, terguride may resemble an agonist or an antagonist in its pharmacological effects. The present study investigated interactions of terguride with the dopamine D2 antagonist haloperidol in the rat. Terguride (0.025 mg/kg, i.p.) lowered, whereas haloperidol (0.025 mg/kg, s.c.) increased serum prolactin levels. When given together there was a tendency for prolactin to be lowered, i.e. terguride fully antagonized the action of haloperidol. Both terguride and haloperidol dose-dependently reduced locomotor activity, with terguride being at least 50 times more potent. However, in the presence of a subthreshold dose of haloperidol (0.1 mg/kg), terguride was effective in reducing locomotor activity. Terguride and haloperidol were equally potent in disrupting performance of lever pressing for food on a VI 120 sec schedule (ED(50) values 0.22 and 0.28 mg/kg, respectively). When given together, there was a statistically significant interaction; a terguride dose of 0.2 mg/kg lowered rates of lever pressing when given with vehicle or a low (0.03 mg/kg) haloperidol dose, but antagonized the effect of 0.3 mg/kg haloperidol. Terguride dose-dependently disrupted lever pressing for intracranial stimulation reward (ED(50) value approx. 0.3 mg/kg). Haloperidol (0.26 mg/kg) also disrupted lever pressing but the two drugs together showed no greater effect than haloperidol alone. These observations are discussed in the context of terguride's suggested partial agonistic properties.     

A functional MRI study of the effects of bromocriptine,a dopamine receptor agonist,on component processes of working memory

Rationale Dopamine is abundant in the prefrontal cortex and striatum, regions implicated in working memory processes. Monkey studies suggest that subpopulations of prefrontal neurons are sensitive to component processes of working memory, and that dopaminergic actions at D₁ and D₂ receptors differentially affect these neurons. However, it is not known to what extent the effects of dopaminergic stimulation may differ in human subjects across the processing stages of working memory, and whether these effects are found throughout the network of task-related brain regions. Objective In this study we tested the effects of the D₂ dopamine agonist bromocriptine during the performance of a delayed recognition task using functional magnetic resonance imaging (fMRI). Methods We measured blood oxygenation level dependent (BOLD) signals as subjects performed a spatial and object delayed recognition task. Subjects were scanned twice, once following 1.25 mg of bromocriptine and once following lactose placebo in a randomized double-blind design. Using an event-related design allowed for separate investigation of encoding, delay, and response period effects of dopaminergic stimulation. Results A group analysis revealed that bromocriptine treatment decreased activity in the task network at encoding and increased activity at response. There was no clear pattern of change in the delay period network. Across subjects, these BOLD signal changes were accompanied by reductions in accuracy and increases in response time during delayed recognition for spatial and object information. Conclusions Decreased activity during encoding suggests that hyperdopaminergic stimulation may have reduced stimulus encoding processes, contributing to impaired performance.     

Effects of the mGluR2/3 agonist LY354740 on computerized tasks of attention and working memory in marmoset monkeys

Rationale LY354740 is a recently developed metabotropic glutamatergic receptor 2 and 3 (mGluR2/3) agonist. A high density of mGluR2 has been reported in terminal fields of the perforant path in rodents and humans, suggesting its involvement in cognitive functions mediated by the temporal lobe, including memory. A small number of in vivo studies in rodents have assessed the effects of LY354740 on memory tasks, reporting the induction of impaired memory for spatial orientation in a water maze task and for delayed match and non-match to position in an operant version of these tasks.Objective In the present primate study, we used radioautography to describe the distribution and intensity of ³H-LY354740 binding in the hippocampal formation of the common marmoset monkey (Callithrix jacchus) relative to the rat. In the major, in vivo part of the study, the effects of systemic LY354740 on computerized tasks of attention and memory were investigated.Methods Adult common marmosets were trained to perform a five-choice serial reaction time (5-CSRT) task and a concurrent delayed match-to-position (CDMP) task from the Cambridge Neuropsychological Automated test Battery (CANTAB). Filter tests of LY354740 effects on motor dexterity and motivation for reward revealed high inter-individual variation in sensitivity; therefore, on the 5-CSRT, subjects were tested at a dose range of 3–10 mg/kg, and on the CDMP, subjects were tested at 1–3 or 3–10 mg/kg.Results Radioautography revealed a relatively low level of ³H-LY354740 binding in the marmoset hippocampal formation compared to the rat. Despite low binding, LY354740 reduced sustained-attention accuracy in the 5-CSRT, and reduced accuracy in two stages of the CDMP.Conclusions The current study provides novel evidence for the importance of mGluR2/3 in the regulation of primate cognitive functioning.     

Evaluation of the D3 dopamine receptor selective agonist/partial agonist PG01042 on l-dopa dependent animal involuntary movements in rats

The substituted 4-phenylpiperazine D3 dopamine receptor selective antagonist PG01037 ((E)-N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)but-2-enyl)-4-(pyridin-2-yl)benzamide) was reported to attenuate l-dopa-associated abnormal involuntary movements (AIMs) in unilaterally lesioned rats, a model of l-dopa-dependent dyskinesia in patients with Parkinson’s Disease (Kumar et al., 2009a). We now report that PG01042 (N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)-4-(pyridin-3-yl)benzamide), which is a D3 dopamine receptor selective agonist for adenylyl cyclase inhibition and a partial agonist for mitogenesis, is also capable of attenuating AIMs scores. The intrinsic activity of PG01037 and PG01042 were determined using a) a forskolin-dependent adenylyl cyclase inhibition assay and b) an assay for agonist-associated mitogenesis. It was observed that the in vivo efficacy of PG01042 increased when administered by intraperitoneal (i.p.) injection simultaneously with l-dopa/benserazide (8 mg/kg each), as compared to a 60 min or 30 min pretreatment. PG01042 was found to attenuate AIM scores in these animals in a dose dependent manner. While PG01042 did not effectively inhibit SKF 81297-dependent AIMs, it inhibited apomorphine-dependent AIM scores. Rotarod studies indicate that PG01042 at a dose of 10 mg/kg did not adversely affect motor coordination of the unilaterally lesioned rats. Evaluation of lesioned rats using a cylinder test behavioral paradigm indicated that PG01042 did not dramatically attenuate the beneficial effects of l-dopa. These studies and previously published studies suggest that both D3 dopamine receptor selective antagonists, partial agonists and agonists, as defined by an adenylyl cyclase inhibition assay and a mitogenic assay, are pharmacotherapeutic candidates for the treatment of l-dopa-associated dyskinesia in patients with Parkinson’s Disease.     

Desipramine attenuates working memory impairments induced by partial loss of catecholamines in the rat medial prefrontal cortex

Rationale The density of tyrosine hydroxylase-immunoreactive (TH-IR) axons in the prefrontal cortex of schizophrenic subjects may be reduced by as much as 50% in the deep cortical layers (Am J Psychiatry 156:1580–1589, 1999). Previously, we demonstrated that ~60% loss of TH-IR axons in the rat medial prefrontal cortex (mPFC) decreases local basal and stress-evoked extracellular dopamine (DA) concentrations, suggesting that moderate loss of DA axons in the mPFC is sufficient to alter the neurochemical activity of the remaining DA neurons (Neuroscience 93:497–505, 1999). Objectives To further assess the functional consequences of partial mPFC DA depletion, we examined the effects of 6-hydroxydopamine lesions of the rat mPFC on behavior in a T-maze delayed-response task. We also assessed whether chronic administration of the norepinephrine (NE) uptake inhibitor, desipramine (DMI), attenuates lesion-induced deficits in T-maze performance. Previous research indicates that inhibition of NE transport in the mPFC results in a concomitant increase in extracellular DA and NE. Results Moderate loss of mPFC DA and NE (~50 and 10% loss, respectively) was sufficient to impair delayed-response behavior, in part due to an increase in perseverative responding. Chronic DMI treatment (3 mg/kg delivered via osmotic pumps) impaired performance of control rats but attenuated the deficits in delayed-response behavior in rats previously sustaining loss of mPFC DA and NE (~75 and 35% loss, respectively). Conclusion These data suggest that moderate loss of DA and NE in the prefrontal cortex is sufficient to impair cognitive function, and these behavioral effects are attenuated by inhibition of the NE transporter.     

S-21007,强效5-羟色胺3受体部份激动剂,对小鼠焦虑的作用(英文)

AIM: To study the effect of S-21007, a 5-HT_3partial agonist in different animal models of anxiety inmice. METHODS: S-21007 effects were evaluatedin the behavior tests after intraperitioneal and oral acutetreatment or in the light/dark test after both acute andchronic treatments. RESULTS: S-21007 presentedanxiolytic-like properties after acute administration inthe light/dark box test, the mirrored chamber test, andthe elevated plus-maze at be doses 10 ng·kg~(-1)-100μg·kg~(-1), 1-100 μg·kg~(-1) and 10-100 μg·kg~(-1),respectively. In the light/dark box test, S-21007 wasactive orally after acute treatment at 100 ng·kg~(-1)-10mg·kg~(-1) and after chronic treatment (14 d) at 1-10μg·kg~(-1). S-21007 was devoid of sedative or stimula-     

Regulation of working memory by dopamine D4 receptor in rats.

Working memory is regulated by neurotransmitters in prefrontal cortex (PFC), including dopamine and norepinephrine. Previous studies of dopamine function in working memory have focused on the D1 and D2 receptors, with most evidence suggesting a dominant role for the D1 receptor. Since the dopamine D4 receptor is highly expressed in PFC, we hypothesize that it may also contribute to working memory. To test this hypothesis, we examined behavioral effects of L-745,870, a highly selective, centrally active, D4 antagonist, using a delayed alternation task in rats. Task performance was dose-dependently affected by the D4 antagonist, depending on individual baseline functional status of working memory. In rats with good baseline performance, the D4 antagonist had no effects at low doses, whereas high doses disrupted working memory. In rats with poor baseline working memory, the D4 antagonist significantly improved working memory at low doses, and higher doses were not distinguishable from vehicle controls. Effects of the D4 antagonist among poor performers were most robust when task demand for working memory was high, with lesser effects at lower demand level, suggesting that such effects were selective for working memory. The present findings indicate a significant role of the D4 receptor in working memory, and suggest innovative, D4-based, treatment of cognitive deficits associated with neuropsychiatric disorders.     

Sulpiride and mnemonic function: effects of a dopamine D2 receptor antagonist on working memory, emotional memory and long-term memory in healthy volunteers

There is now substantial evidence from animal studies showing modulation of cognitive performance after administration of dopaminergic agents. Previous studies have focused on cognitive functions such as working memory (WM), with particular reference to spatial processing. However, to date, studies in normal human volunteers have proved inconsistent. We have therefore tested the effects of the dopamine D2 receptor antagonist sulpiride (400 mg) on WM and learning tasks, including those using auditory, spatial or non-spatial stimuli. A further aim was to explore a broader role of the dopaminergic system in mnemonic function by examining long-term and emotional memory. Eighteen healthy male participants were given a battery of cognitive tests after oral sulpiride or placebo, using the cross-over design. WM was assessed using a spatial searching task, and a task of auditory counting with distraction. Tasks that did not emphasize WM were spatial and non-spatial trial-and-error learning, long-term spatial memory and emotional memory. After dopamine D2 receptor blockade, performance was not impaired on the spatial WM (SWM) task, but was impaired on the auditory counting task with distraction. Sulpiride did not impair, but rather appeared to enhance trial-and-error learning overall. Thus, we were unable to support the notion that dopaminergic modulation preferentially influences spatial over non-spatial processing during learning. In addition, recognition was impaired in the emotional memory task after encoding on drug compared to placebo. These findings question the precise role of dopamine D2 receptor modulation on WM, and highlight the need for sensitive tests to study dopaminergic modulation of emotional processing.     

Effects of repeated treatment with the dopamine D2/D3 receptor partial agonist aripiprazole on striatal D2/D3 receptor availability in monkeys

Rationale

Chronic treatment with dopamine (DA) receptor agonists and antagonists can differentially affect measures of DA D2/D3 receptor number and function, but the effects of chronic treatment with a partial D2/D3 receptor agonist are not clear.

Objective

We used a within-subjects design in male cynomolgus monkeys to determine the effects of repeated (17-day) treatment with the D2/D3 receptor partial agonist aripiprazole (ARI; 0.03 mg/kg and 0.1 mg/kg i.m.) on food-reinforced behavior (n?=?5) and on D2/D3 receptor availability as measured with positron emission tomography (PET; n?=?9).

Methods

Five monkeys responded under a fixed-ratio 50 schedule of food reinforcement and D2/D3 receptor availability was measured before and 4 days after ARI treatment using PET and the D2/D3 receptor-selective radioligand [¹⁸F]fluoroclebopride (FCP). Four additional monkeys were studied using [¹¹C]raclopride and treated sequentially with each dose of ARI for 17 days.

Results

ARI decreased food-maintained responding with minimal evidence of tolerance. Repeated ARI administration increased FCP and raclopride distribution volume ratios (DVRs) in the caudate nucleus and putamen in most monkeys, but decreases were observed in monkeys with the highest baseline DVRs.

Conclusions

The results indicate that repeated treatment with a low-efficacy DA receptor partial agonist produces effects on brain D2/D3 receptor availability that are qualitatively different from those of both high-efficacy receptor agonists and antagonists, and suggest that the observed individual differences in response to ARI treatment may reflect its partial agonist activity.