Altered Accumbens Signaling Following Ethanol Exposure

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Human alcoholics attempting to maintain abstinence often undergo major periods of craving, relapse and continued consumption. To address these problems, it is important to identify alterations in neural function that persist after ethanol exposure has ceased, as these changes are likely to enhance susceptibility to relapse-inducing stimuli. Functional changes within the nucleus accumbens (NAcb) could potently alter nduction of relapse, as the NAcb is implicated in responsiveness to many conditioned stimuli, as well as consumption of and reinstatement for drugs of abuse, and several human imaging studies suggest a role for the NAcb in cravings in alcoholics and cocaine addicts. The major goal of this proposal is to determine whether basic spike firing and dopaminergic modulation of firing in the NAcb are persistently altered during abstinence following repeated ethanol exposure. We focus on spike firing, as it is the predominant mechanism by which neurons transmit information. Spike firing will be analyzed using patchclamp electrophysiology in NAcb brain slices from adult animals that operantly self-administered ethanol for 40-45 days, then underwent 3 weeks of abstinence. Animals self-administering sucrose then undergoing abstinence will act as a control. Our preliminary data provide the first evidence that spike firing in NAcb core neurons is enhanced during abstinence following repeated ethanol exposure, which may be due to inhibition of a calcium-dependent potassium current (I[SKICa2+]). Specific aim 1 will examine whether basic spike firing properties in the NAcb are altered after 3 and 6 months of abstinence following ethanol self-administration. Specific aim 2 will use voltage-clamp methods and specific antagonists to characterize the calcium sources that contribute to I[SKCa2+[ activation, and which might be reduced in ethanol-trained animals during abstinence. Specific aim 3 will investigate whether modulation of spike firing by dopamine is altered following repeated ethanol exposure, as dopamine signaling within the NAcb regulates reinstatement for several drugs of abuse, and NAcb dopamine can contribute strongly during ethanol self-administration. Altered spike firing and dopamine signaling in the NAcb could significantly influence the behavioral contribution of the NAcb, and in this way facilitate the onset of relapse.