The action of cocaine on the central nervous system is complex. Development of acute tolerance to cocaine has been investigated extensively and has been described in both human and animal studies. Acute tolerance is characterized by rapid and sometimes complete loss of behavioral and cardiovascular efficacy of cocaine after prolonged or repeated acute exposure despite a stable, elevated plasma concentration. As indicated by both our preliminary data collected in rats using fMRI to elucidate regions of local neural stimulation and supported by behavioral data in humans, while bolus administration of cocaine stimulates neuronal activity in multiple brain structures, a prolonged infusion results in a progressive reversal of this stimulation process. Therefore, the central hypothesis to be tested by this application is that cocaine acts not only to stimulate neural activity in brain but also to terminate and/or reverse activation in stimulated structures and that this process of acute inactivation is suppressed in the chronically cocaine-exposed state. The purpose of these experiments are three fold. Firstly, they are designed to establish that the reversal of fMRI signal observed during a prolonged, constant infusion of cocaine reflects a cocaine-dependent process exerted upon structures activated by cocaine. Furthermore, we will demonstrate that rapid repeated administration of cocaine produces acute tolerance to the stimulating effects. Secondly, we will demonstrate that the reversal of fMRI activation signal accurately reflects a decrease in neuronal activity in cocaine activated brain structures. Because of the importance of dopamine and the D1 receptor both in brain reward circuitry and the mechanism of central stimulation induced by cocaine, we will investigate the relationship between dopamine release and cocaine-mediated reversal of cocaine induced brain activation. Specifically, we will correlate changes in synaptic dopamine with generation and termination of activation signal. Thirdly, using a rat model of chronic exposure to cocaine in which rats are trained to self-administer drug, we will demonstrate that mesolimbic structures are sensitive to repeated prior exposure to cocaine which results to a shift in the balance between activation and acute inactivation within these regions.
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