Significance of withdrawal-related learning in EtOH craving and relapse

描述(由申请人提供)：乙醇(Etoh)与环境刺激的增强作用的调节是该药物滥用潜力的主要因素。乙醇相关刺激在复吸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，从动物模型中寻找乙醇的条件性因素的行为和神经生物学信息在很大程度上限于来自乙醇非依赖性受试者的信息。在酗酒者中，依赖史与线索诱导的酒精渴求的严重程度之间存在显著的正相关。戒断期间的乙醇消耗修改了受试者的乙醇强化历史，包括了解改善或避免不良戒断状态，作为乙醇强化行动的一个新的和必要的方面，使药物成为一种性质不同的、更有效的增强剂。因此，了解乙醇条件刺激对行为的控制，包括这种药物随着戒断状态的经历而出现的强化维度，对于促进对乙醇成瘾的理解和治疗至关重要。初步数据表明，在戒断过程中刺激乙醇强化可引起显着的恢复，证实了这一理解的必要性。本探索性和发展性项目的目的是调查戒断相关条件反射在寻求乙醇中的意义，并了解调控这一行为的神经回路实施新的方法学。有待检验的行为假说是：(A)在非依赖状态下，与戒断相关的条件反射通过对乙醇寻求的早期条件化线索“推翻”对乙醇寻求的控制；(B)与非依赖状态下的乙醇条件化线索相比，在应激挑战后，在戒断过程中以乙醇强化为条件线索的刺激产生更大的乙醇寻求；以及(C)对乙醇寻求的条件性抑制有更大的抵抗力。平行研究将利用定量Fos免疫组织化学方法，在有和没有戒断相关学习史的大鼠中建立与寻求乙醇相关的神经激活模式。这些研究的指导假设是，与非依赖状态下的乙醇条件化线索相比，在戒断过程中条件化的乙醇线索会产生不同的神经激活模式，与压力调节区的接触更强。最后，为了确认大脑区域在寻求无水乙醇与戒断相关的条件反射中的作用，将使用CFOS-LacZ转基因大鼠中的Daun 02药物遗传失活来选择性地损害这些位置的神经元组。这些发育研究将检验这一假说，即在大脑奖赏和应激回路中可以识别出神经元集合，这些回路优先介导在戒断过程中受乙醇强化的刺激的影响。这项研究将为未来深入研究戒断相关条件作用在乙醇滥用潜能中的意义提供基础，以促进对酒精中毒的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.