Ethanol Modulation of Glycine Receptor Mediated Currents in the Striatum

描述（由申请人提供）：酒精中毒是一种慢性的、无法治愈的、反复发作的疾病。目前，酒精发挥其醉酒和强化作用的机制尚不完全清楚，但酒精寻求、依赖、戒断甚至急性中毒的发展至少部分涉及酒精对神经系统的作用

DESCRIPTION (provided by applicant): Alcoholism is a chronic, cureless, and relapsing condition. Currently, the mechanisms by which alcohol exerts its intoxicating and reinforcing effects are not completely understood, but the development of alcohol seeking, dependence, withdrawal, and even acute intoxication involve, at least in part, the actions of alcohol on neural circuits involving the striatum. In addition, the actions of ethanol on a number of ion channels in the CNS have been established. Strychnine-sensitive glycine receptors (GlyRs) are among such targets of alcohol, and recent evidence demonstrates that GlyRs are expressed in forebrain regions including the striatum. Behavioral pharmacology studies suggest that GlyRs, specifically in the nucleus accumbens, are involved in alcohol consumption. However, the physiology of these particular GlyRs is not well defined, and the effects of ethanol action on native GlyRs in the striatum are not known. This project will specifically investigate GlyR physiology and ethanol pharmacology in the striatum using slice electrophysiology and molecular biology techniques. Our preliminary data suggest the presence of exogenously and tonically activated GlyR currents in the ventral striatum. Aim 1 will characterize GlyR mediated currents and ethanol modulation of GlyR function in the striatum (dorsal and ventral) to test the hypothesis that GlyRs are important mediators of neuronal excitability and that ethanol action at GlyRs may alter striatal neuron activity. Aim 2 will determine which GlyR ¿ subunits are involved in ethanol modulation of striatal GlyR currents using GlyR ¿ subunit knock-out (KO) mice to test the hypothesis that GlyRs containing ¿2 and/or ¿3 subunits may be particularly important for mediating the effects of striatal GlyR activation and ethanol modulation of GlyR function. Overall, findings from these experiments will provide novel insights into the effects of GlyR activation on neuronal excitabilit in the striatum and will contribute to a better understanding of how ethanol modulates striatal activity. Ultimately, by improving our knowledge of the mechanisms by which alcohol exerts its effects, new pharmacotherapies and enhanced treatment options can be developed for the treatment of alcoholism.