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.