Significance of withdrawal-related learning in EtOH craving and relapse

描述（由申请人提供）：环境刺激对乙醇（EtOH）强化作用的调节是该药物滥用潜力的主要因素。在复发的动物模型中，与EtOH相关的刺激引起强烈的EtOH寻求，这些模型被广泛用于研究EtOH渴望和复发的神经生物学基础。然而，从动物模型中寻求EtOH的条件因素的行为和神经生物学信息主要限于来自EtOH非依赖性受试者的信息。在酗酒者中，依赖史与线索诱导的EtOH渴望的严重程度之间存在显著的正相关。戒断期间的EtOH消费改变了受试者的EtOH强化史，包括学习改善或避免不良戒断状态，作为EtOH强化作用的一个新的和必要的方面，使药物在质量上不同，更有效的强化剂。因此，了解在戒断状态中出现的这种药物的强化维度的条件下，对EtOH的刺激对行为的控制，对于促进对EtOH成瘾的理解和治疗至关重要。初步数据表明，戒断期间EtOH强化的刺激物会引起显著的恢复，这证实了这种理解的必要性。这个探索性和发展性项目的目的是研究戒断相关条件作用在寻求EtOH中的意义，并通过新方法了解调节这种行为的神经回路。需要测试的行为假设是：(a)在非依赖状态下，与脱瘾相关的条件反射“超越”了在非依赖状态下被条件反射的EtOH线索对EtOH寻求的控制；(b)与非依赖状态下被条件反射的EtOH线索相比，在脱瘾过程中被条件反射强化的刺激在压力挑战后产生了更大的EtOH寻求；(c)对条件反射抑制EtOH寻求的更大抵抗。平行研究将利用定量Fos免疫组织化学方法，在有或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。这些研究是基于这样的假设：与非依赖状态下的EtOH条件提示相比，戒断期间EtOH条件提示产生了不同的神经激活模式，与压力调节区域的参与更强。最后，为了确认在EtOH中寻求与戒断相关条件相关的脑区域的作用，将在cfos-lacZ转基因大鼠中使用dawn 02药物遗传失活来选择性地损伤这些部位的神经元群。这些发育研究将验证这样一种假设，即神经元集合可以在大脑奖赏和应激回路中被识别出来，这些回路优先介导戒断期间EtOH强化条件反射的刺激效应。本研究将为未来深入研究脱瘾相关条件作用在EtOH滥用潜力中的重要性奠定基础，从而促进对酒精中毒神经生物学和治疗策略的理解。

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. PUBLIC HEALTH RELEVANCE: This proposal addresses the need for better understanding of the neurobehavioral basis of the compulsive and chronically relapsing nature of alcohol addiction. Neurobiological and medications development information from animal models of relapse to alcohol abuse is limited largely to studies in alcohol nondependent animals. To advance the understanding of alcohol addiction and improve treatment strategies, the proposed studies will investigate alcohol seeking induced by stimuli conditioned to the potent reinforcing dimensions of this drug that emerge with the experience of amelioration of withdrawal distress by EtOH consumption as well as the neurobiological basis of this behavior.