Intersection of Pain and Ethanol-Seeking Mechanisms in Ethanol Dependence

描述(申请人提供)：这份K99/R00职业发展奖提案(酒精依赖中疼痛和酒精寻求机制的交集)包含了我过去研究过的与神经机制相关的主题，包括使用大鼠药物依赖模型对体内细胞内信号和强制服药和寻求药物行为的调节。这些研究是在博士后和博士后水平的各个NRSA奖项的支持下进行的。这项建议的目的是结合神经化学(体内微透析)和伤害性行为技术的新培训，并整合比较物种(小鼠)的使用，以补充和丰富这一背景。我觉得这种新技术的组合(在K99阶段学到的)应用于疼痛和寻找酒精的行为的研究将提供对酒精依赖的宝贵洞察力，并且，结合Parsons和Koob博士在像斯克里普斯研究所这样丰富的环境中提供的个性化指导，将极大地促进我在R00阶段过渡到独立的研究生涯。研究发展计划是根据TSRI博士后办公室的个人发展计划(IDP)进行的，并包括专门的培训元素，服务于与技能、有效的科学交流和伦理等主题相关的近期和长期目标。本研究的主要目的是探讨中枢伤害性感受和寻求酒精的生物行为机制在促进和/或维持酒精依赖状态方面的趋同性。基于以前来自疼痛和酒精相关领域的数据，我假设内源性大麻素活性增加和相关的MAP激酶信号增强在前扣带回皮质中参与了这种交叉，并进一步假设慢性疼痛状态通过这一机制促进了从酒精使用到依赖的转变。我提出了一种创新的实验策略，将高度相关的行为技术与体内神经递质水平和从细胞外空间到细胞核的细胞内信号的比较测量相结合，包括突触前和突触后蛋白质磷酸化的测量。在R00阶段进行的实验将建立在K99阶段的工作基础上，并应为我未来对酒精依赖的生物行为机制的研究提供坚实的基础。更好地了解慢性酒精暴露、伤害性改变和强迫性酒精寻求之间的关系，将进一步深入了解从娱乐性酒精使用向酒精中毒转变的潜在机制，并揭示新的治疗机会。

DESCRIPTION (provided by applicant): This K99/R00 career development award proposal (Intersection of Pain and Ethanol-Seeking Mechanisms in Ethanol Dependence) incorporates themes related to neuronal mechanisms I have investigated in the past, including the regulation of in vivo intracellular signaling and compulsive drug taking and drug-seeking behaviors, using models of drug dependence in rats. These studies were conducted with the support of individual NRSA awards at both pre- and postdoctoral levels. The aim of this proposal is to incorporate new training in neurochemistry (in vivo microdialysis) and nociceptive behavioral techniques, and to integrate the use of a comparative species (mice), to complement and enrich this background. I feel that this combination of new techniques (learned during the K99 phase) applied to the investigation of pain and ethanol-seeking behaviors will provide valuable insight into alcohol dependence, and, when combined with the personalized mentoring provided by Drs. Parsons and Koob within an environment as rich as The Scripps Research Institute, will greatly facilitate my transition to an independent research career during the R00 phase. The research development plan is conducted in accordance with the TSRI postdoctoral office's Individual Development Plan (IDP) program, and includes specialized training elements serving both immediate and long-term goals related to such topics as grantsmanship, effective scientific communication, and ethics. The main research objective of the current proposal is to investigate the convergence of central nociceptive and ethanol-seeking biobehavioral mechanisms in promoting and/or maintaining the ethanol-dependent state. Based on previous data from both pain- and ethanol-related fields, I hypothesize a specific role for increased endogenous cannabinoid activity and associated MAP kinase signaling potentiation in the anterior cingulate cortex in mediating this intersection, and further hypothesize that chronic pain states facilitate the transition from ethanol use to dependence via this mechanism. I propose an innovative experimental strategy that combines highly relevant behavioral techniques with comparative in vivo measures of neurotransmitter levels and intracellular signaling spanning from the extracellular space to the nucleus, including measures of both pre- and postsynaptic protein phosphorylation. Experiments conducted during the R00 phase will build on K99 phase work, and should provide a substantial base for my future investigations into the biobehavioral mechanisms of alcohol dependence. A better understanding of the relationship between chronic ethanol exposure, altered nociception, and compulsive ethanol seeking will provide further insight into mechanisms underlying the transition from recreational alcohol use to alcoholism, as well as reveal new treatment opportunities.