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

描述（由申请人提供）：当遇到预期和接收到的强化之间的差异时，刺激和自然奖励之间的习得关联得到增强（例如，“预测误差”）。例如，在联想条件反射，操作性行为和中脑边缘DA神经元的活动时，预期的强化没有收到和增强时，意想不到的强化。中脑被盖区DA能神经元投射至前额叶皮质（PFC）和中脑核（NAcc）终末。这些区域是联想和高阶学习的功能性相互作用的组成部分，并在长期服用可卡因后发生DA活性的改变。然而，它尚未确定是否PFC和NAcc DA反应在联想学习与自然奖励反映类似的修改在药物联想学习，或者如果改变PFC和DA活动发生通过可卡因联想条件反射的过程中。为了开发针对具有不同药物经验的可卡因滥用者的有效治疗方法，了解可卡因经验依赖的神经和行为功能变化至关重要。 我们的初步研究结果表明，可卡因诱导的联想学习是迅速反映在PFC和NAcc DA反应条件线索，但行为的措施是不太敏感的变化。拟定实验将利用自我给药/调节程序结合体内微透析、行为活动评估和免疫组织化学技术，以实现以下目标：1）在有限和广泛的可卡因条件反射经验后，确定NAcc和PFC DA以及对可卡因和线索诱导的预测误差的反应的行为活动水平，2）确定PFC DA神经传递的变化是否调节NAcc DA反应中的可卡因相关变化，以及3）评估慢性可卡因自我施用、消退和药物戒断后的deltaFosB和Cdk 5过表达。

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.