THE ATYPICAL NEUROLEPTIC PROFILE OF THE GLYCINE N-METHYL-D-ASPARTATE RECEPTOR ANTAGONIST, L-701,324, IN RODENTS/

The present study has examined the glycine/N-methyl-D-aspartate antago nist, L-701,324 loro-4-hydroxy-3-(3-phenoxy)-phenyl-2(H)quinolone] in rodent behavioral tests commonly used to predict antipsychotic potenti al and side effect liability in humans. Pretreatment with L-701,324 do se-dependently antagonized amphetamine-induced hyperactivity in the mo use (ED(50) = 1.12 +/- 0.45 mg/kg p.o.), an effect which was similar t o that of the classical neuroleptic, haloperidol, and the atypical neu roleptic, clozapine. In addition, p.o. administration of L-701,324 (2. 5 or 5 mg/kg) attenuated the hyperactivity response induced by ampheta mine infusion into the rat nucleus accumbens. In contrast to haloperid ol, however, stereotyped sniffing and licking/biting, induced by eithe r the systemic administration of apomorphine or infusion of amphetamin e into the striatum, was not altered in rats pretreated with L-701,324 (30 or 100 mg/kg p.o.). Furthermore, L-701,324 failed to impair spont aneous locomotor activity or induce catalepsy in the mouse at doses gr eater than or equal to 100 mg/kg. Although a significant reduction in spontaneous activity was observed in rats pretreated with L-701,324, t he minimum effective dose (10 mg/kg p.o.) was 2-fold greater than that which abolished amphetamine-induced hyperactivity in this species. Th us, L-701,324 selectively blocks behaviors associated with the activat ion of the mesolimbic dopamine system suggesting that glycine/N-methyl -D-aspartate receptor antagonists may offer a novel approach to the tr eatment of schizophrenia in humans.