Cocaine dependence is a chronic disease which causes an immeasurable amount of detriment at both individual and societal levels. Although several promising pharmacological treatments are under development, the process of bringing an investigational drug to market requires substantial investments of both time and money. In view of this, recent research efforts have also been focused on investigating the utility of medications that are currently available for the treatment of other disorders. d-Amphetamine, an FDA-approved medication for the treatment of attention deficit hyperactivity disorder and narcolepsy, has shown promise as an agonist/replacement pharmacotherapy for cocaine dependence in both clinical and preclinical studies. Thus far, studies have shown that the route of administration and treatment regimen greatly influence the therapeutic effectiveness of d-amphetamine in that continuous, but not acute, administration of d-amphetamine decreases the reinforcing effects of cocaine.

The studies presented in Chapters II and III extend the preclinical research by investigating the effects of d-amphetamine treatment via subcutaneous osmotic mini-pump on cocaine self-administration on a progressive ratio (PR) schedule of reinforcement in rats. In Chapter II, we show that continuous d-amphetamine infusion causes a decrease in breakpoints (i.e., the number of cocaine injections self-administered in a PR session) that can last for up to two weeks after the treatment period. These experiments demonstrate that the duration of the d-amphetamine treatment period and the unit dose of self-administered cocaine determine the extent to which d-amphetamine attenuates the reinforcing effects of cocaine. Additionally, we show that cocaine self-administration had to occur during the d-amphetamine treatment period in order for post-treatment breakpoints to be decreased. In Chapter III, we demonstrate that continuous d-amphetamine treatment produces a substantial downward shift in the PR dose-response curve for cocaine which is influenced by the level of cocaine exposure during the d-amphetamine period.

Collectively, these studies suggest that continuous d-amphetamine treatment selectively attenuates the reinforcing efficacy of cocaine. Future study is needed to determine whether this effect is due to a gradual learning process and/or a pharmacological interaction between the two drugs.