DESCRIPTION (provided by applicant): Changes in neuronal excitability and synaptic plasticity are increasingly recognized as cellular substrates of the long-term effects of drugs of abuse. The lateral subdivision of the bed nucleus of the stria terminalis (BNST) is involved in stress responses and in the long-lasting motivational dysregulation associated with drug dependence. We observed that high frequency stimulation (HFS) of the area of the stria terminalis in BNST slices in vitro induced a long term potentiation (LTP) of intrinsic excitability and a persistent increase in the temporal precision of firing of neurons in the juxtacapsular subdivision of the lateral BNST (jcBNST). Induction of this form of neuronal plasticity in the jcBNST was impaired during protracted withdrawal in rats with a history of dependent intake of alcohol, cocaine or heroin. In this application we propose to investigate the induction mechanisms of LTP of intrinsic excitability and temporal fidelity of jcBNST neurons in ethanol dependent rats. The impaired plasticity of the jcBNST described here could be relevant to the emotional dysregulation long hypothesized to underlie the transition to compulsive drug taking in dependent individuals. To address this hypothesis, it is proposed to investigate if treatments that have been shown to reduce increased drinking in dependent rats and reinstatement of alcohol-seeking behavior restore LTP of intrinsic excitability and temporal fidelity of jcBNST neurons in ethanol dependent rats. The elucidation of the mechanisms behind the changes in the jcBNST in animals with a history of alcohol dependence is likely to have heuristic value for the understanding of the neurobiological bases of drugs of abuse.