The aim of the proposed research is to elucidate the mechanisms underlying the regulation of mu opioid receptors and locomotor activity in response to chronic cocaine exposure. The identification of mechanisms of action of cocaine relevant to its abuse is critical to the development of effective pharmacological treatment strategies. In preliminary studies, chronic repeated cocaine administration resulted in upregulation of mu opioid receptors in several brain regions, particularly in regions associated with dopaminergic terminals. In these studies, cocaine was administered to rats in three daily injections given at one-hour intervals for 14 days in older to mimic the binge pattern of administration that is common in human cocaine abusers. The experiments in this proposal are designed to investigate the regulation of mu opioid receptors during cocaine exposure, to characterize the effects of cocaine administered in a binge-like regimen on locomotor activity, and to determine the mechanisms underlying cocaine's modulation of mu receptors and locomotion. Specifically, the temporal sequence of the expression of mu opioid receptors, dopamine D1 and D2 receptors, and dopamine transporter sites during cocaine administration will be characterized. In vitro receptor autoradiography will be used to quantify and localize changes in receptor densities following various durations of cocaine administration. Spontaneous locomotor activity will be monitored in the same animals in which receptors are to be measured The development of behavioral sensitization or tolerance during the binge-like regimen of cocaine administration will be correlated with the time course of changes in the expression of mu opioid receptors, D1 receptors, D2 receptors, and dopamine transporter sites. The mechanism of the regulation of mu opioid receptors by cocaine will then be investigated. To determine whether increased dopamine receptor activation is necessary for upregulation of mu receptors following chronic cocaine exposure, animals will be pretreated with selective dopamine antagonists prior to cocaine administration. The ability of cocaine to regulate mu receptors in the presence of dopamine receptor blockade will be evaluated. It will be determined if behavioral changes produced by cocaine can be attenuated by co-administration of D1 and/or D2 dopamine antagonists. To examine whether increased activation of D1 and/or D2 receptors is sufficient to regulate mu receptor expression, mu receptors will be measured in animals treated chronically with a selective D1 agonist, D2 agonist, or both agonists. To determine if the regulation of p opioid receptors by cocaine is dependent on cocaine's effect on synaptic dopamine concentrations, animals will be pretreated with reserpine prior to chronic cocaine administration and it will be determined if mu receptor regulation occurs in the absence of increased synaptic dopamine levels. The significance of these studies lies in the ability to correlate cocaine-included specific and diverse neurochemical changes in specific brain regions with each other and with behavioral effects.
