The involvement of dopaminergic and adrenergic mechanisms in the stimulus effects of cocaine was studied in rats trained to discriminate cocaine from saline. The cocaine (10mg/kg) cue generalized to compounds that act primarily by inhibiting DA uptake with an order of potency of nomifensine (ED(50) = 0.38mg/kg) > GBR12909 (1-{2-[bis(4-fluorophenyl) methoxy]-ethyl]}-4(3-phenylpropyl) piperazine (ED(50) = 4.38mg/kg) > bupropion (ED(50) = 11.6mg/kg) but not to those that: (1) directly activate postsynaptic DA receptors (bromocriptine), (2) release DA (amantadine), (3) have antagonist actions at presynaptic DA receptors (cis-flupenthixol) or, (4) inhibit the uptake of NE (desipramine, imipramine, nisoxetine). When given in combination with cocaine, the D2 receptors antagonist (-)sulpiride had no significant effects on cocaine-lever selection. These results suggest that inhibition of DA uptake is involved in the discriminative stimulus properties of cocaine since, (1) compounds that act by inhibiting DA uptake rather than through some other mechanism mimic cocaine and, (2) the reported affinities of these drugs for the DA transport site and their order of potency in blocking cocaine are identical.