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 antagonist, L-701-324 [7-chloro-4-hydroxy-3-(3-phenoxy)-phenyl-2 (H)quinolone] in rodent behavioral tests commonly used to predict antipsychotic potential and side effect liability in humans. Pretreatment with L-701,324 dose-dependently antagonized amphetamine-induced hyperactivity in the mouse (ED50 = 1.12 +/- 0.45 mg/kg p.o.), an effect which was similar to that of the classical neuroleptic, haloperidol, and the atypical neuroleptic, clozapine. In addition, p.o. administration of L-701,324 (2.5 or 5 mg/kg) attenuated the hyperactivity response induced by amphetamine infusion into the rat nucleus accumbens. In contrast to haloperidol, however, stereotyped sniffing and licking/biting, induced by either the systemic administration of apomorphine or infusion of amphetamine 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 spontaneous locomotor activity or induce catalepsy in the mouse at doses > or = 100 mg/kg. Although a significant reduction in spontaneous activity was observed in rats pretreated with L-701,324, the minimum effective dose (10 mg/kg p.o.) was 2-fold greater than that which abolished amphetamine-induced hyperactivity in this species. Thus, L-701,324 selectively blocks behaviors associated with the activation of the mesolimbic dopamine system suggesting that glycine/N-methyl-D-aspartate receptor antagonists may offer a novel approach to the treatment of schizophrenia in humans.
Bristow
L J
LJ
Merck, Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, UK.
Flatman
K L
KL
Hutson
P H
PH
Kulagowski
J J
JJ
Leeson
P D
PD
Young
L
L
Tricklebank
M D
MD
D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D015363:Quinolones / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018009:Receptors, Glycine / Q000037:antagonists & inhibitors*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013239:Stereotyped Behavior / Q000187:drug effects
D014150:Antipsychotic Agents; D018691:Excitatory Amino Acid Antagonists; D015363:Quinolones; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; D000661:Amphetamine; C094635:L 701324