Dopaminergic modulation of thalamocortical circuits

描述（由申请人提供）：虽然可卡因成瘾是一个 在这个国家的毁灭性的社会和医疗问题，很少有人知道 可卡因对丘脑-皮层边缘回路的生理作用。 这个回路参与认知和情绪处理，被认为是 与成瘾者的行为障碍有关。在这一提议中， 我们提出了一个研究大脑边缘系统可塑性变化的计划， 重复服用可卡因引起的丘脑-皮层回路 以及多巴胺在这个回路中的调节作用。我们的假设是 重复的可卡因给药会产生持久的变化， 丘脑-皮层回路的内在电生理特性，如 以及通过刺激多巴胺神经元引起的反应的改变， VTA。使用体内细胞内记录，我们将通过以下方式检验这一假设： 1)研究PFC和MD之间的相互兴奋性联系， 在对照动物中通过上行DA传入进行调制，2）研究正常 PFC中锥体细胞的电生理特性，以及 重复可卡因预处理大鼠VTA和MD刺激的影响 注射，和3）建立非天然的电生理特性， MD中的细胞，以及VTA和PFC刺激对动物的影响 反复注射可卡因这些实验的结果 能让我们了解大脑边缘系统变化的潜在机制 电路作为一个结果，重复可卡因管理，并将提供一个 认知和情感缺陷的生理框架， 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.