Potential serotonin 5-HT(1A) and dopamine D(4) receptor modulation of the discriminative stimulus effects of amphetamine in rats.

Activation of the dopaminergic system underlies the behavioral effects of (+)-amphetamine, and plays a major role in its discriminative stimulus properties. Although serotonin receptors modulate dopamine levels in the brain, and 5-HT(1A) and 5-HT(2) receptor agonists do not mimic (+)-amphetamine, pretreatment with 5-HT(2A/2C) agonists significantly potentiates the (+)-amphetamine cue. Further, 5-HT(2) antagonists do not modify the discriminative stimulus effect of (+)-amphetamine, but 5-HT(1A) antagonists have never been tested in (+)-amphetamine-trained rats. This study sought to characterize the effects of the 5-HT(1A) antagonist WAY 100635 on (+)-amphetamine-induced discriminative stimulus effects. Male Sprague-Dawley rats were trained in a two-lever, fixed ratio 50, food-reinforced task with (+)-amphetamine sulfate (1.0 mg/kg, i.p., 30 min pretreatment time) as the discriminative stimulus. Substitution and combination tests with WAY 100635 were then performed. WAY 100635 did not produce substitution in amphetamine-trained rats, but significantly increased behavioral disruption. In combination tests 0.4 and 5.4 mg/kg doses of WAY 100635 potentiated the amphetamine cue. We suggest that low doses of WAY 100635 potentiated the (+)-amphetamine cue by blockade of 5-HT(1A) receptors, but stimulation of the dopamine D(4) receptor by higher doses of WAY 100635 may be responsible for potentiation of amphetamine-induced behavioral sensitization. The high percentage of behavioral disruption in substitution tests might suggest that rats trained to discriminate (+)-amphetamine from saline show behavioral sensitization that is not detectable by the drug discrimination assay but may be expressed as hyperactivity and stereotypic behavior that disrupts operant behavior.