PALLIDAL GABA AND ATYPICALITY OF ANTIPSYCHOTIC DRUGS

非典型抗精神病药物（APD）与典型APD的主要区别在于它们具有较低的运动副作用。研究“重复性”的实验方法通常集中在大脑的皮质、纹状体和边缘多巴胺末端区域。然而，关于运动综合症和精神病的研究结果也支持了纹体-扁桃体γ-氨基丁酸（GABA）途径的关键作用。我们具体的总体假设是，苍白球GABA功能的降低介导了某些APD的非典型特征，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，增加苍白球中的GABA释放，而非典型APD（如氯氮平）产生最小的运动副作用，减少苍白球中的GABA释放。此外，只有氯氮平对腹侧苍白球中GABA的减少有影响，腹侧苍白球是一个被认为优先介导“边缘”纹状体输出的苍白球亚区。注射氯氮平后，神经末梢GABA免疫标记的密度增加，这可能是由于突触前GABA释放受到抑制而产生的非典型APD的作用。这种改变苍白球通路中GABA释放的范例可以提供关于非典型APD运动副作用发生率低的线索，并进一步了解苍白球GABA介导非典型APD作用。本文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。第一组实验将检查系统性和位点特异性施用具有高或低运动副作用特征的药物后细胞外和突触前苍白球GABA的变化。 为了测试5-HT 2受体亚型在介导苍白球GABA功能中发挥作用的可能性，第二系列实验将评估5-HT 2A和5-HT 2C受体对苍白球GABA功能的激动和拮抗作用。在最后一组研究中，将在长时间APD给药后研究苍白球GABA功能和运动活动，这与精神病患者中使用的治疗持续时间相似。这些研究将为APD的作用机制提供新的见解，并提供一种新的方法来识别假定的非典型APD。所获得的信息将有助于开发精神障碍，特别是精神分裂症的最佳药物治疗。

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.