The Role of mGluR5 Receptors in Extinction Learning of Alcohol Cues

7.项目摘要 本K99/R 00提案提出了一个全面的培训和研究计划，将促进职业生涯 候选人的发展（贾斯汀加斯，博士）。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尖端实验室技术的培训， 并增加他在酒精成瘾行为分析方面的现有专业知识。研究计划提出 对于独立的R 00阶段是基于候选人最近的研究，酒精的影响， 相关线索复发，拟议的研究将利用培训下获得的指导 相位在导师（贾德森钱德勒博士）的指导下学习的技术将使博士。 Gass将他的行为学研究扩展到对神经回路和神经网络的调查， 这些行为。大多数神经科学家现在认为灭绝现象是“新的”和“活跃的” 学习，而不再把它看作是简单的“忘记”以前学到的联想。最新进展 在成瘾研究领域，允许详细分析神经元可塑性的变化， 与学习有关。因此，导致寻求毒品行为消失的神经机制 行为可以在细胞水平上进行研究。初步证据表明， 5型代谢型谷氨酸受体（mGluR 5）可促进寻求酒精行为的消退。因此，在本发明中， 这项研究的总体假设是，寻求酒精的行为的消失可能是 通过调节mGluR 5受体而增强，并且这种增强与 在特定的大脑区域内调节灭绝行为的可塑性。本研究将检验以下假设： 1)酒精寻求行为的消失可以通过对大脑皮层的正向别构调节来促进。 mGluR 5受体; 2）酒精寻求消退的增强是通过复杂的神经元介导的。 涉及边缘下皮层（IL-PFC）到核内核（NAc）壳通路的活性; 3） 酒精寻求行为消退的增强与组织形态学的变化有关。 IL-PFC和NAc壳内的树突棘;和4）在IL-PFC和NAc壳内的mGluR 5的正向别构调节， 消除训练将减弱线索诱导的酒精寻求行为的程度。另夕h 这些研究的结果将有助于建立加斯博士的独立研究计划， 研究如何在寻求酒精的行为消失涉及的神经机制可以用来 制定药物干预措施，促进戒酒和减少酒精复发。

7. Project Summary 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.