Stimulus effects of d-amphetamine 1: DA mechanisms

As part of a continuing effort to assess the role of monoaminergic neuronal systems in the subjective effects of CNS stimulants, 10 rats trained to discriminate 1.0 mg/kg d-amphetamine from saline were treated with compounds that act through different dopaminergic mechanisms. In substitution (generalization) tests, 20 mg/kg of the dopamine (DA) uptake inhibitor GBR 12909 mimicked the training drug completely; at a dose of 15 mg/kg, GBR 12909 substituted for d-amphetamine incompletely. Neither the D1 agonist SK&F 38393 (1, 10 mg/kg) nor the D2 agonist quinpirole (LY 171555; 0.05-0.2 mg/kg) had amphetamine-like effects. When given in combination with the training drug, the D1 antagonist SCH 23390 blocked the amphetamine cue completely at a dose of 0.05 mg/kg but did not have significant effects at higher or lower doses; the D2 antagonist metoclopramide did not block d-amphetamine at any dose tested (1-5 mg/kg). These data indicate that: a) The discriminable effects of d-amphetamine are due, at least in part, to inhibition of DA uptake; b) direct stimulation of either D1 or D2 receptor sites is not sufficient to evoke d-amphetamine-like responding; and c) blockade of D1 receptors attenuates the subjective effects of d-amphetamine to a greater extent than blockade of D2 receptors.