Insular Cortical Processing in Alcohol Addiction

描述(申请人提供)：酒精成瘾是一种慢性疾病，涉及大脑中的神经可塑性变化，有助于维持持续的药物使用，并在戒酒一段时间后再次寻求药物。尽管在确定调节过度饮酒和饮酒的神经生物学机制方面取得了实质性进展，但持久的复发易感性仍然是酒精成瘾治疗的主要障碍。已知的维持吸毒和诱发复发的一个关键因素是由感官刺激引起的获得性反应，这些反应与给药反复配对，从而成为预测即将到来的药物强化的显著线索。鉴于其口服给药途径，伴随酒精消费的化学感觉线索是立即预测药物吸收后效应的最亲密和最一致的刺激之一。在啮齿动物模型中，酒精化学感觉刺激诱导饮酒冲动和相应的生理变化，并促进对酒精寻求的复发，但在长期暴露的生物中，介导对酒精感觉线索的获得性反应的潜在神经底物尚未得到很好的建立。本提案旨在研究慢性用药后岛叶皮质内乙醇或感觉信号神经处理的变化，以及岛叶候选亚区的失活在降低对乙醇化学感觉线索的获得性反应性及其诱导酒精寻找反应的能力方面的影响。在特定目标1下的实验将测量慢性酒精暴露动物脑岛内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岛叶皮质内脏亚区在抑制对酒精化学感觉线索的高行为反应中的作用。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岛内神经反应，以及岛上味觉和感觉间区域的失活以破坏线索诱导的乙醇寻求的恢复的能力。在本项目结束时，我们将产生有价值的数据，说明暴露在酒精感觉线索中的既定酒精寻求反应背后的神经机制，这对于确定治疗目标以减少强迫药物寻求和持续的复发易感性至关重要。更广泛地说，这些研究将继续加强我们对中枢神经系统处理酒精感觉信息的理解，这是一个未被充分研究但很重要的研究领域。

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.