Homeostatic Plasticity in the BNST and Drug Abuse

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): The bed nucleus of the stria terminalis (BNST) plays important roles in the coordination of neuroendocrine, autonomic, somatomotor responses and the effects of drugs of abuse. The juxtacapsular nucleus of the BNST (jcBNST) in the dorsolateral BNST receives dense glutamatergic projections primarily from the posterior part of the BLA and, in turn, sends GABAergic projections to the medial central nucleus of the amygdala (CeAm), the main output nucleus of the amygdala. Thus, changes in the integration properties of jcBNST neurons can contribute to the emotional dysregulation associated with drug dependence and withdrawal. We recently described a form of long-term potentiation of the intrinsic excitability (LTP-IE) of neurons of the jcBNST in response to stimulation of the stria terminalis that was impaired during protracted withdrawal from escalated heroin, cocaine, and alcohol self-administration and in rats chronically treated with corticotropin releasing factor (CRF) intracerebroventricularly. These results provide a novel neurobiological target for vulnerability to drug and alcohol abuse. In particular they suggest the hypothesis that changes in the excitability of jcBNST neurons could result in inadequate inhibition of the CeAm, contributing to the negative affective state that characterizes protracted abstinence in post-dependent individuals. To test this hypothesis here we proposed to 1) investigate changes in synaptic and intrinsic properties of jcBNST neurons associated with heroin dependence using a combination of conventional electrophysiological methods and the dynamic clamp, an innovative computer-based method to study neuronal excitability in brain slices by approximating the high-conductance state of the intact brain; 2) to investigate if heroin dependence is also associated with plastic changes in CeAm neurons; 3) to use the dynamic clamp to investigate the functional significance of LTP-IE in the BLA-jcBNST-CeA circuit as well as of the plastic changes in jcBNST and CeAm neurons associated with opiate dependence. Ultimately, knowledge of the adaptive and counter-adaptive changes induced by drug dependence in the microcircuit BLA-jcBNST-CeA will allow us to identify therapeutic targets to restore normal neuronal excitability and circuit functioning with adequate inhibitory control over amygdala output.