More than a Replacement Therapy: Amphetamine Treatment Reverses the Behavioral and Neurochemical Consequences of Cocaine Self‐ Administration

Abstract

Cocaine abuse results in disruption of dopamine (DA) system function, and it has been postulated that this hypodopaminergic state underlies maladaptive behaviors in addiction. As such, an effort has been made to identify compounds that normalize the DA system deficits in order to improve treatment outcomes for cocaine addiction. Although amphetamine (AMPH) has been examined as a potential treatment, with promising behavioral results in rodents, monkeys and humans, the mechanism for AMPH‐induced decreases in cocaine reinforcement has yet to be elucidated. Cocaine SA has been shown to result in escalation of cocaine intake, and increased reinforcing efficacy of cocaine, effects that are thought to model the transition from recreational use to addiction. We found that continuous AMPH treatment (5 mg/kg/day) during cocaine SA attenuated both escalation of intake, and increases in cocaine reinforcement, suggesting that AMPH treatment has a protective effect against the behavioral consequences of repeated cocaine use. Using ex vivo voltammetry we found that AMPH treatment blocked cocaine SA‐induced reductions in basal phasic DA signaling and prevented the development of cocaine tolerance at the DA transporter. In addition, AMPH, when administered during abstinence, completely reversed cocaine tolerance and alterations in phasic signaling. Together, these data demonstrate that some effects of AMPH on cocaine intake are independent of agonist replacement therapy. While agonist therapies for cocaine addiction are controversial and AMPH has a high abuse potential, these data may be to drive the design of more targeted pharmacotherapies with limited abuse liability.