Phentermine pretreatment antagonizes the cocaine-induced rise in mesolimbic dopamine

Coadministration of phentermine and fenfluramine has been used to treat cocaine dependence. Patients who relapse while receiving this treatment report diminished subjective effects of cocaine. Due to the importance of mesolimbic dopamine (DA) in mediating cocaine reinforcement, we hypothesized that phentermine might attenuate the effects of cocaine on DA transmission. We examined this proposal directly using in vivo microdialysis methods in the nucleus accumbens of awake rats. Rats were pretreated with saline or phentermine (1 mg kg-1, i.v.) and then challenged with cocaine (3 mg kg-1, i.v.). Phentermine alone caused a modest increase in DA, and phentermine pretreatment substantially reduced the cocaine-induced rise in extracellular DA. Phentermine did not alter the stimulatory effect of cocaine on 5-HT. Our findings suggest that phentermine may antagonize the subjective effects of cocaine in humans via a DA mechanism.