The Role of mGluR5 Receptors in Extinction Learning of Alcohol Cues

描述（由申请人提供）：此K99/R 00提案提出了一个全面的培训和研究计划，将促进候选人（贾斯汀加斯，博士）的职业发展。在该奖项的指导K99阶段，Gass博士将接受神经生理学和细胞生物学前沿实验室技术的培训，这将扩大和增强他在酒精成瘾行为分析方面的现有专业知识。针对独立R 00阶段提出的研究计划是基于候选人最近对酒精相关线索在复发中的影响的研究，并且提出的研究将利用在指导阶段获得的培训。在导师（贾德森钱德勒博士）的指导下学习的技术将使加斯博士能够将他的行为研究扩展到对这些行为背后的电路和神经网络的调查。大多数神经科学家现在认为这种消失现象是“新的”和“主动的”学习，而不再把它看作是简单的“忘记”以前学习过的联想。成瘾研究领域的最新进展允许详细分析与学习相关的神经元可塑性的变化。因此，可以在细胞水平上研究导致寻求毒品行为消失的神经机制。初步证据表明，5型代谢型谷氨酸受体（mGluR 5）的变构调节可以促进酒精寻求行为的消退。因此，这项研究的总体假设是，通过调节mGluR 5受体可以增强酒精寻求行为的消退，并且这种增强与调节消退行为的特定大脑区域内的可塑性变化有关。本研究将验证以下假设：1）mGluR 5受体的正向别构调节可促进酒精寻求行为的消退：2）酒精寻求消退的增强是通过复杂的神经元活动介导的，涉及边缘下皮层（infraalimbic cortex，IL-PFC）到丘脑核（nucleus delibens，NAc）壳通路; 3）趋酒行为消退的增强与IL-PFC和NAc壳内树突棘形态的改变有关;（4）消退训练过程中mGluR 5的正向别构调节可减弱线索诱导的酒精寻求行为。此外，这些研究的结果将有助于建立Gass博士的独立研究计划，该计划将调查如何使用参与酒精寻求行为灭绝的神经机制来开发促进戒酒和减少酒精复发的药理干预措施。 公共卫生相关性：酒精中毒是一种慢性复发性疾病，与强迫性饮酒行为有关。酒精复发的主要原因之一是与酒精相关的环境线索引起的渴望。这些线索是由正常的学习和记忆原则形成的，对帮助形成这些关联的大脑机制的理解可以导致药物和/或行为疗法的开发，以减少这些线索对酗酒者的影响。

DESCRIPTION (provided by applicant): This K99/R00 proposal presents a comprehensive training and research plan that will facilitate the career development of the Candidate (Justin Gass, PhD). During the mentored K99 phase of the award, Dr. Gass will receive training in cutting-edge laboratory techniques in neurophysiology and cellular biology that will expand and augment his existing expertise in the behavioral analysis of alcohol addiction. The research plan proposed for the independent R00 phase is based upon the Candidate's recent studies into the influence of alcohol- associated cues in relapse, and the proposed research will utilize the training obtained under the mentored phase. The techniques to be learned under the direction of the Mentor (Dr. Judson Chandler) will allow Dr. Gass to expand his behavioral studies into an investigation of the circuitry and neuronal networks that underly these behaviors. Most neuroscientists now consider the phenomenon of extinction to be "new" and "active" learning, and no longer view it as the simple "forgetting" of previously learned associations. Recent advances in the field of addiction research allow for the detailed analysis of changes in neuronal plasticity that are associated with learning. Therefore, the neural mechanisms that underlie the extinction of drug-seeking behavior can be investigated at the cellular level. Preliminary evidence indicates that allosteric modulation of type 5 metabotropic glutamate receptors (mGluR5) can facilitate extinction of alcohol-seeking behavior. Thus, the overall hypothesis of the research under this proposal is that extinction of alcohol-seeking behavior can be enhanced through modulation of mGluR5 receptors, and that this enhancement is associated with changes in plasticity within specific brain regions that regulate extinction behavior. This study will test the hypotheses that: 1) The extinction of alcohol-seeking behavior can be facilitated through positive allosteric modulation of the mGluR5 receptor; 2) The enhancement of extinction of alcohol-seeking is mediated through complex neuronal activity involving the infralimbic cortex (IL-PFC) to nucleus accumbens (NAc) shell pathway; 3) The enhancement of extinction of alcohol-seeking behavior is associated with changes in the morphology of dendritic spines within the IL-PFC and NAc shell; and 4) The positive allosteric modulation of mGluR5 during extinction training will attenuate the magnitude of cue-induced alcohol-seeking behavior. Additionally, the results from these studies will aid in the establishment of Dr. Gass's independent research program that will investigate how the neural mechanisms involved in the extinction of alcohol-seeking behavior can be used to develop pharmacological interventions that promote abstinence and reduce alcohol relapse. PUBLIC HEALTH RELEVANCE: Alcoholism is a chronic relapsing disorder that is associated with compulsive alcohol-seeking behavior. One of the main causes of alcohol relapse is the craving caused by environmental cues that are associated with alcohol. These cues are formed by normal learning and memory principles and the understanding of the brain mechanisms that help form these associations can lead to the development of drugs and/or behavior therapies that reduce the impact that these cues have on alcoholics.