The Neural Regulation of Negative Affect in a New Model of Cocaine Seeking

描述（由申请人提供）：长期吸毒导致的消极情绪状态的发展对药物滥用障碍有深远的影响，目前尚未全面建模。该奖项将为这种模型的改进提供基础，该模型将与最先进的神经电化学和电生理测量技术结合使用，以探索负面情绪对药物寻找的影响。这一训练将为私家侦探提供一套独特的技能，并让他们了解药物滥用是如何改变和篡夺神经回路的，而神经回路是用来处理自然奖励的动机和享乐属性的。具体目标1将确定伏隔核（NAc）核心和外壳的快速多巴胺释放是否同样受到奖励和厌恶的味觉刺激的改变，以及在预测可卡因的情况下与不预测可卡因的情况下对自然奖励的改变。该结果将拓宽我们对多巴胺在联想学习和享乐加工中的作用的理解。我们已经证明，可预测可卡因的味觉线索会诱发一种消极的情感状态，这种状态与早期吸毒的增加有关。这种厌恶状态可能类似于提示诱导的戒断状态。具体目标2将通过检查负面情感状态对颅内自我刺激（ICSS）反应的影响来验证这一假设。本研究的结果将证明ICSS阈值是否在可卡因预测味道出现后升高，与线索诱导的戒断状态一致。具体目标3将确定NAc的不同子区域是否选择性地处理习得性厌恶可卡因相关线索的联想方面，而不是享乐方面，从而促进药物寻求。在Specific Aim 4中，两个实验将探讨这种现象的广度以及这种负面情感状态对药物寻找的控制。这些研究的结果将证明非味觉、药物预测线索是否也会引发一种消极的情感状态，从而延缓消退反应并促进复发。这些实验将在各自领域专家的指导下，在电化学和行为学技术方面提供培训的同时，严格测试负面情绪在大鼠药物寻找中的作用。

DESCRIPTION (provided by applicant): The development of negative emotional states as a result of chronic drug use has a profound impact on substance abuse disorder and has yet to be comprehensively modeled. This award will provide the basis for the refinement of such a model to be used in conjunction with state of the art neural electrochemical and electrophysiological measurement techniques to probe the influence of negative affect on drug seeking. This training will provide the PI a unique skill set and understanding of the manner by which drugs of abuse alter and usurp the neural circuitry evolved to process the motivational and hedonic properties of natural rewards. Specific Aim 1 will determine if rapid dopamine release in the nucleus accumbens (NAc) core and shell is similarly altered by rewarding and aversive taste stimuli as well a for a natural reward in situations in which it predicts cocaine versus when it does not. The results will broaden our understanding of the role of dopamine in associative learning and hedonic processing. We have shown that a cocaine-predictive taste cue induces a negative affective state that is linked to increased early-session drug taking. This aversive state may be akin to a cue-induced withdrawal state. Specific Aim 2 will test this hypothesis by examining the influence of the negative affective state on responding for intracranial self-stimulation (ICSS). The results of this study will demonstrate whether ICSS thresholds are elevated after the presentation of the cocaine predictive taste, consistent with a cue-induced withdrawal state. Specific Aim 3 will determine if distinct subregions of the NAc selectively process associative, versus hedonic aspects of the learned aversion to the cocaine-associated cue that promotes drug seeking. In Specific Aim 4, two experiments will probe the breadth of this phenomenon and the control this negative affective state exerts on drug seeking. The results of these studies will demonstrate whether non-gustatory, drug-predictive cues also elicit a negative affective state that retards extinction responding and promotes relapse. Together these experiments will rigorously test the role of negative affect on drug seeking in rats while providing training in electrochemical and behavioral techniques under the guidance of experts in their respective fields. PUBLIC HEALTH REVELANCE: The findings of these studies will shape our view and treatment of substance abuse disorders. A negative emotional state is associated with drug seeking and relapse in human addicts. The PI will investigate the motivational properties and neural underpinnings of this state that promotes drug seeking. Such investigations could lead to new pharmacotherapies aimed at disrupting the motivation to seek cocaine.