Cognitive Aspects of Addiction-Related Behavior

描述(申请人提供)：在之前的资助期间，评估了个体记忆系统在调节在八臂径向迷宫中研究的联想学习过程中的作用以及在大鼠自我给药维持/恢复模型中研究的行为调节中的作用。这些结果产生了特定的假说，认为(1)杏仁核基底外侧区的吻侧和尾侧亚区在功能上是不同的，因此可能对多巴胺激动剂和拮抗剂具有不同的敏感性，以改变维持和恢复条件下的寻药行为；(2)外侧背侧纹状体可能调节自用可卡因的剂量相关效应；(3)海马亚亚区可能在上下文编码(获得)阶段调控寻药行为，但在上下文信息巩固之后不起作用；(4)在会话中，额叶外侧皮质DA神经传递的变化可能调节会话中正常观察到的寻药行为模式的变化。《特定目标1》将检验这四个假设。为了达到特定的目的2，我们将探讨在两个平行的皮质纹状核-丘脑-下丘脑回路(基底节和边缘系统之间的接口)内相互连接的记忆系统之间的相互作用。要测试的特定假设将通过使用我们新开发的药物寻找行为的神经计算模型进行模拟来指导。在体内实验中，将结合不对称GABA激动剂失活技术来测量可卡因成瘾过程不同阶段伏隔核中Fos蛋白的表达，以帮助阐明这些不同电路的组成部分在调节成瘾相关行为方面是合作、竞争还是独立发挥作用。这些目标的完成将促进我们对神经认知底物如何调控药物使用和复发的理解。通过研究记忆系统功能及其在可卡因成瘾过程不同阶段的相互作用，洞察成功治疗可卡因成瘾者所面临的复杂挑战将浮出水面，并可能指导药物开发。

DESCRIPTION (provided by applicant): During the previous funding period, individual memory systems were evaluated for their role in regulating associative learning processes studied in an eight-arm radial maze as well as in regulating behavior studied in a self-administration maintenance/reinstatement model in rats. The results generated specific hypotheses to suggest (1) that the rostral and caudal subregions of basolateral amygdala are functionally heterogeneous and may therefore have a differential sensitivity to dopamine agonists and antagonists for modifying drug-seeking under maintenance and reinstatement conditions; (2) that the lateral dorsal striatum may regulate the dose-related effects of self-administered cocaine; (3) that the hippocampal subicular subregions may regulate drug-seeking behavior during the contextual encoding (acquisition) stage, but not after contextual information is consolidated; and (4) that within session changes in DA neurotransmission in the lateral prefrontal cortex may regulate the within session changes in the pattern of drug-seeking behavior normally observed. Specific aim 1 will test these four hypotheses. For specific aim 2, the interactions between memory systems that are interconnected within two parallel corticostriatalpallidothalamic circuits as well as within the corticostriatalpallido-subthalamic circuit (interface between the basal ganglia and limbic system) will be explored. Specific hypotheses to be tested will be guided by conducting simulations with our newly developed neurocomputational model of drug-seeking behavior. In in vivo experiments, Fos protein expression in the nucleus accumbens at different phases of the cocaine addiction process will be measured in conjunction with the asymmetric GABA agonist inactivation technique to help elucidate if components of these different circuits work cooperatively, competitively or independently in regulating addiction-related behavior. The completion of these aims will advance our understanding of how neurocognitive substrates may regulate drug use and relapse. By studying memory system functions and their interactions during different phases of the cocaine addiction process, insight into the complex challenges that face successful treatment of cocaine-addicted individuals will surface and perhaps guide medications development.