Cocaine and amphetamine attenuate the discriminative stimulus effects of naltrexone in opioid-dependent rhesus monkeys

This study tested the hypothesis that stimulants (indirect dopamine agonists) attenuate the discriminative stimulus of naltrexone in monkeys chronically treated with L-α-acetylmethadol (LAAM). Four rhesus monkeys (Macaca mulatta) received LAAM (1.0 mg/kg s.c.) twice daily and discriminated a withdrawal-precipitating dose of naltrexone (0.0178 mg/kg s.c.) from saline. Cocaine (0.1-1.78 mg/kg), amphetamine (0.32-1.78 mg/kg), haloperidol (0.01-0.1 mg/kg), sulpiride (1.0-10.0 mg/kg), propranolol (0.32-3.2 mg/kg), clonidine (0.001-0.1 mg/kg), desipramine (0.32-3.2 mg/kg), and imipramine (1.0-10.0 mg/kg) were given s.c. before cumulative doses of naltrexone. Cocaine and amphetamine antagonized the discriminative stimulus effects of naltrexone, each shifting the naltrexone dose-effect curve significantly (e.g., 100-fold) rightward or downward. In contrast, the dopamine antagonist haloperidol shifted the naltrexone dose-effect curve 5-fold leftward. Sulpiride, desipramine, clonidine, and propranolol had comparatively less effect on the naltrexone discriminative stimulus, whereas some doses of imipramine attenuated the naltrexone stimulus in a manner similar to that of cocaine and amphetamine. These results support the notion that multiple neurotransmitter systems are involved in the discriminative stimulus effects of opioid withdrawal. Furthermore, these data are consistent with reports that dopamine levels decrease during opioid withdrawal and provide evidence that enhancing dopamine or other monoamine levels may attenuate subjective effects of opioid withdrawal.