BLOCKADE OF THE DISCRIMINATIVE STIMULUS EFFECTS OF D-AMPHETAMINE IN RHESUS-MONKEYS WITH SEROTONIN 5-HT1A AGONISTS

Rhesus monkeys (n = 4) were trained in a two-lever drug discrimination paradigm to discriminate d-amphetamine (AMPH; 0.56 or 1.0 mg/kg, i.g. , 60 min pre-session) from saline. Lever pressing was maintained under a discrete-trials shock avoidance schedule of reinforcement (30 trial s/day, 30-s intertrial interval, fixed-ratio 1). Before test sessions, in which responding on either lever avoided shock, the monkeys were i nfused (i.g.) with saline or various doses of AMPH (0.1-1.7 mg/kg), al one or in combination with intramuscular injections of the serotonin ( 5-HT1A) agonists buspirone (0.3-1.0 mg/kg), gepirone (0.56-3.0 mg/ kg) , 8-hydroxy-2(di-n-propylamino) tetralin (8-OH-DPAT; 0.01-0.1 mg/kg), the dopamine D2 antagonist raclopride (0.03 and 0.1 mg/kg), or pentoba rbital (10 mg/kg). Doses of the 5-HT1A 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 m onkeys, while pentobarbital had no effect. For the 5-HT1A agonists, th e order of potency for attenuating the AMPH discriminative stimulus wa s 8-OH-DPAT > buspirone > gepirone, similar to their binding affinitie s at 5-HT1A receptors. Raclopride was equipotent to 8-OH-DPAT. In addi tion, although the effect of buspirone and gepirone could be surmounte d by increasing the dose of AMPH, the effect of 8-OH-DPAT, the 5-HT1A agonist with the highest intrinsic activity (efficacy), was insurmount able in two of the three monkeys tested. These results suggest that th e discriminative stimulus effect of AMPH can be modulated by stimulati on of 5-HT1A receptors to an extent comparable with that seen with a D 2 antagonist. Further, these results suggest that 5-HT1A agonists may attenuate the subjective effects of psychomotor stimulants in humans.