Interactive influences of catecholamines and corticotropin-releasing factor in anxiety responses and the reinstatement of cocaine seeking in rats: role of withdrawal duration

在表征大鼠新一轮药物寻找的基本神经生物学底物方面已经取得了重大进展。这一努力的核心是基于复发的动物模型进行的研究，该模型被称为复原法。在这个过程中，一只动物被训练为对药物注射做出行为反应。随后，通过停止吸毒来消除这种行为，此时，暴露在某一事件中，如注射毒品、暴露于与药物相关的线索或暴露于应激源，会触发恢复寻求毒品的行为。在复职研究中需要考虑的一个重要因素是退职持续时间。事实上，影响戒毒后一次复职倾向的动机和相应的神经生物学因素可能与另一次截然不同。这些实验旨在系统地研究焦虑反应和恢复寻求可卡因之间的关系作为戒断持续时间的函数，以及相应的神经过程。该提案的一般假设是，特定应激反应大脑回路中的活动平衡，包括那些含有神经化学物质促肾上腺皮质激素释放因子、去甲肾上腺素和多巴胺的回路，根据终止给药以来的时间而变化，这些变化反映在行为上，包括焦虑样行为的表现和应激诱导的可卡因寻求的恢复。此外，还假设引起焦虑样反应的条件与压力诱导的恢复寻求可卡因之间缺乏对应关系。这项工作对于理解影响药物自我给药后不同时间恢复反应的动机因素，以及更广泛地阐明成瘾、恢复和寻求药物的调节机制具有重要意义。

Significant advances have been made toward characterizing the basic neurobiological substrates underlying renewed drug seeking in rats. Central to this effort are studies based on an animal model of relapse, known as the reinstatement procedure. In this procedure, an animal is trained to perform a behavioural response for drug infusions. Subsequently, the behaviour is extinguished by withholding drug, at which time the reinstatement of drug seeking is triggered by exposure to an event, such as a priming injection of drug, exposure to drug-associated cues, or exposure to a stressor. An important factor to consider in the study of reinstatement is withdrawal duration. Indeed, the motivational and corresponding neurobiological factors affecting the propensity for reinstatement at one time following termination of drug taking may be very different than at another time. The proposed experiments are designed to provide a systematic investigation of the relationship between anxiety responses and reinstatement of cocaine seeking as a function of withdrawal duration, and the corresponding neuronal processes. The general hypothesis of the proposal is that the balance of activity within specific stress-responsive brain circuits, including those containing the neurochemicals corticotropin-releasing factor, noradrenaline, and dopamine, changes depending on time lapsed since the termination of cocaine self-administration, and these changes are reflected in behaviour, including the expression of anxiety-like behaviour and stress-induced reinstatement of cocaine seeking. Furthermore, it is hypothesized that there is a lack of correspondence between conditions that elicit anxiety-like responses and the stress-induced reinstatement of cocaine seeking. This work is important toward understanding the motivational factors that influence reinstatement responding at different times following the termination of drug self-administration and, more generally, toward clarifying the mechanisms mediating addiction, reinstatement, and drug seeking.