Clonidine and yohimbine in opioid-dependent humans responding under a naloxone novel-response discrimination procedure

Abstract

Opioid-maintained volunteers were trained to distinguish between a low dose of the opioid antagonist naloxone (0.15 mg/70 kg, i.m.; i.e. Drug A) and placebo (i.e. Drug B), under an instructed novel-response drug discrimination procedure in which subjects identify the drug condition as 'A', 'B', or 'N' (neither A nor B - 'novel'). Once the discrimination was acquired, doses of naloxone, the alpha2-adrenergic antagonist yohimbine, the alpha2-adrenergic agonist clonidine, and the training dose of naloxone in combination with clonidine were tested. Naloxone and yohimbine each produced a dose-related increase and decrease in naloxone- and 'novel'-appropriate responding, respectively, with the naloxone stimulus partially generalizing to yohimbine. Clonidine produced primarily placebo-appropriate responding. Naloxone produced expected changes in self-reports, but effects of yohimbine and clonidine were unremarkable, and yohimbine was never identified as an opioid antagonist. Clonidine partially attenuated naloxone-occasioned responding in a non-dose-related manner, and attenuated some, but not all, naloxone-induced changes in self-report measures. Naloxone attenuated or enhanced several clonidine-induced changes in self-report and physiological measures. These findings indicate that adrenergic mechanisms are involved in the expression of opioid withdrawal, but the involvement is indirect.