Effects of N-Acetylaspartylglutamate (NAAG) Peptidase Inhibition on Release of Glutamate and Dopamine in Prefrontal Cortex and Nucleus Accumbens in Phencyclidine Model of Schizophrenia*

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.

Study at a glance

Abstract

Background: Inhibitors of the enzyme that inactivates the peptide transmitter N-acetylaspartylglutamate reduce behaviors induced by PCP in animal models of schizophrenia. Results: NAAG peptidase inhibition reduces PCP-induced glutamate release in two brain areas implicated in this disorder. Conclusion: Peptidase-mediated inhibition of glutamate release is consistent with the glutamate model of this disorder. Significance: NAAG peptidase inhibitors warrant further biochemical characterization as potential antipsychotic drugs. The “glutamate” theory of schizophrenia emerged from the observation that phencyclidine (PCP), an open channel antagonist of the NMDA subtype of glutamate receptor, induces schizophrenia-like behaviors in humans. PCP also induces a complex set of behaviors in animal models of this disorder. PCP also increases glutamate and dopamine release in the medial prefrontal cortex and nucleus accumbens, brain regions associated with expression of psychosis. Increased motor activation is among the PCP-induced behaviors that have been widely validated as models for the characterization of new antipsychotic drugs. The peptide transmitter N-acetylaspartylglutamate (NAAG) activates a group II metabotropic receptor, mGluR3. Polymorphisms in this receptor have been associated with schizophrenia. Inhibitors of glutamate carboxypeptidase II, an enzyme that inactivates NAAG following synaptic release, reduce several behaviors induced by PCP in animal models. This research tested the hypothesis that two structurally distinct NAAG peptidase inhibitors, ZJ43 and 2-(phosphonomethyl)pentane-1,5-dioic acid, would elevate levels of synaptically released NAAG and reduce PCP-induced increases in glutamate and dopamine levels in the medial prefrontal cortex and nucleus accumbens. NAAG-like immunoreactivity was found in neurons and presumptive synaptic endings in both regions. These peptidase inhibitors reduced the motor activation effects of PCP while elevating extracellular NAAG levels. They also blocked PCP-induced increases in glutamate but not dopamine or its metabolites. The mGluR2/3 antagonist LY341495 blocked these behavioral and neurochemical effects of the peptidase inhibitors. The data reported here provide a foundation for assessment of the neurochemical mechanism through which NAAG achieves its antipsychotic-like behavioral effects and support the conclusion NAAG peptidase inhibitors warrant further study as a novel antipsychotic therapy aimed at mGluR3.