Blockade of the discriminative stimulus effects of d-amphetamine in rhesus monkeys with serotonin 5-HT(1A) agonists.

Abstract

Rhesus monkeys (n = 4) were trained in a two-lever drug discrimination paradigm to discriminate d-amphetamine (AMPH; 0.56 or 1.0mg/kg, i.g., 60min pre-session) from saline. Lever pressing was maintained under a discrete-trials shock avoidance schedule of reinforcement (30 trials/day, 30-s intertrial interval, fixed-ratio 1). Before test sessions, in which responding on either lever avoided shock, the monkeys were infused (i.g.) with saline or various doses of AMPH (0.1-1.7mg/kg), alone or in combination with intramuscular injections of the serotonin (5-HT(1A)) agonists buspirone (0.3-1.0mg/kg), gepirone (0.56-3.0mg/kg), 8-hydroxy-2(di-n-propylamino) tetralin (8-OH-DPAT; 0.01-0.1mg/kg), the dopamine D2 antagonist raclopride (0.03 and 0.1mg/kg), or pentobarbital (10mg/kg). Doses of the 5-HT(1A) agonists and raclopride, which occasioned only saline-lever responding when tested alone, shifted the AMPH dose-response function 0.5 to 1.0 log unit to the right in all monkeys, while pentobarbital had no effect. For the 5-HT(1A) agonists, the order of potency for attenuating the AMPH discriminative stimulus was 8-OH-DPAT>buspirone>gepirone, similar to their binding affinities at 5-HT(1A) receptors. Raclopride was equipotent to 8-OH-DPAT. In addition, although the effect of buspirone and gepirone could be surmounted by increasing the dose of AMPH, the effect of 8-OH-DPAT, the 5-HT(1A) agonist with the highest intrinsic activity (efficacy), was insurmountable in two of the three monkeys tested. These results suggest that the discriminative stimulus effect of AMPH can be modulated by stimulation of 5-HT(1A) receptors to an extent comparable with that seen with a D2 antagonist. Further, these results suggest that 5-HT(1A) agonists may attenuate the subjective effects of psychomotor stimulants in humans.