Activation of dopaminergic (DA) systems is a necessary component of the behavior effects of d-amphetamine, but other neurotransmitters such as norepinephrine (NE) and serotonin (5-HT) appear to modulate DA input; thus, they might have an important role in the stimulus (subjective) effects of this drug. Therefore, rats were trained to discriminate d-amphetamine (1 mg/kg) from saline and given combination (antagonism, potentiation) or substitution (generalization) tests with drugs that act through DA, noradrenergic, or serotonergic (5-HT) mechanisms. In the first of two experiments, the D1 antagonist SCH 39166 blocked the effects of d-amphetamine (1 mg/kg) at doses of 0.05, 0.1, and 0.2 mg/kg. NE and 5-HT antagonists including prazosin (0.5-2 mg/kg), idazoxan (1.25-5 mg/kg), ketanserin (0.06-0.15 mg/kg), and metergoline (5-20 mg/kg) had no significant effects on the d-amphetamine cue. In the second experiment, neither the alpha 2-NE agonist clonidine (0.0025-0.1 mg/kg), the beta-NE agonist salbutamol (0.05-0.25 mg/kg), nor the NE uptake inhibitor nisoxetine (5-15 mg/kg) had d-amphetamine-like effects. The alpha 2-NE antagonist yohimbine (0.5-2 mg/kg) and the beta-NE antagonist propranolol (0.5-3 mg/kg) failed to alter the d-amphetamine cue. ICS 205-930 (10 mg/kg) neither mimicked nor blocked the effects of 1 mg/kg of d-amphetamine. Indeed, this 5-HT3 antagonist potentiated the actions of lower doses of d-amphetamine (0.25-0.4 mg/kg); the potentiation of the 0.25-mg/kg dose was blocked significantly by the alpha 1-NE antagonist prazosin (1 mg/kg).(ABSTRACT TRUNCATED AT 250 WORDS)