Synaptic Plasticity in Animal Models of Addiction

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。可卡因在大脑中活动的关键部位， 在人类和实验动物中，伏隔核(NAC)都是一种动力调节 行为。反复接触可卡因会导致NAC的持续适应，这被认为是 在已建立的成瘾动物模型中，行为异常是基础，例如行为 敏化。NAC中谷氨酸能突触传递的适应性似乎特别 很重要。最近的研究已经证实，反复接触可卡因会导致强健的行为 敏化还导致前额叶形成的谷氨酸能突触的突触效能降低 NAC的皮质传入神经。我们建议的研究将把行为分析和全细胞研究结合起来 NAC脑片电生理学研究可卡因诱导突触可塑性的关系 和行为敏感化。我们假设NAC谷氨酸能突触的抑制是一个关键因素 用于敏化的神经底物。因此，控制行为适应的基本因素，如 由于剂量、时间模式和给药环境将类似地调节NAC突触可塑性和 细胞修饰的时间进程将反映出行为的变化。在实现本组织的目标方面 目前的建议是，对暴露于滥用药物的动物脑片中突触功能的研究应该 提供必要的必要信息，使药物诱导的适应之间在 分子和基因表达对这些系统水平的适应，最终肯定会导致上瘾。

Cocaine abuse in the United States is a dangerous and pervasive health, social and economic issue that consumes an enormous amouth 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 behavioraladaptations, such as dose, temporal pattern and context of drug administrationwill 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 expressionto those systems level adaptations that ultimately must underlieaddiction.