Rationale To date, there is no medication specifically approved for cocaine addiction. Agonist medications are used clinically in the treatment of other addictions, which suggests that this method of drug therapy could potentially be successful in treating cocaine addiction as well. Objectives The objective of this study was to determine the effect of extended d-amphetamine treatment on responding on a progressive ratio (PR) schedule reinforced by cocaine. Methods Rats were trained to self-administer cocaine (0.19, 0.38, 0.75, or 1.5 mg/kg/injection) or food on a PR schedule. After stable baseline breakpoints (the number of reinforcers earned in one session) were established over 3 days, animals were implanted with osmotic mini-pumps that continuously delivered d-amphetamine (5 mg/kg/day) for a duration of either 7 or 14 days. Breakpoints were then determined during and/or after this treatment period. Results Rats demonstrated dose-dependent decreases in cocaine-reinforced responding over the d-amphetamine treatment period. Breakpoints for doses of 0.75 mg/kg/injection and below decreased significantly when compared to baseline and remained decreased for up to 14 days after mini-pump removal whereas those for the highest dose of cocaine remained unchanged. Additionally, d-amphetamine treatment during a 14-day abstinence period from cocaine self-administration had no effect on breakpoints when tested the day after mini-pump removal. Conclusions These data suggest that the reduction in cocaine-reinforced responding after continuous d-amphetamine treatment cannot be accounted for by tolerance alone. Instead, the roles of learning and the interaction between cocaine and d-amphetamine must be considered and examined in future studies.

Rationale-Recent studies have investigated d-amphetamine as a potential agonist medication for cocaine dependence. In rats, a 14-day continuous infusion of d-amphetamine via osmotic mini-pump has been shown to decrease cocaine-reinforced responding under a progressive ratio (PR) schedule of reinforcement.Objectives-This study was designed to assess the influences of the d-amphetamine treatment dose and self-administered cocaine dose on the magnitude of this effect. Materials and methods-Experiment 1:Rats were trained to self-administer 1.5 mg/kg/inj cocaine under a PR schedule, then implanted with d-amphetamine mini-pumps for 14 days (days 1-7: 5 mg/kg/day; days 8-14: 7.5 mg/kg/day). Breakpoints were evaluated throughout the treatment period and 14 days post-treatment. Experiment 2: Rats were trained to self-administer cocaine under a PR schedule and initial dose-response curves were determined before implantation of damphetamine mini-pumps. During the 14-day d-amphetamine (5 mg/kg/day) treatment period, rats self-administered one of four cocaine doses (0.19, 0.38, 0.75 or 1.5 mg/kg/inj). A post-treatment PR dose-response curve and responding under a fixed ratio 1 (FR1) schedule were evaluated after minipump removal.Results-Experiment 1: Breakpoints for 1.5 mg/kg/inj cocaine were unchanged by the increasing dose of d-amphetamine. Experiment 2: The PR dose-response curve was shifted downward after the treatment period in rats that had self-administered 0.19 and 0.38 mg/kg/inj cocaine. In contrast, rats in the 0.75 and 1.5 mg/kg/inj groups demonstrated increased rates of cocaine intake under an FR1 schedule after the treatment period.Conclusions-These data suggest that continuous d-amphetamine treatment attenuates the reinforcing effects of cocaine.

Rationale Continuous administration of d-amphetamine has shown promise as a treatment for psychostimulant addiction. In rodent studies, constant infusion of d-amphetamine (5 mg/kg/day) has been shown to reduce cocaine-reinforced responding in the dose range of 0.19 - 0.75 mg/kg/inf. Objectives The present study tested whether these effects were a reflection of pharmacological interactions between d-amphetamine and cocaine or if they resulted from associative learning mechanisms. Methods After stable progressive ratio (PR) baselines were established, rats were implanted with subcutaneous osmotic mini-pumps filled with either d-amphetamine (5 mg/kg/day - groups 1 and 2) or saline (group 3). During the treatment period, groups 1 and 3 self-administered cocaine at a dose that was previously shown to produce the most robust effects in combination with d-amphetamine treatment (0.19 mg/kg/inf), while group 2 received passive cocaine infusions. Results In replication of previous studies, d-amphetamine treatment resulted in a significant (35%) decrease in breakpoints relative to saline controls. By contrast, no reductions in breakpoints were observed in animals that received passive cocaine infusions during the treatment period (group 2). Conclusions Active self-administration of cocaine during the treatment period appears to be an important factor in reducing cocaine-reinforced breakpoints. These findings suggest learning mechanisms are involved in the therapeutic effects of continuous d-amphetamine, and pharmacological interaction mechanisms such as cross-tolerance cannot completely account for the observed decreases in cocaine seeking.