Recent clinical studies demonstrated that metabotropic glutamate receptor 2/3 (mGluR2/3) agonist possesses clinically significant antipsychotic efficacy; however, currently available treatments for schizophrenia do not improve the cognitive dysfunction associated with this disease. The study by Nikiforuk et al. demonstrates the ability of the positive allosteric modulator (PAM) of mGlu2 receptors, N-(4-(2-methoxyphenoxy)-phenyl-N-(2,2,2-trifluoroethylsulfonyl)-pyrid-3-ylmethylamine (LY487379), to improve cognitive flexibility and impulsive-like responses in rats. The selective mGluR2 PAM LY487379 does not exert any impairing effects of its own, but instead enhances cognitive flexibility and inhibitory control, suggesting that frequency-dependent modulation of neurotransmission may result in a more favorable pharmacological profile than that of mGluR2/3 agonists. Microdialysis experiments also demonstrated increases in norepinephrine, which is involved in the control of impulsive behavior, and serotonin, which is involved in cognitive flexibility, but not increases of glutamine in the prefrontal cortex of LY437379-treated rats. Together with the previously reported antipsychotic-like effects of LY487379, further evaluation of the therapeutic potential of mGluR2 stimulation in the treatment of cognitive deficits associated with schizophrenia is warranted.
See article at J Pharmacol Exp Ther 2010, 335:665–673.
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