Dopaminergic modulation of thalamocortical circuits

描述(由申请人提供)：虽然可卡因成瘾是一种 在这个国家毁灭性的社会和医疗问题，人们对此知之甚少 可卡因对丘脑-皮质边缘环路的生理作用。 这一回路涉及认知和情绪处理，被认为是 与在吸毒者身上观察到的行为障碍有关。在这份提案中， 我们概述了一个研究边缘产生的可塑性变化的计划。 反复服用可卡因所致的丘脑-皮质环路 以及多巴胺在这个回路中的调节作用。我们最重要的假设 反复服用可卡因会产生持久的变化 丘脑-皮质环路的内在电生理特性 以及刺激脑内多巴胺神经元引起的反应的改变 VTA。利用体内的细胞内记录，我们将通过以下方式验证这一假设： 1)研究了PFC和MD之间的互激互连及其相互作用。 对照动物递增DA传入的调制作用，2)正常对照研究 前额叶锥体细胞的电生理特性 反复可卡因预刺激对大鼠VTA和MD的影响 注射，以及3)建立非固有电生理特性 MD中的细胞以及VTA和PFC刺激对动物的影响 经过反复注射可卡因的预处理。这些实验的结果 将使我们了解大脑边缘改变的潜在机制 作为反复注射可卡因的结果，并将提供 认知和情感缺陷的生理学框架 可卡因成瘾的后果。

DESCRIPTION (provided by applicant): Although cocaine addiction is a devastating social and medical problem in this country, little is known about the physiological actions of cocaine on the thalamo-cortical limbic circuit. This circuit engages cognitive and emotive processing and is thought to be involved in the behavioral dysfunctions observed in addicts. In this proposal, we outline a plan to study the plastic changes produced in the limbic thalamo-cortical circuit as a consequence of repeated administration of cocaine and the modulatory role of dopamine in this circuit. Our overlying hypothesis is that repeated cocaine administration produces enduring changes in the intrinsic electrophysiological properties of the thalamo-cortical circuit, as well as alterations in responses evoked by stimulating dopamine neurons in the VTA. Using intracellular recordings in vivo, we will test this hypothesis by: 1) Study the reciprocal excitatory interconnection between PFC and MD and it modulation by ascending DA afferents in control animals, 2) Study the normative electrophysiological properties of pyramidal cells in the PFC, as well as the effects of VTA and MD stimulation in rats pretreated with repeated cocaine injections, and 3) Establish the nonnative electrophysiological properties of cells in the MD, as well as the effects of VTA and PFC stimulation in animals pretreated with repeated cocaine injections. The results of these experiments will allow us to understand the mechanisms underlying changes in the limbic circuit as a consequence of repeated cocaine administration and will provide a physiological framework for the cognitive and affective deficits that occur as a consequence of cocaine addiction.