Effects of N-Acetylaspartylglutamate (NAAG) Peptidase Inhibition on Release of Glutamate and Dopamine in Prefrontal Cortex and Nucleus Accumbens in Phencyclidine Model of Schizophrenia*
Journal of Biological Chemistry May 8, 2012 Daiying Zuo, T. Bzdȩga, R. Olszewski et al.
Inhibiting the enzyme that breaks down the peptide transmitter N-acetylaspartylglutamate (NAAG) reduces schizophrenia-like behaviors and brain chemical changes caused by PCP in animal models. Two NAAG peptidase inhibitors, ZJ43 and 2-(phosphonomethyl)pentane-1,5-dioic acid, elevated NAAG levels and blocked PCP-induced increases in glutamate in the medial prefrontal cortex and nucleus accumbens, brain areas linked to psychosis. The inhibitors also reduced PCP-induced motor activation. These effects were prevented by an mGluR2/3 antagonist, indicating the mechanism involves metabotropic glutamate receptors. The findings support further study of NAAG peptidase inhibitors as potential antipsychotic drugs targeting mGluR3.