Insular Cortical Processing in Alcohol Addiction

描述（由申请人提供）：酒精成瘾是一种慢性疾病，涉及大脑的神经可塑性改变，既有助于维持持续的药物使用，又有助于在戒断一段时间后重新寻求药物。尽管在确定介导过度酒精寻求和消费的神经生物学机制方面取得了重大进展，但持久的复发易感性仍然是治疗酒精成瘾的主要障碍。已知维持药物服用和加速复发的一个关键因素是由感觉刺激引起的习得性反应，这种反应与药物施用反复配对，因此成为预测即将发生的药物强化的显著线索。鉴于其口服给药途径，伴随饮酒的化学感觉线索是最亲密和一致的刺激之一，可以立即预测药物的吸收后效应。在啮齿类动物模型中，乙醇化学感觉刺激会诱发酗酒者的饮酒冲动和相应的生理变化，并促进酒精寻求的复发，但在长期暴露的生物体中，介导对乙醇感觉线索的学习反应的潜在神经基质尚未得到很好的确定。本研究旨在研究长期服用药物后，脑岛皮质内乙醇或感觉信号的神经处理过程的变化，以及脑岛候选亚区失活对降低对乙醇化学感觉线索的习得性及其诱导乙醇寻求反应的能力的影响。具体目标1下的实验将测量长期酒精暴露动物中脑岛对乙醇化学感觉信号的中枢神经反应的变化，以及直接药物沉默初级味觉和内脏亚区在抑制对乙醇化学感觉信号的增强行为反应中的作用。Aim 2下的实验将测量在自我给药消失后再次暴露于乙醇化学感觉线索所引发的脑岛神经反应，以及脑岛味觉和内感受区失活的能力，以破坏线索诱导的乙醇寻找的恢复。在本项目结束时，我们将获得有关暴露于酒精感官线索所引发的既定酒精寻求反应的神经机制的宝贵数据，这对于确定治疗目标以减少强迫性药物寻求和持续复发的脆弱性至关重要。更广泛地说，这些研究将继续增强我们对中枢神经系统处理酒精感觉信息的理解，这是一个研究不足但重要的研究领域。

DESCRIPTION (provided by applicant): Alcohol addiction is a chronic disorder involving neuroplastic changes in the brain that contribute both to the maintenance of ongoing drug use and relapse to drug seeking after periods of abstinence. Although substantial progress has been made in identifying neurobiological mechanisms that mediate excessive alcohol seeking and consumption, enduring susceptibility to relapse remains a major obstacle in the treatment of alcohol addiction. A key factor known to maintain drug taking and to precipitate relapse are learned responses elicited by sensory stimuli that have been repeatedly paired with drug administration and thus become salient cues predictive of impending drug reinforcement. Given its oral route of administration, the chemosensory cues accompanying alcohol consumption are among the most intimate and consistent stimuli immediately predictive of the drug's postabsorptive effects. Ethanol chemosensory stimuli induce urges to drink and corresponding physiologic changes in alcoholics and promote relapse to ethanol seeking in rodent models, yet the underlying neural substrates mediating learned responses to ethanol sensory cues in chronically exposed organisms are not well established. The present proposal aims to investigate alterations in the neural processing of ethanol orosensory signals within the insular cortex following chronic experience with the drug and the effects of inactivation of candidate subregions of the insula in reducing learned reactivity to ethanol chemosensory cues and their ability to induce ethanol-seeking responses. Experiments under Specific Aim 1 will measure alterations in central neural response to ethanol chemosensory signals within the insula in chronically ethanol- exposed animals and the effects of direct pharmacological silencing of primary gustatory and visceral subregions of the insular cortex in suppressing heightened behavioral reactivity to ethanol chemosensory cues. Experiments under Aim 2 will measure neural response within the insula elicited by re-exposure to ethanol chemosensory cues following extinction of self-administration and the ability of inactivation of gustatory and interoceptive regions of the insula to disrupt cue-induced reinstatement of ethanol seeking. At the conclusion of this project, we will have produced valuable data regarding neural mechanisms underlying established alcohol- seeking responses elicited by exposure alcohol sensory cues, essential to identifying targets for treatment to reduce compulsive drug seeking and persistent vulnerability to relapse. More broadly, these studies will continue to enhance our understanding of the central nervous system processing of alcohol sensory information, an understudied but important area of research.