Cocaine & Brain: Progressive Changes in Behavior/DA/Fos

描述（由申请人提供）：当预期和收到的强化之间存在差异时，刺激和自然奖励之间的习得关联会增强（例如，“预测错误”）。例如，在联想条件反射过程中，当没有收到预期的强化时，操作行为和中边缘DA神经元的活动会减少，而当出现意外的强化时，操作行为和中边缘DA神经元的活动会增强。腹侧被盖区DA神经元投射到前额皮质（PFC）和伏隔核（NAcc）终端。这些区域是联想学习和高阶学习的功能交互组成部分，并且在长期服用可卡因后发生DA活动的改变。然而，在自然奖励的联想学习过程中，PFC和NAcc的DA反应是否反映了药物联想学习过程中类似的变化，或者PFC和DA活动的改变是否发生在可卡因联想条件作用过程中，目前还不清楚。为了开发有效的治疗可卡因滥用者不同的药物经验，至关重要的是要了解可卡因经验依赖的神经和行为功能的变化。

DESCRIPTION (provided by applicant): Learned associations between stimuli and natural rewards are enhanced when discrepancies between anticipated and received reinforcement are encountered (e.g., "prediction errors"). For instance, during associative conditioning, operant behaviors and mesolimbic DA neuronal activity are decreased when anticipated reinforcement is not received and enhanced when unexpected reinforcement is presented. Ventral tegmental area DA neurons project to prefrontal cortex (PFC) and nucleus accumbens (NAcc) terminals. These regions are functionally interactive components of associative and higher order leaming, and undergo modifications in DA activity after chronic cocaine administration. However, it has yet to be determined whether PFC and NAcc DA responses during associative leaming with natural rewards reflect similar modifications during drug-associative learning, or if alterations in the PFC and DA activity occur through the course of cocaine-associative conditioning. To develop effective treatments for cocaine abusers with different drug experiences, it is crucial to understand cocaine experience-dependent changes in neural and behavioral functions. Our preliminary findings indicate that cocaine-induced associative learning is rapidly reflected in PFC and NAcc DA responsiveness to conditioned cues, but behavioral measures are less sensitive to change. The proposed experiments will utilize a self-administration/conditioning procedure in conjunction with in vivo microdialysis, behavioral activity assessment and immunohistochemical techniques to address the following aims: 1) To determine NAcc and PFC DA and behavioral activity levels in response to cocaine and cue-induced prediction errors after limited and extensive cocaine conditioning experience, 2) To determine whether changes in PFC DA neurotransmission modulate cocaine-associative changes in NAcc DA responses, and 3) To assess deltaFosB and Cdk5 overexpression after chronic cocaine self-administration, extinction and drug abstinence.