Phencyclidine and dizocilpine induced behaviors reduced by N-acetylaspartylglutamate peptidase inhibition via metabotropic glutamate receptors.
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.
Olszewski
Rafal T
RT
Department of Biology, Georgetown University, Washington D.C. 20057, USA.
Wegorzewska
Marta M
MM
Monteiro
Ana C
AC
Krolikowski
Kristyn A
KA
Zhou
Jia
J
Kozikowski
Alan P
AP
Long
Katrice
K
Mastropaolo
John
J
Deutsch
Stephen I
SI
Neale
Joseph H
JH
D000378:Agonistic Behavior / Q000187:drug effects; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005106:Exploratory Behavior / Q000187:drug effects; D043425:Glutamate Carboxypeptidase II / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D010622:Phencyclidine; D018094:Receptors, Metabotropic Glutamate / Q000502:physiology*; D012559:Schizophrenia / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D013239:Stereotyped Behavior / Q000187:drug effects; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology
D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D018094:Receptors, Metabotropic Glutamate; C486211:ZJ43; D016291:Dizocilpine Maleate; D014508:Urea; D043425:Glutamate Carboxypeptidase II; D010622:Phencyclidine