Altered Accumbens Signaling Following Ethanol Exposure

描述(申请人提供)：试图保持戒酒的人类酗酒者通常经历渴望、复发和持续消费的主要时期。为了解决这些问题，重要的是确定在酒精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强对复发诱导刺激的敏感性。伏隔核(NAcb)的功能变化可能会有效地改变复发的发生，因为NAcb与对许多条件刺激的反应有关，以及对滥用药物的消费和恢复，几项人类成像研究表明，NAcb在酒精和可卡因成瘾者的渴望中发挥了作用。这项建议的主要目的是确定在反复酒精暴露后的戒断过程中，NAcb区的基本棘波放电和多巴胺能放电调制是否会持续改变。我们把重点放在放电，因为它是神经元传递信息的主要机制。将使用膜片钳电生理学对成年动物的NAcb脑片的棘波放电进行分析。成年动物手术自服乙醇40-45天，然后经历3周的禁欲。动物自我给予蔗糖，然后进行禁欲，将起到控制作用。我们的初步数据提供了第一个证据，表明在反复酒精暴露后戒断过程中，NAcb核心神经元的放电增强，这可能是由于抑制了钙依赖的钾电流(I[SKICa2])。具体目标1将检查在自我注射乙醇后戒断3个月和6个月后，NAcb的基本尖峰放电特性是否发生改变。具体目标2将使用电压钳方法和特定的拮抗剂来表征有助于激活i[SKCa2]的钙源，并且在酒精训练的动物禁欲期间，这种钙源可能会减少。具体目标3将调查反复酒精暴露后，多巴胺对尖峰放电的调制是否发生改变，因为NAcb内的多巴胺信号调节几种滥用药物的恢复，而NAcb多巴胺可以在乙醇自我给药过程中做出重大贡献。NAcb内放电和多巴胺信号的改变可以显著影响NAcb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.