Background
N-methyl-d-aspartate (NMDA) receptor open channel blockers phencyclidine (PCP) and dizocilpine
(MK-801) elicit schizophrenia-like symptoms in humans and in animal models. Group
II metabotropic glutamate receptor agonists reverse the behavioral effects of PCP
and MK-801 in animal models. N-acetylaspartylglutamate (NAAG), the third most prevalent neurotransmitter in the
mammalian nervous system, is a selective group II metabotropic glutamate receptor
agonist. We previously reported that ZJ43, a potent inhibitor of the enzymes that
inactivate synaptically released NAAG, reduced motor and stereotypic effects of PCP
in the rat.
Methods
To confirm the efficacy of NAAG peptidase inhibition in decreasing motor behaviors
induced by PCP and MK-801, ZJ43 was tested in additional schizophrenia models.
Results
ZJ43 reduced MK-801-induced motor activation in a mouse model that has been used to
characterize the efficacy of a wide range of pharmacotherapies for this human disorder.
In a second mouse strain, the peptidase inhibitor reduced PCP-induced stereotypic
movements. ZJ43 also reduced PCP-induced negative symptoms in a resident-intruder
assay. The group II metabotropic glutamate receptor antagonist, LY341495, blocked
the effect of NAAG peptidase inhibition in these mouse models of positive and negative
PCP- and MK-801-induced behaviors. Additionally, LY341495 alone increased some PCP-induced
behaviors suggesting that normal levels of NAAG act to moderate the effect of PCP
via a group II mGluR.
Conclusions
These data support the proposal that NAAG peptidase inhibition and elevation of synaptic
NAAG levels represent a new therapeutic approach to treating the positive and negative
symptoms of schizophrenia that are modeled by open channel NMDA receptor antagonists.
Key Words
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Article info
Publication history
Published online: June 30, 2007
Accepted:
April 13,
2007
Received in revised form:
April 13,
2007
Received:
March 13,
2007
Identification
Copyright
© 2008 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
