Altered Accumbens Signaling Following Ethanol Exposure

描述（由申请人提供）：人类嗜酒者试图保持戒酒，通常经历主要的渴望期、复发期和持续消费期。为了解决这些问题，重要的是要确定乙醇暴露停止后持续存在的神经功能变化，因为这些变化可能会增加对诱发复发刺激的易感性。伏隔核（NAcb）内的功能变化可能会潜在地改变复发的诱导，因为NAcb涉及对许多条件刺激的反应，以及滥用药物的消耗和恢复，并且一些人体成像研究表明，NAcb在酗酒者和可卡因成瘾者的渴望中起作用。本研究的主要目的是确定在反复酒精暴露后的戒断期间，nab的基本spike放电和多巴胺能调节放电是否持续改变。我们将重点放在脉冲放电上，因为它是神经元传递信息的主要机制。研究人员将利用膜片钳电生理学对成年动物的nab脑切片进行分析，这些成年动物在40-45天内自行施用乙醇，然后进行3周的禁欲。动物自行服用蔗糖，然后戒断，作为对照。我们的初步数据提供了第一个证据，证明在反复接触乙醇后，nab核心神经元的spike放电在禁欲期间增强，这可能是由于钙依赖性钾电流（I[SKICa2+]）的抑制。具体目标1将检查是否在3个月和6个月戒酒后，nab的基本spike放电特性发生改变。Specific aim 2将使用电压钳法和特异性拮抗剂来表征有助于I[SKCa2+]激活的钙源，并且在戒酒期间酒精训练的动物中可能会减少。具体目标3将研究多巴胺对spike放电的调节是否会在重复乙醇暴露后发生改变，因为在NAcb内的多巴胺信号调节几种药物滥用的恢复，并且NAcb多巴胺在乙醇自我给药过程中发挥重要作用。nab中尖峰放电和多巴胺信号的改变可能显著影响nab的行为贡献，从而促进复发的发生。

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.