Significance of withdrawal-related learning in EtOH craving and relapse

性状（由申请方提供）：乙醇（EtOH）的环境刺激增强作用的调节是该药物滥用潜力的主要因素。乙醇相关刺激在复发动物模型中引起强烈的乙醇寻求，这些模型被广泛用于研究乙醇渴求和复发的神经生物学基础。然而，行为和神经生物学信息的条件因素，乙醇寻求动物模型在很大程度上是有限的，从乙醇非依赖的主题。在酗酒者中，依赖史和线索诱导的乙醇渴望的严重程度之间存在显着的正相关。在戒断过程中的EtOH消耗改变了受试者的EtOH强化史，包括了解不良戒断状态的改善或避免，作为EtOH强化作用的一个新的和重要的方面，使药物成为一种质的不同，更有效的兴奋剂。因此，了解控制行为的条件下，包括加强维度的这种药物出现的经验，戒断状态的条件下，由刺激条件EtOH将是至关重要的推进理解和治疗EtOH成瘾。初步的数据表明，刺激条件乙醇加固在撤退引起显着的恢复证实需要这种理解。这个探索性和发展性项目的目的是研究乙醇寻求中与戒断相关的条件反射的意义，并了解调节这种行为的神经回路，实施新的方法。待检验的行为假设是：（a）戒断相关条件反射“超越”了在非依赖状态下早期对EtOH条件反射的线索对EtOH寻求的控制;（B）与在非依赖状态下对EtOH条件反射的线索相比，戒断过程中对EtOH强化条件反射的刺激在压力挑战后产生更大的EtOH寻求;以及（c）对EtOH寻求的条件抑制有更大的抵抗力。平行研究将使用定量Fos免疫组织化学在有和没有戒断相关学习史的大鼠中建立与EtOH寻求相关的神经激活模式。这些研究的指导下的假设，线索条件乙醇在撤退过程中产生不同的模式的神经激活，具有更强的参与的压力调节区，相比线索条件乙醇在非依赖状态。最后，为了证实脑区域在EtOH寻求中的作用与戒断相关的条件反射有关，将采用cfos-lacZ转基因大鼠中的Daun 02药物遗传学失活来选择性地损伤这些部位中的神经元集合。这些发展研究将测试的假设，神经元合奏可以确定在大脑奖励和压力电路，优先介导的影响，条件刺激乙醇加固在撤退。这项研究将为未来深入研究戒断相关条件反射在乙醇滥用潜力中的意义奠定基础，以促进对神经生物学和酒精中毒治疗策略的理解。

DESCRIPTION (provided by applicant): The conditioning of ethanol's (EtOH) reinforcing effects with environmental stimuli is a major factor in the abuse potential of this drug. EtOH-related stimuli elicit strong EtOH seeking in animal models of relapse and these models are widely employed to study the neurobiological basis of EtOH craving and relapse. However, behavioral and neurobiological information on conditioning factors in EtOH seeking from animal models is limited largely to that from EtOH nondependent subjects. In alcoholics, a significant positive correlation exists between the history of dependence and the severity of cue-induced EtOH craving. EtOH consumption during withdrawal modifies subjects' EtOH reinforcement history to include learning about amelioration or avoidance of adverse withdrawal states as a novel and essential aspect of EtOH's reinforcing actions, rendering the drug a qualitatively different, more potent reinforcer. Thus, understanding the control of behavior by stimuli conditioned to EtOH under conditions that encompass the reinforcing dimension of this drug that emerges with the experience of withdrawal states will be essential for advancing the understanding and treatment EtOH addiction. Preliminary data that stimuli conditioned to EtOH reinforcement during withdrawal elicit significant reinstatement confirm the need for this understanding. The purpose of this exploratory and developmental project is to investigate the significance of withdrawal-related conditioning in EtOH seeking and to gain understanding of the neurocircuitry regulating this behavior implementing novel methodology. Behavioral hypotheses to be tested are (a) that withdrawal-related conditioning "overrides" the control of EtOH seeking by cues conditioned to EtOH earlier in the nondependent state, (b) that, compared to cues conditioned to EtOH in the nondependent state, stimuli conditioned to EtOH reinforcement during withdrawal produce greater EtOH seeking following a stress challenge, and (c) greater resistance to conditioned suppression of EtOH seeking. Parallel studies will establish neural activation patterns associated with EtOH seeking in rats with and without histories of withdrawal-related learning using quantitative Fos immunohistochemistry. These studies are guided by the hypothesis that cues conditioned to EtOH during withdrawal produce a different pattern of neural activation, with a stronger engagement of stress-regulatory regions, compared to cues conditioned to EtOH in the nondependent state. Finally, to confirm a role of brain regions in EtOH seeking linked to withdrawal-related conditioning, Daun 02 pharmacogenetic inactivation in cfos-lacZ transgenic rats will be employed to selectively lesion neuronal ensembles in these sites. These developmental studies will test the hypothesis that neuronal ensembles can be identified within brain reward and stress circuitry that preferentially mediate the effects of stimuli conditioned to EtOH reinforcement during withdrawal. This research will provide the groundwork for future in-depth investigations of the significance of withdrawal-related conditioning in the abuse potential of EtOH to advance understanding of the neurobiology and of treatment strategies for alcoholism.