PALLIDAL GABA AND ATYPICALITY OF ANTIPSYCHOTIC DRUGS

非典型抗精神病药物（apd）与典型抗精神病药物的主要区别在于它们具有较低的运动副作用。研究“非典型性”的实验方法通常集中在大脑皮层、纹状体和边缘多巴胺终端区域。然而，运动综合征和精神疾病的研究结果也支持纹状伞状细胞γ -氨基丁酸（GABA）通路的关键作用。我们的具体假设是，苍白质GABA功能的减少介导了某些apd的非典型特征，并可能是运动副作用发生率低的关键机制。我们实验室最近的数据表明，典型的apd（如氟哌啶醇）产生运动副作用并增加苍白球中GABA的释放，而非典型apd（如氯氮平）产生最小的运动副作用并减少苍白球中GABA的释放。此外，只有氯氮平对减少侧侧苍白球GABA有作用，而侧侧苍白球亚区被认为优先调节“边缘”纹状体输出。非典型apd的作用可能是由于氯氮平注射后神经末梢GABA免疫标记密度增加，从而抑制突触前GABA释放。这种在苍白质通路中GABA释放改变的模式可能为非典型APD运动副作用的低发生率提供线索，并进一步加深我们对苍白质GABA介导非典型APD作用的理解。这里提出的一系列研究将利用急性和慢性APD给药的啮齿动物模型来回答几个问题。第一组实验将检查在系统和部位特异性给药后细胞外和突触前白斑GABA的变化，这些药物具有高或低的运动副作用。为了验证5-HT2受体亚型介导苍白质GABA功能的可能性，第二系列实验将评估5-HT2A和5-HT2C受体对苍白质GABA功能的激动和拮抗作用。在最后一组研究中，将在延长APD治疗时间（类似于精神病患者的治疗时间）后研究苍白质GABA功能和运动活动。这些研究将为apd的作用机制提供新的见解，并为鉴定推定的非典型apd提供新的方法。所获得的信息将促进精神障碍，特别是精神分裂症的最佳药物治疗的发展。

Atypical anti-psychotic drugs (APDs) are primarily differentiated from typical APDs in that they possess a lower motor side effects profile. Experimental approaches to study "atypicality" have generally focused on cortical, striatal, and limbic dopamine terminal regions of the brain. However,, research findings on motor syndromes and psychosis also support the critical role of striatopallidal gamma-aminobutyric acid (GABA) pathways. Our specific global hypothesis is that decreases in pallidal GABA function mediate the atypical profile of certain APDs and may be a critical mechanism for the low incidence of motor side effects. Recent data from our laboratory has shown that typical APDs (e.g. haloperidol) produce motor side effects and increase GABA release in the globus pallidus, while atypical APDs (e.g. clozapine) produce minimal motor side effects and decrease GABA release in the globus pallidus. Furthermore, only clozapine has an effect on decreasing GABA in the ventral pallidum, a pallidal subregion believed to preferentially mediate "limbic" striatal output. The effect of atypical APDs may result form an inhibition of presynaptic release of GABA, since the density of nerve terminal GABA immunolabeling is increased after clozapine injection. This paradigm of altered GABA release in pallidal pathways could provide clues regarding the low incidence of motor side effects with atypical APDs and further our understanding of pallidal GABA in mediating atypical APD action. The series of studies proposed here will utilize a rodent model of acute and chronic APD administration to answer several questions. The first set of experiments will examine changes in extracellular and presynaptic pallidal GABA after systematic and site- specific administration of drugs with a high or low motor side effect profile. In order to test the possibility that 5-HT2 receptor subtypes play a role in mediating pallidal GABA function, a second series of experiments will assess 5-HT2A and 5-HT2C receptor agonism and antagonism on pallidal GABA function. In a final set of studies, pallidal GABA function and motor activity will be studied after prolonged periods of APD administration which are similar to the treatment durations utilized in psychotic patients. These studies will provide new insights on the mechanisms of action of APDs and provide a novel means of identifying putative atypical APDs. The information obtained will facilitate the development of optimal pharmacotherapy for mental disorders, particularly schizophrenia.