PCP AND MIDBRAIN DOPAMINE NEURONS: CELLULAR NEUROBIOLOGY

苯环利定(PCP)仍然是一种滥用药物，可以 在人的行为中产生深刻的变化，需要实质性的 要了解其对中央银行的影响，努力是至关重要的。 神经系统功能。中描述的研究的总体目标 本建议旨在确定五氯苯酚对正常人体的作用机制(S) 大鼠中枢神经系统内的神经生物学过程。 具体地说，五氯苯酚对中脑多巴胺神经元(A10)的影响。 腹侧被盖区(VTA)及VTA传入对其的影响 这些细胞已经被选中进行研究。与其他滥用药物一样 (如可卡因)、A10-多巴胺神经元和中脑边缘-中皮质 它们所支配的结构被认为是解剖学和 可能与增强性能有关的生化底物 五氯苯酚。此外，这些相同的结构被认为是 精神分裂症的病理生理学，因此，似乎与 常由五氯酚引起的精神病样效应。在现在 建议，我们将使用细胞外的电生理方法 结合选择性损伤和药理学的记录 用于确定发射机标识对以下任一项的贡献的操作 PCP独特的兴奋/抑制作用的增强或减弱 对VTA神经元的影响。此外，细胞内的录音来自 体外制备的VTA脑片中的神经元将用于 提供对急性和慢性PCP影响的深入分析 神经细胞膜特性、化学突触和电压敏感离子 神经元A10多巴胺细胞的电导。概述的项目 这应该使我们能够表征PCP对VTA A10的影响 神经元的直接作用以及传入对神经元的不同贡献 对这些效果的投入。从这些实验中得出的数据将 提供有关五氯苯酚独特药理作用的基本信息 对这个中脑多巴胺系统的作用。这反过来又可能 帮助描述苯环利定滥用的神经生物学后果，以及 因此可能导致更合理的治疗设计 与滥用五氯苯酚有关的各种行为影响和精神病理。

The fact that phencyclidine (PCP) continues to be an abused drug which can produce in man profound alterations in behavior, requires that substantial efforts are crucially necessary to understand its effects on central nervous system function. The overall goal of the studies described in this proposal is to determine the mechanism(s) of action of PCP on normal neurobiological processes within the rat central nervous system. Specifically, the effects of PCP on midbrain dopamine neurons (A10) within the ventral tegmental area (VTA) and the influence of VTA afferents on those cells have been selected for study. As with other drugs of abuse (e.g. cocaine), the A10- dopamine neurons and the mesolimbic-mesocortical structures they innervate have been implicated as anatomical and biochemical substrates likely to be involved in the reinforcing properties of PCP. Also, these same structures are considered underpinnings in the pathophysiology of schizophrenia and, as such, plausibly linked to the psychosis-like effects frequently elicited by PCP. In the present proposal, we will use electrophysiological methods of extracellular recording combined with selective lesions and pharmacological manipulations to determine the transmitter identity contribution to either the intensification or diminishment of PCP's unique excitatory/inhibitory effects on VTA neurons. In addition, intracellular recordings from neurons in the in vitro VTA brain slice preparation will be used to provide an indepth analysis of the effects of acute and chronic PCP on neuronal membrane properties, chemical synapses, and voltage sensitive ion conductances of the neuronal A10 dopamine cells. The projects outlined here should enable us to characterize the consequences of PCP on VTA A10 neurons directly, and the relative contributions made various by afferent inputs to these effects. The data derived from these experiments will provide essential information regarding PCP's unique pharmacological actions on this midbrain dopamine containing system. This in turn may help delineate the neurobiological consequence of phencyclidine abuse, and as such possibly lead to a more rational design of treatments for the various behavioral effects and psychopathologies related to PCP abuse.