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

描述(由申请人提供)：当遇到预期强化和接收强化之间的差异(例如，“预测误差”)时，刺激和自然奖励之间的获得性关联被增强。例如，在联合条件反射过程中，当没有收到预期的强化时，操作行为和中脑边缘DA神经元的活动减少，而当意外强化出现时，操作行为和中脑边缘DA神经元的活性增强。腹侧被盖区DA神经元投射到前额叶皮质(PFC)和伏核(NAcc)终末。这些区域是联想学习和高阶学习的功能交互成分，在长期服用可卡因后，DA活动发生改变。然而，PFC和NAcc DA在自然奖赏的联想学习过程中的反应是否反映了药物联想学习过程中的类似变化，或者是否在可卡因关联条件作用过程中发生了PFC和DA活性的变化还有待确定。为了开发针对不同吸毒经历的可卡因滥用者的有效治疗方法，了解可卡因经验依赖于神经和行为功能的变化是至关重要的。 我们的初步发现表明，可卡因诱导的联想学习迅速反映在PFC和NAcc DA对条件线索的反应中，但行为测量对变化不那么敏感。拟议的实验将结合体内微透析、行为活动评估和免疫组织化学技术来解决以下目标：1)确定在有限和广泛的可卡因调节经验后，对可卡因和线索诱导的预测错误做出反应的NAcc和PFC DA和行为活动水平，2)确定PFC DA神经递质的变化是否调节NAcc DA反应的可卡因相关变化，以及3)评估长期给药、戒断和戒毒后DeltaFosB和CDK5的过度表达。

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.