PALLIDAL GABA AND ATYPICALITY OF ANTIPSYCHOTIC DRUGS

非典型抗精神病药物(APD)与典型APDS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的皮质、纹状体和边缘多巴胺终末区域。然而，关于运动综合症和精神病的研究结果也支持纹状体苍白质伽玛-氨基丁酸(GABA)通路的关键作用。我们特定的全球假设是，苍白球GABA功能的降低介导了某些APDS的不典型特征，并可能是运动副作用发生率较低的关键机制。我们实验室最近的数据表明，典型的APDS(如氟哌啶醇)会产生运动副作用，增加苍白球的GABA释放，而非典型的APDS(如氯氮平)会产生最小的运动副作用，减少苍白球的GABA释放。此外，只有氯氮平能降低腹侧苍白球内的GABA，苍白球区域被认为优先调节“边缘”纹状体的输出。非典型APDS的作用可能是由于注射氯氮平后神经末梢GABA免疫标记密度增加，从而抑制了突触前GABA的释放。这种苍白球通路中GABA释放变化的范例可以为非典型APDS的运动副作用的低发生率提供线索，并进一步理解苍白球GABA在介导非典型APD作用中的作用。这里提出的一系列研究将利用急性和慢性给药的啮齿动物模型来回答几个问题。第一组实验将检测系统性和局部给药后细胞外和突触前苍白球GABA的变化，这些药物具有高或低运动副作用。为了验证5-HT2受体亚型在调节苍白球GABA功能中的作用，第二系列实验将评估5-HT2A和5-HT2C受体对苍白球GABA功能的激动性和拮抗性。在最后一组研究中，苍白球GABA功能和运动活动将在长时间的APD给药后进行研究，这与精神病患者使用的治疗时间相似。这些研究将为APDS的作用机制提供新的见解，并为识别假定的非典型APD提供一种新的手段。所获得的信息将有助于开发治疗精神障碍，特别是精神分裂症的最佳药物疗法。

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.