Cocaine-Seeking and the Transfer of Behavioral Control

描述(由申请者提供)：人们对滥用药物颠覆正常学习和决策过程的可能性越来越感兴趣，从而导致强迫的、病态的药物寻求行为的发展。长期接触可卡因等精神刺激物会导致黑质纹状体和边缘中脑多巴胺通路的敏感化，这两个通路在习惯的养成(即僵硬的刺激反应)和激励动机的表达(即与奖励相关的提示以促进食欲行为或诱导想要的能力)中起着至关重要的作用。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)，以及药物暴露加强了与奖励相关的环境线索对表现的影响。我们的计划是使用仔细控制的行为程序和成熟的神经化学检测技术的组合来回答以下问题：(I)仪器训练期间释放的多巴胺是否与被认为负责管理习惯形成的基于预测误差的强化信号的轮廓匹配？(Ii)预先接触可卡因对习惯性行为的获得和表达以及强化相关的多巴胺信号有何影响？(Iii)中脑边缘多巴胺的外流是否调节了引导基于线索的行为选择的激励动机过程？(Iv)以及，重复接触可卡因对基于线索的行为选择和对奖赏相关线索的中脑边缘多巴胺反应有什么影响？最近的研究表明，与非反应性可卡因相比，反应性可卡因引起更强的神经化学效应，并导致多巴胺释放的回路发生更戏剧性和更持久的变化。这些发现对评估实验者给药对学习、行为控制和脑化学影响的研究的有效性提出了质疑。因此，当前应用的次要目标是确定反复接触可卡因的行为和神经化学影响是否取决于药物输送方式。

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.