Stimulus effects of d-Amphetamine II: DA, NE, and 5-HT mechanisms

Abstract

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 D 1 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 α 2-NE agonist clonidine (0.0025–0.1 mg/kg), the β-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 α 2-NE antagonist yohimbine (0.5–2 mg/kg) and the β-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-HT 3 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 α 1-NE antagonist prazosin (1 mg/kg). These results suggest that the discriminative 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-HT 3 receptors; this similarity could be mediated by α 1-NE mechanisms.