Cocaine-Seeking and the Transfer of Behavioral Control

描述（由申请人提供）：滥用药物可能会破坏正常的学习和决策过程，导致强迫性的、病态的药物寻求行为的发展，这一点越来越引起人们的兴趣。长期暴露于精神兴奋剂，如可卡因，会导致黑质纹状体和中脑边缘多巴胺通路的敏化，这些通路在习惯的习得（即僵硬的、刺激约束的反应）和激励动机的表达（即与奖励相关的线索促进食欲行为或诱导“欲望”的能力）中起关键作用。在这个项目中，我们将评估两种不同的（但不是相互排斥的）成瘾理论：药物暴露允许习惯主导对行动选择的控制（以慎重的、目标导向的行动选择为代价），以及药物暴露增强了与奖励相关的环境线索对表现的影响。我们的计划是结合使用精心控制的行为程序和完善的神经化学检测技术来回答以下问题：(i)在工具训练期间多巴胺的释放是否与基于预测误差的强化信号相匹配，这些信号被认为是负责控制习惯形成的？（ii）可卡因预暴露对习惯性行为的获得和表达以及与强化相关的多巴胺信号的影响是什么？（iii）中脑边缘多巴胺外溢是否介导了引导基于线索的行动选择的激励动机过程？（iv）和，重复可卡因暴露对基于线索的行动选择和中脑边缘多巴胺对奖励相关线索的反应有什么影响？最近的研究表明，与非偶然可卡因相比，反应偶然可卡因会引起更强的神经化学作用，并导致多巴胺释放背后的回路发生更剧烈、更持久的变化。这些发现提出了关于评估实验者给药对学习、行为控制和脑化学影响的有效性的问题。因此，当前应用的第二个目标是确定反复暴露于可卡因的行为和神经化学效应是否取决于给药方式。

DESCRIPTION (provided by applicant): There is growing interest in the possibility that drugs of abuse subvert normal learning and decision- making processes, leading to the development of compulsive, pathological drug-seeking behavior. Chronic exposure to psychostimulants, like cocaine, results in sensitization of nigrostriatal and mesolimbic dopamine pathways, which are critically involved in the acquisition of habits (i.e., rigid, stimulus-bound responses) and the expression of incentive motivation (i.e., the capacity for a reward-related cue to facilitate appetitive behaviors, or induce 'wanting'). In this project, we will evaluate two distinct (but not mutually exclusive) theories of addiction: that drug exposure allows habits to dominate the control of action selection (at the expense of deliberative, goal-directed action selection), and that drug exposure potentiates the influence of reward-related environmental cues over performance. Our plan is to use a combination of carefully controlled behavioral procedures and well-established neurochemical detection techniques to answer the following questions: (i) Does dopamine release during instrumental training match the profile of the prediction error-based reinforcement signal assumed to be responsible for governing habit formation? (ii) What are the effects of cocaine pre-exposure on the acquisition and expression of habitual performance and on reinforcement-related dopamine signaling? (iii) Does mesolimbic dopamine efflux mediate the incentive motivational processes that guide cue-based action selection? (iv) and, What are the effects of repeated cocaine exposure on cue-based action selection and on the mesolimbic dopamine response to reward-related cues? Recent studies have shown that response-contingent cocaine elicits stronger neurochemical effects and results in more dramatic and longer-lasting changes in the circuitry underlying dopamine release than noncontingent cocaine. Such findings raise questions about the validity of studies assessing the effects of experimenter-administered drugs on learning, behavioral control, and brain chemistry. Therefore, a secondary objective of the current application is to determine whether the behavioral and neurochemical effects of repeated cocaine exposure depend on the mode of drug delivery. PUBLIC HEALTH RELEVANCE: Repeated exposure to drugs of abuse, including psychostimulants like cocaine, can significantly alter the neurocircuitry that supports learning and decision-making. Modern theories of addiction propose that these alterations lead to the compulsive, pathological drug-seeking behavior displayed by addicts. The current application combines well-established behavioral tests with neurochemical analysis to investigate how taking cocaine influences the way organisms acquire and select actions.