Cocaine-Conditioned Avoidance Behavior, Mechanisms and Relevance for Drug-Seeking

描述（由申请人提供）：可卡因和其他成瘾药物的奖励特性已被广泛研究，但对这些药物的厌恶特性知之甚少。许多研究发现，即使是小剂量或不经常服用的可卡因和其他药物也会产生强烈的回避反应，从而减少或防止吸毒。这些反应中的一些可能解释了为什么有些人尽管药物具有强烈的奖励作用，但并没有发展到强迫性药物使用，但对这些现象的了解相对较少，部分原因是他们的潜在神经回路还没有得到很好的理解。最近，一系列顺序相连的大脑区域越来越多地与厌恶行为有关;这组区域包括脚内核（EPN），外侧缰核（LHb）和吻内侧被盖核（RMTg）。这些结构的激活强烈抑制多巴胺神经元，我们最近发表的工作和初步数据暗示这些区域对可卡因的厌恶反应。我们进一步证实，可卡因回避条件反射是由这些途径在特定时间和通过特定的多巴胺受体亚型激活驱动的。最后，我们认为这些通路功能的个体差异可能与个体的药物寻求倾向有关。在测试这些假设时，该项目可以进一步了解药物的厌恶特性及其在个体之间的差异，同时还可以确定可能的新靶点。 药物寻求行为的治疗调节。

DESCRIPTION (provided by applicant): The rewarding properties of cocaine and other addictive drugs have been extensively studied, but much less is known about these drugs' aversive properties. Numerous studies have found that even small or infrequent doses of cocaine and other drugs produce strong avoidance responses that can attenuate or prevent drug-seeking. Some of these responses may explain why some individuals do not progress to compulsive drug use despite the drugs' intense rewarding effects, but relatively little is known about these phenomena, in part because their underlying neural circuitry is not well understood. Recently, a sequentially linked series of brain regions has become increasingly well implicated in aversive behavior; this set of regions includes the entopeduncular nucleus (EPN), lateral habenula (LHb), and rostromedial tegmental nucleus (RMTg). Activations of these structures strongly inhibit dopamine neurons, and our recently published work and preliminary data implicate these regions in aversive responses to cocaine. We further posit that cocaine avoidance conditioning is driven by activation of these pathways at specific times and via specific dopamine receptor subtypes. Finally, we posit that individual variability in the functioning of these pathways may relate to individual differences in drug- seeking propensity. In testing these hypotheses, this project could further our understanding of the aversive properties of drugs and their variation between individuals, while also identifying novel targets for possible therapeutic modulation of drug-seeking behavior.