Despite evidence linking "mesolimbic dopamine sensitization" to hypersensitivity to reward-paired cues during protracted cocaine withdrawal;the molecular mechanisms underlying this phenomenon are poorly understood. Here, we test the novel hypothesis that changes in energy utilization within dopamine neurons brought about by repeated cocaine exposure result in disruption of insulin signaling, which negatively impacts synaptic dopamine clearance via the dopamine transporter (DAT). This then results in heightened dopamine transmission in response to cocaine-paired cues, thereby precipitating cocaine-seeking behaviors. The synergistic influence of dietary changes associated with cocaine use on these processes will be assessed using a high-fructose diet that we have previously shown to disrupt insulin signaling in the brain. Markers of mitochondrial function and insulin signaling will be assessed in ventral tegmental area dopamine neurons, post-mortem, collected after varying durations of cocaine self-administration followed by withdrawal, with and without access to a high-fructose diet. In parallel studies, the impact of such exposures on dopamine clearance will be assessed by fast-scan-cyclic voltammetry while monitoring the impact of cocaine-paired cues on cocaine seeking actions. Finally, a causal link between insulin signaling dysregulation and these neurochemical and behavioral phenomena will be assessed by blocking development of insulin resistance with pioglitazone, a drug currently approved for the treatment of Type 2 diabetes. These studies will provide fundamental information regarding the role of cocaine-induced metabolic aberrations in lowering the threshold for relapse and may uncover new targets for therapeutic intervention.
This project will examine the impact of cocaine self-administration on regulation of dopamine neuron energy utilization in rats and how this may mediate hypersensitivity to cocaine-paired cues in withdrawal. The potential synergistic influence of changes in dietary patterns induced by cocaine will also be determined.