Discriminative Stimulus Properties of Cocaine: Enhancement by Monoamine Reuptake Blockers

Abstract

In this study we examined the ability of compounds varying in theirin vitro potencies as inhibitors of dopamine (DA), norepinephrine (NE) or serotonin (5-HT) reuptake to enhance the discriminative stimulus (DS) effects of cocaine. Compounds were administered in combination with cocaine (2.5 mg/kg i.p.) to rats trained to discriminate a low dose from a high dose of cocaine (2.5vs. 10 mg/kg i.p.) in a two-lever, FR10 drug discrimination paradigm. All the monoamine reuptake blockers produced high-dose-appropriate responding in a dose-related manner when combined with a low dose of cocaine, but compounds from other pharmacological classes (benztropine, caffeine, diazepam, or 8-hydroxy-2-(di-n-propylamino)tetralin) did not enhance the DS effects of cocaine. Analysis of the relationship between behavioral andin vitro biochemical potencies indicated that inhibition of DA and 5-HT transport is responsible for the cocaine-enhancing effects of the monoamine reuptake blockers we examined. In contrast, NE reuptake apparently does not play a strong role, despite the finding that desipramine, talsupram and nortriptyline enhanced the DS effects of cocaine. However, pretreatment with the alpha-1 adrenergic antagonist prazosin failed to alter completely the ability of desipramine to enhance the DS effects of the low training dose of cocaine, but did produce dose-related decreases in the cocaine-enhancing effects of the beta adrenergic antagonist propranolol (10 mg/kg i.p.). These findings suggested that, under some conditions, NE interactions can modulate the DS effects of cocaine. In all, the results confirm reports that monoamine reuptake blockers enhance the DS effects of cocaine and indicate that 5-HT and DA can effectively modulate the DS effects of cocaine, but suggest that NE interactions may be relatively less important in the rat.