The literature on cocaine clearly suggests that several experimental factors have a profound influence on the subsequent behavioral effects of cocaine. For example, the continuous cocaine administration via osmotic minipump results in tolerance to the behavioral effects of cocaine. However, the dose and time dependency of these results, as well as the mechanistic bases of these effects, are not entirely understood. The present application proposes to systematically evaluate the factors that induce tolerance following continuous cocaine administration, as well as changes in DA autoreceptor function, and dopamine transporter (DAT) binding following different continuous cocaine administration regimens. Specifically, the present application will evaluate the dose-dependent nature of tolerance, as well as the time course of tolerance following continuous cocaine administration, as well as the corresponding changes in DA autoreceptor function. The present proposal will extend the data base regarding tolerance. The rats will be exposed to pretreatment regimen involving either the continuous infusion of saline or cocaine via osmotic minipump. The rats will then be withdrawn from this pretreatment regiment for 3, 7, 14 or 28 days, and assessed for behavioral, DA autoreceptor, and DAT and serotonin transporter (SET) binding changes. Specifically, the present application will examine, at three different levels of analysis: (1) the induction of tolerance, DA autoreceptor supersensitivity, and changes in DAT and SET binding, by the continuous administration 40 mg/kg cocaine via osmotic minipump for 5, 10, or 15 days. (2) the induction of tolerance, DA autoreceptor supersensitivity, and changes in DAT and SET binding, by the continuous administration of 0, 5, 10, 20 or 40 mg/kg cocaine, via osmotic minipump for 14 days. (3) the time course of DA autoreceptor supersensitivity (assessed behaviorally and voltammetrically), and changes in DAT and SET binding, following the continuous administration of 40 mg/kg cocaine, via osmotic minipump for 14 days. Over the last several years we have documented the residual effects of continuously administered, high dose cocaine. The present experiments are a logical extension of this research. Hence, the present experiments will further elucidate the parameters of cocaine tolerance, and the role of the DA autoreceptor in cocaine abuse and withdrawal, and may aid in the development of effective pharmacotherapies for the treatment of cocaine abuse.
