CCK AND MIDBRAIN DA SYSTEMS: SPECIFICITY OF ACTIONS

多巴胺（DA）神经元的亚群， 中脑的A9和A10区域含有肽 胆囊收缩素（CCK）。 脑内和微离子导入 施用CCK有效地激发DA细胞亚群 其可以对应于也含有CCK的那些细胞。 在 除了这种短暂的兴奋，CCK发挥更持久的 对DA神经元敏感性的调节作用 静脉注射阿扑吗啡的抑制作用， 微离子电渗DA。初步研究表明， CCK的兴奋和调节作用也可以发生 独立和不同的DA途径起源于 中脑似乎受到静脉内CCK的不同影响。 鉴于中脑DA系统与我们目前的 关于几种神经系统的神经生物学假设， 精神疾病，一系列的研究建议开始， 更详细地探索CCK与已鉴定DA的相互作用 神经元亚群 总的来说， CCK研究一直受到缺乏具体和 强大的对手。 几种新的高活性CCK拮抗剂 对中枢和/或外周CCK受体的亲和力已经被 开发 在本发明的建议中，这些化合物将是 用于研究受体特异性的 CCK对已鉴定亚群的电生理效应 DA神经元 此外，直接和调节 CCK对纹状体神经元的电生理作用将是 表征并与刺激的效果进行比较， 纹状体CCK传入。 希望所获得的信息 这些研究将有助于更好地了解 不同的中脑DA神经元通路的生理学。 这 知识，结合解剖学和 生物化学技术，可能有助于制定可测试的 与中枢神经系统相关的疾病病因学假说 DA神经元功能障碍。

Subpopulations of dopamine (DA)-containing neurons within the A9 and A10 regions of the midbrain contain the peptide cholecysto-kinin (CCK). Intravenously and microiontophoretically administered CCK potently excites a subpopulation of DA cells that may correspond to those cells which also contain CCK. In addition to this transient excitation, CCK exerts a more enduring modulatory effect on DA neurons with regard to their sensitivity to the inhibitory effects of intravenous apomorphine and microiontophoretic DA. Preliminary studies have shown that the excitatory and modulatory effects of CCK can also occur independently and that distinct DA pathways originating in the midbrain appear to be differentially affected by intravenous CCK. Given the relevance of midbrain DA systems to our current hypotheses regarding the neurobiology of several neurological and psychiatric disorders, a series of studies are proposed to begin to explore in more detail the interactions of CCK with identified DA neuronal subpopulations. In general, advancements in the field of CCK research have been hindered by the lack of specific and potent antagonists. Several new CCK antagonists with high affinity for central and/or peripheral CCK receptors have been developed. In the present proposal, these compounds will be employed to investigate the receptor specificity of the electrophysiological effects of CCK on identified subpopulations of DA neurons. In addition, the direct and modulatory electrophysiological effects of CCK on striatal neurons will be characterized and compared to the effects of stimulation of striatal CCK afferents. It is hoped that the information obtained from these studies will lead to a better understanding of the physiology of distinct midbrain DA neuronal pathways. This knowledge, combined with that obtained with anatomical and biochemical techniques, may aid in the formulation of testable hypotheses concerning the etiology of disorders linked to central DA neuronal dysfunction.