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

可卡因寻求新模式中负面情绪的神经调节

• 批准号: 7570250
• 负责人: ROBERT A WHEELER
• 金额: $ 8.68万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7570250
• 关键词: Affect; Affective; American Psychiatric Association; Animals; Arts; Award; Behavior; Behavioral; Brain; Cells; Chronic; Cocaine; Complex; Cues; Data; Development; Disease; Dopamine; Dorsal; Drug usage; Event; Exhibits; Extinction (Psychology); Feeling; Food; Foxes; Goals; Human; Individual; Infusion procedures; Investigation; Lead; Learning; Link; Measurement; Mediating; Modeling; Motivation; Negative Reinforcements; Neurons; Nucleus Accumbens; Pharmaceutical Preparations; Pharmacotherapy; Play; Principal Investigator; Process; Property; Public Health; Quinine; Rattus; Relapse; Rewards; Rodent; Role; Self Administration; Self Stimulation; Self-Administered; Series; Shapes; Solutions; Stimulus; Substance abuse problem; Taste Perception; Techniques; Testing; Training; Water; Withdrawal; base; classical conditioning; craving; design; drug of abuse; drug withdrawal; experience; hedonic; motivational processes; negative emotional state; neural circuit; neuromechanism; neuroregulation; novel; reinforcer; relating to nervous system; research study; response; reward processing; skills; sweet taste perception; theories

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.

描述（由申请人提供）：慢性药物使用导致的负面情绪状态的发展对药物滥用障碍有着深远的影响，尚未全面建模。该奖项将为改进这种模型提供基础，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，以探索负面影响对药物寻求的影响。这种培训将为PI提供一套独特的技能，并了解滥用药物改变和篡夺神经回路的方式，这些神经回路是为了处理自然奖励的动机和享乐特性而进化的。具体目标1将确定是否快速多巴胺释放的核丘脑（NAc）的核心和外壳是类似的改变奖励和厌恶的味觉刺激，以及一个自然的奖励的情况下，它预测可卡因与当它不。这些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，可卡因预测的味觉线索诱导了一种消极的情感状态，这种状态与早期药物服用的增加有关。这种厌恶状态可能类似于线索诱导的退缩状态。具体目标2将通过检查负面情感状态对颅内自我刺激（ICSS）反应的影响来检验这一假设。本研究的结果将证明在呈现可卡因预测性味道后ICSS阈值是否升高，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对可卡因相关线索的习得性厌恶的关联性和享乐性方面，这些线索促进了药物寻求。在具体目标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求的控制。这些研究的结果将证明非味觉的药物预测线索是否也会引起一种消极的情感状态，从而延缓消退反应并促进复发。这些实验将严格测试负面影响对大鼠药物寻求的作用，同时在各自领域专家的指导下提供电化学和行为技术的培训。 公共卫生报告：这些研究的结果将塑造我们对药物滥用障碍的看法和治疗。消极的情绪状态与人类成瘾者的药物寻求和复吸有关。PI将研究这种促进药物寻求的状态的动机特性和神经基础。这类调查可能会导致新的药物疗法，旨在破坏寻求可卡因的动机。