Effects of chronic d-amphetamine administration on the reinforcing strength of cocaine in rhesus monkeys

Abstract

Rationale: Agonist medications have been proven effective in treating opioid and nicotine dependence; results from clinical studies suggest that the indirect dopamine agonist d-amphetamine may reduce cocaine abuse. In preclinical studies, chronic d-amphetamine treatment decreased ongoing cocaine self-administration.

Objectives: The present study extended previous results by determining effects of chronic d-amphetamine treatment on the reinforcing strength of cocaine under conditions in which access to cocaine was suspended during d-amphetamine treatment.

Methods: Daily operant conditioning sessions consisted of morning access to food pellets delivered under a 50-response fixed-ratio schedule and evening access to cocaine (0.005-0.48 mg/kg per injection, i.v.) under a progressive-ratio schedule. After responding maintained by 0.045 mg/kg per injection cocaine stabilized, self-administration sessions were suspended and d-amphetamine (0.01-0.1 mg/kg per hr, i.v.) was administered continuously for 5 days. On the following day, d-amphetamine treatment was discontinued and daily self-administration sessions resumed.

Results: Following termination of d-amphetamine treatment, food- and cocaine-maintained responding was decreased in a dose-related manner. Decreases in the reinforcing strength of cocaine were larger and lasted longer than effects on food reinforcement. However, cocaine self-administration was unaltered if 6 days elapsed between discontinuation of d-amphetamine treatment and the next cocaine self-administration session.

Conclusions: The necessity of a self-administration session in the presence of d-amphetamine suggests that the protracted decrease in cocaine self-administration may be a manifestation of behavioral tolerance. Regarding treatment of cocaine dependence, data suggest that prolonged d-amphetamine treatment may be necessary to produce a sustained reduction in the reinforcing effects of cocaine.

Fig. 1

Cocaine self-administration under a PR schedule in rhesus monkeys (n=4). Ordinate Mean (±SEM) number of cocaine injections received, Abscissa available cocaine dose. Point above S indicates number of injections earned during saline availability. *p<0.05, significantly different from saline

Fig. 2

Food- and cocaine-reinforced responding during and after d-amphetamine treatment. Ordinate number of food pellets (top) or cocaine injections (bottom), expressed as a percent of reinforcers earned under baseline conditions. Points represent mean (±SEM) data for four monkeys. Abscissa day during (top only) or after treatment with one of three doses of d-amphetamine (24 h/day, i.v.). *p<0.05, significantly different from baseline reinforcers

Fig. 3

Food- and cocaine-reinforced responding during and after d-amphetamine treatment. Ordinate number of reinforcers, expressed as a percent of reinforcers earned under baseline conditions. Points represent mean (±SEM) data for three monkeys. Abscissa day during d-amphetamine treatment (0.03 mg/kg/h), during a 6-day drug-free period and during cocaine self-administration. Other details as in Fig. 2