Synaptic Plasticity in Animal Models of Addiction

描述（由申请人提供）：在美国，可卡因滥用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。可卡因在人类和实验动物大脑中作用的一个关键部位是神经核（NAc）-一种动机行为的调节器。反复接触可卡因导致NAc的持续适应，这被认为是成瘾的成熟动物模型中行为异常的基础，例如行为敏化。在NAc中的神经元能突触传递的适应似乎特别重要。最近的研究已经确定，重复可卡因暴露，诱导强大的行为敏化，也诱导抑郁症的突触效能在前额叶皮层传入NAc形成的突触。我们的研究将联合收割机行为分析与NAc脑切片的全细胞电生理学相结合，以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神经元突触的抑制是致敏的关键神经基质。因此，控制行为适应的基本因素，如给药的剂量、时间模式和背景，将类似地调节NAc突触可塑性，细胞修饰的时间过程将反映行为变化。为了实现本提案的目标，对接触滥用药物的动物脑切片中的突触功能进行研究，应提供必要的关键信息，以便在分子和基因表达水平上的药物诱导适应与最终必然成为成瘾基础的系统水平适应之间建立联系

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