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

长期使用毒品导致的负面情绪状态的发展对 药物滥用障碍，尚未建立全面的模型。这项裁决将为 这种模型的改进将与最先进的神经电化学和 电生理测量技术探讨负性情绪对药物寻找的影响。这个 本奖项第一阶段的培训为PI提供了独特的技能和对方式的理解 通过滥用药物改变和篡夺神经回路来处理动机和享乐性 自然奖赏的性质。特异性靶点1确定了核内快速释放多巴胺 伏隔(NAC)的核心和外壳被奖赏和厌恶的味觉刺激以及 在预测可卡因的情况下获得自然回报，而不是在预测不会的情况下。这样做的结果 研究表明，预测可卡因的味觉线索会诱导一种负面的情感状态，这种状态与 更多的早期服药。这种厌恶状态似乎类似于提示诱导的戒断。 状态和特定目标2的结果表明，这种消极的情感状态会使颅内升高 自我刺激(ICSS)奖赏阈值，与条件性戒断状态一致。具体目标3将 确定NAC的不同子区域是否选择性地处理关联方面，而不是享乐方面 习得性厌恶与可卡因有关的线索，这种线索会促使他们寻求毒品。在具体目标4中，两 实验将探究这一现象的根源以及这种负面情绪状态对其的控制。 寻找毒品。这些研究的结果将证明非味觉的、药物预测的线索是否也 引发一种消极的情感状态，这种状态会延缓灭绝反应，并促进复发。把这些放在一起 实验将严格测试负面影响对大鼠寻求药物的作用，并允许更好的 对环境如何影响动物的情感和随后的行为的一般理解。

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 ofthe art neural electrochemical and electrophysiological measurement techniques to probe the influence of negative affect on drug seeking. The training from the first phase of this award provided the PI a unique skillset and understanding ofthe 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 determined that rapid dopamine release in the nucleus accumbens (NAc) core and shell was differentially altered by rewarding and aversive taste stimuli as well as for a natural reward in situations in which it predicts cocaine versus when it does not. The results of this study 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 appears to be akin to a cue-induced withdrawal state and the results of Specific Aim 2 demonstrated that this negative affective state elevates intracranial self-stimulation (ICSS) reward thresholds, consistent with a conditioned withdrawal state. Specific Aim 3 will determine if distinct subregions ofthe NAc selectively process associative, versus hedonic aspects ofthe learned aversion to the cocaine-associated cue that promotes drug seeking. In Specific Aim 4, two experiments will probe the breadtl;) 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 and allow for a better general understanding of how the environment influences an animal's affect and subsequent behavior.