STIMULUS EFFECTS OF D-AMPHETAMINE-II - DA, NE, AND 5-HT MECHANISMS

Activation of dopaminergic (DA) systems is a necessary component of th e behavior effects of d-amphetamine, but other neurotransmitters such as norepinephrine (NE) and serotonin (5-HT) appear to modulate DA inpu t; 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 a ct through DA, noradrenergic, or serotonergic (5-HT) mechanisms. In th e first of two experiments, the D-1 antagonist SCH 39166 blocked the e ffects 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 upt ake 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 an tagonist propranolol (0.5-3 mg/kg) failed to alter the d-amphetamine c ue. 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 t he actions of lower doses of d-amphetamine (0.25-0.4 mg/kg); the poten tiation of the 0.25-mg/kg dose was blocked significantly by the (alpha (1)-NE antagonist prazosin (1 mg/kg). These results suggest that the d iscriminative stimulus effects of d-amphetamine are mediated primarily by DA neuronal systems and that these effects are similar to those of drugs that act through 5-HT3 receptors; this similarity could be medi ated by alpha(1)-NE mechanisms.