(+/-)Cyclazocine blocks the dopamine response to nicotine.

Abstract

(+/-)Cyclazocine, synthesized by Archer in 1962, was originally tested as a treatment for heroin addiction. (+/-)Cyclazocine is a mu opioid antagonist and kappa opioid agonist, and because of these actions, would be expected to modulate dopamine release in the nucleus accumbens as well as the reinforcing effects of drugs of abuse. In a recent study (+/-)cyclazocine was reported to decrease cocaine self-administration in rats. The aim of the present study was to determine whether (+/-)cyclazocine would alter the dopaminergic effects of nicotine that are thought to mediate its rewarding effects. Using in vivo microdialysis in awake and freely moving rats, we investigated the effect of (+/-)cyclazocine (0.5 mg/kg, i.p.) on the acute dopamine response to nicotine (0.32 mg/kg, i.v. over a 5 min period, infused 30 min later) in the nucleus accumbens. (+/-)Cyclazocine significantly attenuated the increase in extracellular dopamine levels induced by the nicotine infusion and enhanced nicotine-induced increases in dopamine metabolites. (+/-)Cyclazocine alone did not significantly affect extracellular dopamine levels. However, both the (+) and (-) enantiomers of cyclazocine did alter basal dopamine levels and these effects made it difficult to assess their individual interactions with nicotine. The results suggest that the effects of both enantiomers contribute to the effects of the racemate; (+/-)cyclazocine may decrease the rewarding effect of nicotine and may be the prototype of a potentially novel treatment for smoking.