Reward Homeostasis, Accumbens AMPA Receptor Trafficking and Drug Abuse

项目摘要 丧失自然奖赏是药物滥用和成瘾的公认风险因素。在动物模型中，丢失 社会或性接触，从富裕的住房中移除，以及获得和消费食物的机会减少 所有这些都被证明增加了寻求毒品和自我管理的程度。我们实验室过去的研究已经 研究表明，食物限制降低了伏隔核多巴胺的基础传递，并诱导了 钙通透性AMPA受体的突触结合(CP-AMPAR)。行为研究，使用 多个方案，已表明这些CP-AMPAR介导了受限食物的增强反应性 大鼠对药物的滥用和以前的环境背景与它们的主观影响成对。这些结果 与其他实验室的研究表明，突触插入CP- AMPAR是对培养中神经元缺乏输入的一种动态平衡反应，在体内发生在 停止特殊的奖励刺激(如滥用药物和“垃圾食品”)。这个项目开始 验证新的假设，即NAC中CP-AMPAR的突触插入是对 失去奖励，一个不适应的后果是对药物的行为反应增加 滥用和相关环境。它进一步假设，这些报酬损失的后果可能是 通过引入替代奖励来抵消全部或部分。初步数据表明这一点得到了支持 环境富集化阻止了食物限制对d-D行为反应的增强效应。 安非他命。因此，拟议的目标1的目标是测试将受食物限制的老鼠转移到 丰富的环境阻止NAC突触结合CP-AMPAR和增加 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能力的预测 从富饶的环境到贫瘠的环境诱导NAC突触结合CP-AMPAR和 以依赖于CP的方式增加与可卡因配对的环境的激励效果- AMPAR。本申请中提议的工作有可能通过提供对以下方面的洞察而有益于人类健康 奖赏稳态的神经生物学及其药物对其机制基础的颠覆 暗示。更广泛地说，这些结果可能会为环境风险因素与环境风险之间的关系提供新的线索。 上瘾的生物学。

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.