IN VITRO ELECTROPHYSIOLOGY OF MIDBRAIN DOPAMINE SYSTEMS

中脑多巴胺系统的体外电生理学

• 批准号: 2245401
• 负责人: ANTHONY A GRACE
• 金额: $ 11.37万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-09-30 至 1996-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2245401
• 关键词: NMDA receptors; Parkinson's disease; action potentials; adrenergic agents; afferent nerve; albino rat; antiadrenergic agents; apomorphine; axon; cell population study; corpus striatum; dendrites; dopamine; dopamine receptor; electrophysiology; fluorescent dye /probe; glutamates; histochemistry /cytochemistry; membrane permeability; membrane potentials; membrane transport proteins; mesencephalon; microdialysis; microelectrodes; neural transmission; neurochemistry; neuropharmacology; neurotransmitter metabolism; radiotracer; receptor sensitivity; stainings; tissue /cell culture; voltage /patch clamp

Dysfunctions of dopaminergic systems are thought to play a role in the etiology of several neurological and psychiatric disorders, such as Parkinson's disease and schizophrenia. However, models of these disorders to date have often failed to take into account the large amount of homeostatic regulation that comes into play whenever these systems are perturbed, and which serve to reset the system towards normality. Another possible approach to investigating the normal functions of this system and its role in disease would be to examine in detail the modes of autoregulation that modulate the activity of dopamine-containing neurons, with a predisposition to examining how deficits in these processes could precipitate dysfunctional states. We have been investigating the membrane processes involved in the self-regulation of dopamine neuron activity using the in vitro rat brain slice preparation, in which confounding environmental or afferent influences can be better controlled. In this proposal, we plan to extend this investigation into dopamine neuron regulation by studying five processes believed to play a role in their function: 1) identifying the spike generating zones within dopamine neurons and their morphological correlates, and in this way enable the study of dopamine neuron regulation in terms of its functional subcompartments; 2) testing the involvement of glutamatergic afferents in the regulation of dopamine neuron firing pattern; 3) examining the functional mechanism of autoreceptor stimulation and factors involved in regulating its sensitivity, for the purpose of studying the autonomous control exerted by the dopamine neuron on its responsivity to its own neurotransmitter; 4) determining the important factors which play a role in controlling dopamine release from dendritic stores, and thus elucidating whether this release is an autoregulatory process or is mediated, as it is in the striatum, by glutamatergic afferent processes; and 5) analyzing the functional implications of the different peptidergic cotransmitters contained within subpopulations of dopamine neurons, detailing their involvement in cell firing and how their co-release may influence autoreceptor sensitivity and peptide interactions in identified subsets of dopamine neurons, which will be classified by combining retrograde labelling from their projection sites and intracellular staining. The validity of the results to the in situ cell class will be determined by carrying out parallel experiments in vivo, when feasible. This type of combined functional and morphological analysis of individual dopamine neurons may thus facilitate the development of models concerning states of psychiatric dysfunction. Furthermore, by examining in detail how these regulatory processes differ between identified subpopulations of dopamine neurons, it may be possible to derive new therapeutic approaches by pharmacologically targeting these regulatory sites, and thereby avoid the debilitating side effects often associated with the use of direct-acting drugs.

多巴胺能系统的功能障碍被认为是在 几种神经和精神疾病的病因，如 帕金森病和精神分裂症。 然而，这些疾病的模型 到目前为止，往往没有考虑到大量的 当这些系统被激活时， 扰动，并用于将系统重置为正常状态。 另一 调查该系统正常功能的可能方法， 它在疾病中的作用将是详细检查 调节含多巴胺神经元活性的自动调节， 倾向于研究这些过程中的缺陷如何 导致机能失调 我们一直在研究 参与多巴胺神经元活动的自我调节过程， 体外大鼠脑片制备，其中混杂 可以更好地控制环境或传入影响。 在这 我们计划将这项研究扩展到多巴胺神经元， 通过研究五个过程来调节，这些过程被认为在其 功能：1）识别多巴胺神经元内的锋电位产生区 以及它们的形态学相关性，并以这种方式使研究 多巴胺神经元的功能亚区调节; 2） 测试多巴胺能传入神经参与调节 多巴胺神经元放电模式; 3）检查的功能机制， 自身受体刺激及其调节因子 灵敏度，目的是研究由 多巴胺神经元对自身神经递质的反应性; 4） 确定控制多巴胺的重要因素 从树枝状存储释放，从而阐明这种释放是否是 一个自动调节过程，或者是介导的，因为它是在纹状体， 神经元传入过程;和5）分析功能性 不同的肽能共递质的影响， 多巴胺神经元的亚群，详细说明了它们参与细胞 以及它们的共同释放如何影响自身受体敏感性， 肽相互作用在确定的多巴胺神经元，这将 通过结合来自其投射部位的逆行标记进行分类 和细胞内染色。 研究结果对现场的有效性 细胞类别将通过进行体内平行实验来确定， 在可行的情况下。 这种功能和形态相结合的分析 因此，单个多巴胺神经元的发育可能有助于 关于精神功能障碍状态的模型。 此外，通过 详细研究这些监管程序在以下方面的差异： 确定多巴胺神经元的亚群，可能会得出 新的治疗方法，通过靶向这些调节 网站，从而避免衰弱的副作用往往与 使用直接作用的药物