Potentiation of opioid-induced conditioned place preference by the selective serotonin reuptake inhibitor fluoxetine

The ability of the selective serotonin reuptake inhibitor, fluoxetine, to modify the effects of morphine, N-((S)-2-benzyl-3[(S) 2-amino-4-methylthio)butyldithio-]-1-oxopropyl)-l-alanine benzylester (RB 120; mixed inhibitor of enkephalin metabolism), and 4-{[2-[[3-(1H-indol-3-yl))-2-methyl-1-oxo-2-[[(tricyclo[3,3,1,1] dec-2-yloxy) carbonyl] amino} propyl] amino]-1-phenylethyl] amino}-4-oxo-[R-(R*,R*)]-butanoate N-methyl-d-glucamine (CI 988; cholecystokinin receptor subtype [CCK2] antagonist), was assessed using conditioned place preference. RB 120 and morphine both induced significant, dose-dependent conditioned place preference, whilst CI 988 failed to elicit conditioned place preference. A subthreshold dose of fluoxetine (2.5 mg/kg) potentiated the morphine submaximal response. Notably, the combination of a subthreshold dose of fluoxetine (2.5 mg/kg) with RB 120 (5 mg/kg) or CI 988 (3 mg/kg) was devoid of any significant conditioned place preference properties. Fluoxetine may act via enhanced serotonergic activity to modulate enkephalinergic tone. Agents that increase enkephalinergic tone more directly such as RB 120 and CI 988, at submaximal doses, did not induce conditioned place preference when co-administered with fluoxetine. These data suggest that fluoxetine, in combination with CI 988 or RB 120, might prove to be a beneficial treatment strategy for opioid drug addiction, though further studies are necessary