The involvement of monoamine neurotransmitter uptake in the discriminative stimulus effects of cocaine was examined in rats (n = 48) trained to discriminate 10mg/kg of this substance from saline in a two-level, water-reinforced (FR 20), drug discrimination situation. Compounds that act primarily by inhibiting dopamine (DA) uptake substituted for the cocaine cue; the order of potency was mazindol > nomifensine > GBR 12909 > bupropion, although efficacy was lowest with GBR 12909. Desipramine, which inhibits norepinephrine (NE) uptake, substituted partially for cocaine while two drugs that inhibit serotonin (5-HT) uptake, citalopram and fluoxetine, did not mimic cocaine. When given in combination with cocaine, cis flupenthixol and SCH 23390 reduced responding on the cocaine-appropriate lever significantly and to a greater extent than either haloperidol, (+/-) sulpiride or (-) sulpiride; neither (+) sulpiride nor metergoline had significant effects. Cocaine substitutions with DA uptake inhibitors were also attenuated to varying extents by cis-flupenthixol, SCH 23390 and haloperidol, but not by metergoline. These data, in conjunction with results reported previously, suggest that inhibition of DA uptake is involved to a greater extent than either NE or 5-HT uptake in the discriminative stimulus properties of cocaine and related compounds. Since both the cocaine cue and its substitution by DA uptake inhibitors appear to be blocked most effectively, reliably and potently by compounds that act either non-selectively at DA receptors (cis-flupenthixol) or primarily at D1 receptors (SCH 23390), D1 mechanisms may play a particularly important role in the neuronal substrates of these behavioral effects.