"It was recently reported that administration of the metabotropic glutamate 2 and 3 (mGlu2/3) receptor agonist prodrug LY2140023 to schizophrenic patients decreased positive symptoms. However, at the single, potentially suboptimal, dose that was tested, LY2140023 trended towards being inferior to olanzapine on several indices of efficacy within the Positive and Negative Syndrome Scale," scientists writing in the journal Psychopharmacology report (see also Life Sciences).

"In this study, we examined whether the antipsychotic potential of mGlu2/3 receptor agonism can be enhanced with 5-HT2A receptor antagonism. Specifically, we characterized the effects of coadministering submaximally effective doses of the 5-HT2A receptor antagonist M100907 (0.2 mg/kg) and the mGlu2/3 receptor agonist LY379268 (1 mg/kg) on amphetamine-induced and MK-801-induced psychomotor activity in rats, an assay sensitive to antipsychotics. We also determined the effects of coadministering these two compounds on MK-801-induced dopamine and norepinephrine efflux in the nucleus accumbens (NAc). At the submaximally effective doses tested, the effects of M100907 and LY379268 on amphetamine-induced and MK-801-induced psychomotor activity were significantly greater when given together than when given separately. Furthermore, coadministration of these doses of M100907 and LY379268 reduced MK-801-induced dopamine efflux in the NAc. This effect on dopamine release was not observed with the administration of either compound alone, even at higher doses that attenuated MK-801-induced psychomotor activity," wrote J.M. Uslaner and colleagues, Merck & Company, Inc.

The researchers concluded: "Our results suggest that a single compound having both mGlu2/3 receptor agonist and 5-HT2A receptor antagonist activity, or coadministration of two compounds selective for these receptors, could be superior in terms of efficacy and/or reduced side-effect liability relative to an mGlu2/3 receptor agonist alone."

Uslaner and colleagues published their study in Psychopharmacology (Combined administration of an mGlu2/3 receptor agonist and a 5-HT2A receptor antagonist markedly attenuate the psychomotor-activating and neurochemical effects of psychostimulants. Psychopharmacology, 2009;206(4 Sp. Iss.):641-651).

Additional information can be obtained by contacting J.M. Uslaner, Merck & Co. Inc., Dept. of Schizophrenia Research, WP46-100, 770 Sumneytown Pike, POB 4, West Point, PA 19486, USA.

The publisher of the journal Psychopharmacology can be contacted at: Springer, 233 Spring St., New York, NY 10013, USA.