Reward Homeostasis, Accumbens AMPA Receptor Trafficking and Drug Abuse

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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.