The metabotropic glutamate 2/3 receptor agonists LY354740 and LY379268 selectively attenuate phencyclidine versus d-amphetamine motor behaviors in rats

Previous animal studies have indicated that drugs targeted at metabotropic glutamate (mGlu) receptors may be useful for treatment of psychosis. In thi s article, the effects of the novel, potent, and selective mGlu2/3 receptor agonists LY354740 and LY379268, and the clinically effective agents clozap ine and haloperidol, were investigated using phencyclidine (PCP; 5 mg/kg)- versus d-amphetamine (AMP; 3 mg/kg)- evoked motor activities. LY354740 (1-1 0 mg/kg s.c.), LY379268 (0.3-3 mg/kg s.c.), clozapine (1-10 mg/kg s.c.), an d haloperidol (0.03-1 mg/kg s.c.) reversed the increases in ambulations, fi ne motor (nonambulatory) movements, and decreased time at rest evoked by PC P. Furthermore, the inhibitions of the PCP response by the mGlu2/3 agonist LY379268, but not by clozapine, were completely reversed by the selective m Glu2/3 receptor antagonist LY341495. Doses of LY354740 and LY379268 that bl ocked the effects on PCP had no effects on rotorod performance, and (with t he exception of rearing behavior) had minimal effects on AMP-evoked motor a ctivities. Clozapine blocked AMP-induced rearing but enhanced AMP-induced a mbulations and fine movements at the lower doses (1 and 3 mg/kg). Unlike th e mGlu2/3 agonists, the highest dose of clozapine tested (10 mg/kg) impaire d animals on the rotorod. Haloperidol potently blocked all PCP and AMP effe cts, but only at doses associated with motor impairment. These data demonst rate that mGlu2/3 receptor agonists act via a unique mechanism to selective ly block PCP-induced behaviors. Moreover, the marked mGlu2/3 receptor-media ted inhibitions of PCP-evoked behaviors by LY354740 and LY379268, with mini mal effects on AMP, may indicate potential antipsychotic effects in humans in the absence of dopamine mediated extrapyramidal side effects.