Synaptic Plasticity in Animal Models of Addiction

成瘾动物模型中的突触可塑性

• 批准号: 7037335
• 负责人: Mark John Thomas
• 金额: $ 25.51万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7037335
• 关键词: behavioral habituation /sensitization; brain; cocaine; depression; model

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

描述（由申请人提供）：可卡因滥用在美国是一个危险且普遍的健康、社会和经济问题，消耗大量联邦和州资源。无论是在人类还是在实验动物中，可卡因在大脑中发挥作用的一个关键部位是伏隔核 (NAc)，它是动机行为的调节器。反复接触可卡因会导致 NAc 持续适应，这被认为是成熟动物成瘾模型中行为异常的基础，例如行为过敏。 NAc 中谷氨酸能突触传递的适应似乎特别重要。最近的研究表明，反复接触可卡因会引起强烈的行为敏化，也会导致由前额皮质传入 NAc 形成的谷氨酸突触的突触功效下降。我们提出的研究将行为分析与 NAc 脑切片的全细胞电生理学相结合，以描绘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 谷氨酸突触的抑制是致敏的关键神经底物。因此，控制行为适应的基本因素，例如剂量、时间模式和给药环境将类似地调节 NAc 突触可塑性，并且细胞修饰的时间过程将反映行为变化。为了实现当前提案的目标，对滥用药物的动物脑切片中突触功能的研究应该提供必要的关键信息，以在分子水平上的药物诱导适应与这些系统水平上的基因表达之间建立联系。最终必须成为成瘾基础的适应