DISCRIMINATIVE STIMULUS PROPERTIES OF COCAINE - ENHANCEMENT BY MONOAMINE REUPTAKE BLOCKERS

In this study we examined the ability of compounds varying in their in vitro potencies as inhibitors of dopamine (DA), norepinephrine (NE) o r 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 fr om a high dose of cocaine (2.5 vs. 10 mg/kg i.p.) in a two-lever, FR10 drug discrimination paradigm. All the monoamine reuptake blockers pro duced high-dose-appropriate responding in a dose-related manner when c ombined with a low dose of cocaine, but compounds from other pharmacol ogical classes (benztropine, caffeine, diazepam, or 8-hydroxy-2-(di-n- propylamino)tetralin) did not enhance the DS effects of cocaine. Analy sis of the relationship between behavioral and in vitro biochemical po tencies indicated that inhibition of DA and 5-HT transport is responsi ble for the cocaine-enhancing effects of the monoamine reuptake blocke rs we examined. In contrast, NE reuptake apparently does not play a st rong role, despite the finding that desipramine, talsupram and nortrip tyline 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 traini ng dose of cocaine, but did produce dose-related decreases in the coca ine-enhancing effects of the beta adrenergic antagonist propranolol (1 0 mg/kg i.p.). These findings suggested that, under some conditions, N E interactions can modulate the DS effects of cocaine. In all, the res ults confirm reports that monoamine reuptake blockers enhance the DS e ffects of cocaine and indicate that 5-HT and DA can effectively modula te the DS effects of cocaine, but suggest that NE interactions may be relatively less important in the rat.