Effects of quaternary naltrexone and chlordiazepoxide in squirrel monkeys with enhanced sensitivity to the behavioral effects of naltrexone.

Dose-effect curves were determined for the effects of the opioid antagonist, naltrexone, on lever-pressing responses of squirrel monkeys maintained under a 30-response fixed-ratio schedule of food presentation. Cumulative doses of naltrexone up to 3 mg/kg i.m. had little or no effect on fixed-ratio responding, whereas higher doses reduced responding in all monkeys. After initial determinations of the dose-effect curve for naltrexone, repeated daily injections of high doses of naltrexone resulted in enhanced sensitivity to its behavioral effects. The cumulative dose-effect curve for naltrexone determined after termination of daily injections was shifted more than 3-fold to the left. In these same monkeys, the dose-effect curve for naltrexone methobromide, a quaternary derivative of naltrexone with limited access to the central nervous system, was similar to the initial dose-effect curve for naltrexone. Chlordiazepoxide given 1 hr before the experimental session shifted the naltrexone dose-effect curve back toward its initial position before the regimen of daily injections, but had no systematic effect on the dose-effect curve for quaternary naltrexone. Enhanced sensitivity to the behavioral effects of naltrexone in these experiments appears to depend on a central component of action and is attenuated by chlordiazepoxide.