Cognitive Aspects of Addiction-Related Behavior

描述（由申请人提供）：在之前的资助期内，我们评估了个体记忆系统在八臂放射状迷宫中调节联想学习过程的作用，以及在大鼠自我给药维持/恢复模型中调节行为的作用。结果产生了特定的假设，表明(1)基底外侧杏仁核的吻侧和尾侧亚区在功能上是异质的，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药物寻求；(2)侧背纹状体可能调节自用可卡因的剂量相关效应；(3)海马丘下亚区可能在情境编码（习得）阶段调控药物寻求行为，但在情境信息巩固后不起调控作用；(4)外侧前额叶皮层DA神经传递的变化可能调节通常观察到的药物寻求行为模式的会话内变化。具体目标1将测试这四个假设。对于特定的目标2，将探讨在两个平行的皮质状体-丘脑回路以及皮质状体-丘脑下回路（基底神经节和边缘系统之间的界面）内相互连接的记忆系统之间的相互作用。具体的假设将通过我们新开发的药物寻找行为的神经计算模型进行模拟来进行测试。在体内实验中，将结合不对称GABA激动剂失活技术测量可卡因成瘾过程中不同阶段伏核Fos蛋白的表达，以帮助阐明这些不同回路的组成部分在调节成瘾相关行为时是合作、竞争还是独立工作。这些目标的完成将促进我们对神经认知底物如何调节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中不同阶段的相互作用，我们将深入了解成功治疗可卡因成瘾个体所面临的复杂挑战，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.