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有益特性已被广泛研究，但对这些药物的厌恶特性知之甚少。许多研究发现，即使是小剂量或不频繁的可卡因和其他药物也会产生强烈的回避反应，可以减弱或防止寻求毒品。其中一些反应可能解释了为什么一些人在药物具有强烈的奖励作用的情况下没有进展到强迫药物使用，但对这些现象相对知之甚少，部分原因是他们潜在的神经电路没有被很好地理解。最近，一系列相互关联的脑区越来越多地与厌恶行为有关；这一组区域包括内丘脑内核(EPN)、外侧缰核(LHb)和被盖旋转内侧核(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表明，这些区域与可卡因的厌恶反应有关。我们进一步假设，可卡因回避条件作用是由这些通路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，我们假设这些通路功能的个体差异性可能与个体寻求药物倾向的差异有关。在检验这些假说的过程中，这个项目可以进一步加深我们对药物的厌恶特性以及它们在个体之间的差异的理解，同时还可以确定可能的新靶点 药物寻觅行为的治疗性调节。

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.