Reward Homeostasis, Accumbens AMPA Receptor Trafficking and Drug Abuse

项目摘要 失去自然奖赏是药物滥用和成瘾的公认危险因素。在动物模型中， 社会或性接触，从丰富的住房中迁移，以及获得和消费食物的机会减少 都被证明会增加寻求毒品和自我管理。我们实验室过去的研究 表明食物限制减少了丘脑核中的基础多巴胺传递， 钙渗透性AMPA受体（CP-AMPAR）的突触掺入。行为研究，使用 多个协议，已显示这些CP-AMPAR介导的食物限制的反应性增强， 大鼠的药物滥用和环境背景先前配对与他们的主观影响。这些结果 已被认为是与那些从其他实验室表明，突触插入CP- AMPAR是对培养物中神经元输入剥夺的稳态反应，并且在培养后在体内发生。 从特殊的奖励刺激（例如滥用药物和“垃圾食品”）中撤出。该项目开始于 测试新的假设，即NAc中CP-AMPAR的突触插入是对 奖励的丧失，一个适应不良的后果是对药物的行为反应增加， 虐待和相关环境。进一步假设，奖励损失的这些后果可以是 通过引入替代奖励来全部或部分抵消。初步数据表明， 丰富的环境阻止了食物限制对d- 安非他明因此，提出的目标1的目的是测试将食物限制大鼠转移到 丰富的环境阻止了CP-AMPAR的NAc突触结合， 可卡因配对环境的激励效应。目的2检验自由采食大鼠转移的预测 从富集到贫乏的环境诱导CP-AMPAR的NAc突触掺入， 以依赖于CP的方式增加可卡因配对环境的激励效应， AMPAR。本申请中提出的工作有可能通过提供以下方面的见解而有益于人类健康： 奖赏稳态的神经生物学和药物对其机制基础的颠覆， 线索更一般地说，研究结果可以揭示环境风险因素与环境污染之间的关系。 成瘾的生物学

Project Summary Loss of natural reward is a recognized risk factor for drug abuse and addiction. In animal models, loss of social or sexual contact, removal from enriched housing, and decreased access to and consumption of food have all been shown to increase drug-seeking and self-administration. Past research in our laboratory has shown that food restriction decreases basal dopamine transmission in nucleus accumbens and induces synaptic incorporation of calcium-permeable AMPA receptors (CP-AMPARs). Behavioral studies, using multiple protocols, have shown these CP-AMPARs to mediate the enhanced responsiveness of food restricted rats to drugs of abuse and environmental contexts previously paired with their subjective effects. These results have been considered in conjunction with those from other laboratories indicating that synaptic insertion of CP- AMPARs is a homeostatic response to deprivation of input to neurons in culture, and occurs in vivo after withdrawal from exceptional reward stimulation (e.g. drugs of abuse and “junk food”). This project begins to test the novel hypothesis that synaptic insertion of CP-AMPARs in NAc is a general homeostatic response to loss of reward, with one maladaptive consequence being increased behavioral responsiveness to drugs of abuse and associated environments. It is further hypothesized that these consequences of reward loss can be offset, in whole or part, by introducing alternative rewards. This is supported by preliminary data indicating that environmental enrichment prevents the enhancing effect of food restriction on behavioral responsiveness to d- amphetamine. The goal of proposed Aim 1 is therefore to test the prediction that transfer of food restricted rats to an enriched environment prevents both the NAc synaptic incorporation of CP-AMPARs and increased incentive effects of a cocaine-paired environment. Aim 2 tests the prediction that transfer of ad libitum fed rats from an enriched to impoverished environment induces NAc synaptic incorporation of CP-AMPARs and increases the incentive effects of a cocaine-paired environment in a manner that is dependent on CP- AMPARs. The work proposed in this application has potential to benefit human health by providing insight into the neurobiology of reward homeostasis and subversion of its mechanistic underpinnings by drugs and their cues. More generally, results could shed new light on the nexus between environmental risk factors and the biology of addiction.