5-Hydroxytryptamine 1a receptor agonists block prepulse inhibition of acoustic startle reflex

Presentation of a nonstartling stimulus (prepulse) 100 msec before a startle-eliciting auditory stimulus (pulse) reduces startle reflex amplitude in mammals. Prepulse inhibition of acoustic startle reflex is smaller in schizophrenics than in nonschizophrenics, a phenomenon that has been hypothesized to reflect sensorimotor gating deficits underlying schizophrenic psychosis. Five 5-hydroxytryptamine1a (5-HT1a, serotonin) receptor agonists: 8-hydroxy-2-(di-n-propylamino) tetraline (8-OHDPAT), 5-methoxydimethyltryptamine, buspirone, gepirone and ipsapirone, were tested for effects on prepulse inhibition and startle reflex amplitude in rats. All five agents reduced prepulse inhibition at doses that had no effect on startle reflex amplitude or motor activity. Reduction of prepulse inhibition by 8-OHDPAT was antagonized by (-)propranolol, a 5-HT1a receptor antagonist, and partially by haloperidol, a dopamine D2 receptor antagonist, but not by ketanserin or methysergide, 5-HT2 receptor antagonists. 8-OHDPAT did not reduce prepulse inhibition in subjects pretreated with reserpine or tetrabenazine to deplete neuronal amines, but interpretation of this result is complicated because reserpine and tetrabenazine given alone reduced prepulse inhibition. The results indicate that 5-HT1a receptor agonists block prepulse inhibition of acoustic startle reflex, possibly via dopaminergic mechanisms.