Effects of 5-HT1A agonists and 5-HT2 antagonists on haloperidol-induced dyskinesias in squirrel monkeys: no evidence for reciprocal 5-HT-dopamine interaction

Abstract

Dyskinetic movements and dystonic postures may be induced by neuroleptics in monkeys that have undergone previous neuroleptic treatment, and these motor abnormalities constitute a primate model of drug-induced extrapyramidal symptomatology. In view of previous suggestions that brain serotonergic systems may tonically inhibit dopamine neurons, the effects of several new and selective 5-HT2 receptor antagonists and 5-HT1A receptor agonists were investigated in this model. Setoperone, a dopamine D2 receptor antagonist with extremely potent 5-HT2 antagonism, caused dyskinetic movements. Although ritanserin is a potent 5-HT2 antagonist with very weak dopamine antagonist properties, this drug did not antagonize dyskinesias but induced them when administered at a high dose (30 mg/kg). Buspirone induced dyskinesias and blocked apomorphine-induced climbing, supporting prior reports that it has dopamine antagonist effects. Gepirone, a 5-HT1A agonist with less marked dopamine antagonist properties, induced dyskinesias in only one of six monkeys at 30 mg/kg and did not block haloperidol-induced dyskinesias. 8-OH-DPAT partly attenuated haloperidol-induced dyskinesias, an effect possibly attributable to its weak dopamine agonist properties. Tonic inhibition of brain extrapyramidal dopamine systems by serotonin systems does not appear to characterize neuroleptic-related dyskinesias in squirrel monkeys.