Cue-triggered reward seeking

描述（由申请人提供）：本项目研究奖励线索如何触发强烈寻求奖励行为的生物心理学机制。例如，药物线索可能导致人类成瘾者重新陷入强迫性药物寻求行为，即使在长期戒除药物使用之后。我们称这种现象为线索触发的奖励“欲望”，因为奖励条件刺激过度地突出了奖励。我们建立了一个行为模型来研究大鼠线索触发激励动机的神经行为机制，即纯条件激励范式。使用天然的奖励，蔗糖，允许暴露激励突出的“想要”机制，而不受药物戒断的污染。我们证明，将安非他命微量注射到伏隔核中，特异性地增强了线索触发的对蔗糖奖励的“渴望”，提高了400%以上。我们的行为模型排除了线索效应中脑边缘中介的其他解释（条件强化、联想习惯等）。我们还发现，先前服用安非他明引起的致敏相关变化会导致线索触发的对奖励的“渴望”持续增加，正如激励-致敏假设所预测的那样。在拟议的研究中，我们将研究特异性多巴胺受体在线索触发的“欲望”中的作用（使用特异性多巴胺激动剂和拮抗剂的显微注射）。我们还将阐明伏隔核壳与核的神经解剖学作用（通过显微注射作图实验和使用兴奋毒性病变）。重要的是，我们将评估中脑边缘激活是否会增加线索触发的对蔗糖的“想要”，也会增加对蔗糖的“喜欢”（使用对蔗糖“喜欢”的味觉反应性测量）。最后，我们将测试先前使用可卡因、安非他明或吗啡引起的线索触发的“想要”致敏相关增加的持续时间，并将通过药物显微注射研究致敏与中脑边缘激活的相互作用。这些研究将阐明自然线索触发“想要”的基本机制，并将有助于理解线索触发人类药物成瘾复发的机制。

DESCRIPTION (provided by applicant): This project investigates biopsychological mechanisms of how reward cues trigger intense seeking behavior for their reward. For example, drug cues can cause human addicts to relapse into compulsive drug seeking behavior, even after long abstinence from drug use. We call this phenomenon, cue-triggered 'wanting' of reward, due to excessive attribution of incentive salience to the reward conditioned stimulus. We have developed a behavioral model to study the neurobehavioral mechanism of cue-triggered incentive motivation in rats, the pure conditioned incentive paradigm. Using a natural reward, sucrose, allows exposure of incentive salience 'wanting' mechanisms without contamination by drug withdrawal. We demonstrated that microinjection of amphetamine into nucleus accumbens specifically enhanced cue-triggered 'wanting' for sucrose reward by over 400%. Our behavioral model ruled out alternative explanations for mesolimbic mediation of cue effects (conditioned reinforcement, associative habits, etc.). We have also found that sensitization-related changes caused by prior amphetamine administration leads to a persistent increase in cue-triggered 'wanting' for reward as predicted by the incentive-sensitization hypothesis. In the proposed studies, we will investigate the role of specific dopamine receptors in cue-triggered 'wanting' (using microinjection of specific dopamine agonists and antagonists). We will also clarify the neuroanatomical roles of accumbens shell versus core (in a microinjection mapping experiment and using excitotoxic lesions). Importantly, we will assess whether mesolimbic activation that increase cue-triggered 'wanting' for sucrose also increases 'liking' for sucrose (using the taste reactivity measure of sucrose 'liking'). Finally, we will test the duration of the sensitization-related increase in cue-triggered 'wanting' caused by prior cocaine, amphetamine or morphine administration, and will investigate the interaction of sensitization with mesolimbic activation by drug microinjection. These studies will clarify basic mechanisms of natural cue-triggered 'wanting', and will be useful in understanding mechanisms of cue-triggered relapse in human drug addiction.