Dopaminergic modulation of thalamocortical circuits

点击翻译按钮获取中文摘要

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.