Cocaine-seeking produced by experimenter-administered drug injections: dose-effect relationships in rats

Rationale: Relapse to drug taking is a major obstacle to the effective treatment of cocaine abuse. Animal studies have determined that various drugs are able to reinstate extinguished drug-taking behavior. Objectives: This study was designed to determine whether there is specificity in the ability of drugs to lead to cocaine-seeking and to compare potency and efficacy of a variety of drug primes. Another objective was to compare the effect of drugs with a primary dopaminergic mechanism with those having a secondary effect on dopaminergic substrates. Methods: Following acquisition of cocaine self-administration, the ability of injections of cocaine (5.0-20.0 mg/kg), amphetamine (0.30-3.0 mg/kg), methylphenidate (2.0-20.0 mg/kg), nicotine (0.0375-0.60 mg/kg), caffeine (1.25-20.0 mg/kg), morphine (0.10-10.0 mg/kg) or (Delta)9THC (0.3-3.0 mg/kg) to reinstate extinguished drug taking was measured. Tests were conducted in a single day and were comprised of three phases. The first phase consisted of a 60-min period of cocaine self-administration. During phase 2, the cocaine solution was replaced with saline and responding was extinguished during the next 3-h period. During phase 3, in which saline again was the only solution available for self-administration, responding was monitored for 3-8 h following an injection of a drug prime. Results: Reinstatement was produced by experimenter-administered injections of cocaine, amphetamine, methylphenidate and caffeine but not nicotine, morphine or (Delta)9THC. The potency and efficacy of cocaine, methylphenidate and caffeine were comparable, whereas amphetamine was more potent and efficacious. Cocaine seeking occurred primarily during the first hour following the injection. Conclusions: These findings suggest that cocaine seeking is only produced following administration of specific drugs. It is suggested that effective drug primes are those that produce a discriminative stimulus that generalizes to the stimulus produced by the reinforcing effects of cocaine.