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

由于长期使用毒品而产生的消极情绪状态的发展， 药物滥用障碍，尚未全面建模。该奖项将提供基础， 这种模型的改进将与现有技术的神经电化学和 电生理测量技术，探讨负性情绪对药物寻求的影响。的 该奖项第一阶段的培训为PI提供了独特的技能和理解方式 滥用药物改变和篡夺神经回路进化处理动机和享乐 自然奖励的性质。特异性目标1确定了多巴胺在核中的快速释放 奖赏性和厌恶性味觉刺激以及 在它预测可卡因的情况下与在它不预测可卡因的情况下的自然奖励。的结果 研究表明，可卡因预测性味觉线索诱导了一种消极情感状态， 增加了早期的药物服用。这种厌恶状态似乎类似于线索诱导的退缩 状态和具体目标2的结果表明，这种负面的情感状态会提高颅内 自我刺激（ICSS）奖励阈值，与条件性退缩状态一致。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， 对可卡因相关线索的习得性厌恶促进了药物寻求。在具体目标4中， 实验将探索这种现象的广度和这种消极情感状态对情绪的控制。 药物寻求这些研究的结果将证明非味觉的药物预测线索是否也 引发一种消极的情感状态，延缓消退反应并促进复发。综合这些 实验将严格测试负面情绪在大鼠药物寻求中的作用，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.