Synaptic Plasticity in Animal Models of Addiction

描述(申请人提供)：可卡因滥用在美国是一个危险和普遍的健康、社会和经济问题，消耗了大量的联邦和州资源。在人类和实验动物的大脑中，可卡因活动的一个关键部位是伏隔核(NAC)--一种动机行为的调节器。反复接触可卡因会导致NAC的持续适应，这被认为是已建立的成瘾动物模型行为异常的基础，如行为敏化。NAC中谷氨酸能突触传递的适应性似乎特别重要。最近的研究已经证实，反复暴露可卡因可以诱导强烈的行为敏化，也会导致NAC的前额叶皮质传入形成的谷氨酸能突触的突触效率下降。我们提出的研究将结合行为分析和NAC脑片的全细胞电生理学来描述可卡因诱导的突触可塑性和行为敏化之间的关系。我们假设NAC谷氨酸能突触的抑制是敏化的关键神经底物。因此，控制行为适应的基本因素，如给药的剂量、时间模式和环境，将类似地调节NAC突触的可塑性，细胞修饰的时间进程将反映行为的变化。为了实现当前建议的目标，对暴露于滥用药物的动物脑片中的突触功能的研究应该提供必要的关键信息，使药物诱导的分子水平和基因表达的适应与最终必然导致成瘾的系统水平的适应之间建立联系。

DESCRIPTION (provided by applicant): Cocaine abuse in the United States is a dangerous and pervasive health, social and economic issue that consumes an enormous amount of federal and state resources. A key site of cocaine's actions in the brain, both in humans and in experimental animals, is the nucleus accumbens (NAc)-a regulator of motivated behaviors. Repeated exposure to cocaine results in persistent adaptations in the NAc that are thought to underlie behavioral abnormaltites in well-established animal models of addiction, such as behavioral sensitization. Adaptations in glutamatergic synaptic transmission in the NAc appear to be particularly important. Recent studies have established that repeated cocaine exposure that induces robust behavioral sensitization also induces a depression in synaptic efficacy at glutamatergic synapses formed by prefrontal cortical afferents to the NAc. Our proposed studies will combine behavioral analysis with whole-cell electrophysiology in NAc brain slices to delineate the relationship between cocaine-induced synaptic plasticity and behavioral sensitization. We hypothesize that depression at NAc glutamatergic synapses is a critical neural substrate for sensitization. As such, fundamental factors controlling the behavioral adaptations, such as dose, temporal pattern and context of drug administration will similarly regulate NAc synaptic plasticity and the time course of the cellular modification will mirror the behavioral changes. In fulfilling the aims of the current proposal, the study of synaptic function in brain slices from animals exposed to drugs of abuse should provide crucial information necessary to make the link between drug-induced adaptations at the level of molecules and gene expression to those systems level adaptations that ultimately must underlie addiction