title: NAAG peptidase inhibitors block cognitive deficit induced by MK-801 and motor activation induced by d-amphetamine in animal models of schizophrenia.
abstract: The most widely validated animal models of the positive, negative and cognitive symptoms of schizophrenia involve administration of d-amphetamine or the open channel NMDA receptor blockers, dizocilpine (MK-801), phencyclidine (PCP) and ketamine. The drug ZJ43 potently inhibits glutamate carboxypeptidase II (GCPII), an enzyme that inactivates the peptide transmitter N-acetylaspartylglutamate (NAAG) and reduces positive and negative behaviors induced by PCP in several of these models. NAAG is an agonist at the metabotropic glutamate receptor 3 (mGluR3). Polymorphisms in this receptor have been associated with expression of schizophrenia. This study aimed to determine whether two different NAAG peptidase inhibitors are effective in dopamine models, whether their efficacy was eliminated in GCPII knockout mice and whether the efficacy of these inhibitors extended to MK-801-induced cognitive deficits as assessed using the novel object recognition test. ZJ43 blocked motor activation when given before or after d-amphetamine treatment. (R,S)-2-phosphono-methylpentanedioic acid (2-PMPA), another potent NAAG peptidase inhibitor, also reduced motor activation induced by PCP or d-amphetamine. 2-PMPA was not effective in GCPII knockout mice. ZJ43 and 2-PMPA also blocked MK-801-induced deficits in novel object recognition when given before, but not after, the acquisition trial. The group II mGluR antagonist LY341495 blocked the effects of NAAG peptidase inhibition in these studies. 2-PMPA was more potent than ZJ43 in a test of NAAG peptidase inhibition in vivo. By bridging the dopamine and glutamate theories of schizophrenia with two structurally different NAAG peptidase inhibitors and demonstrating their efficacy in blocking MK-801-induced memory deficits, these data advance the concept that NAAG peptidase inhibition represents a potentially novel antipsychotic therapy.
authors: Department of Biology, Georgetown University, Washington, DC 20057-1225, USA.
authors: R T
authors: RT
authors: Olszewski
authors: K J
authors: KJ
authors: Janczura
authors: S R
authors: SR
authors: Ball
authors: J C
authors: JC
authors: Madore
authors: K M
authors: KM
authors: Lavin
authors: J C-M
authors: JC
authors: Lee
authors: M J
authors: MJ
authors: Lee
authors: E K
authors: EK
authors: Der
authors: T J
authors: TJ
authors: Hark
authors: P R
authors: PR
authors: Farago
authors: C P
authors: CP
authors: Profaci
authors: T
authors: T
authors: Bzdega
authors: J H
authors: JH
authors: Neale
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D003913:Dextroamphetamine; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005106:Exploratory Behavior / Q000187:drug effects; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009943:Organophosphorus Compounds / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists*; D021641:Recognition, Psychology / Q000187:drug effects; D018967:Risperidone / Q000494:pharmacology*; D012559:Schizophrenia / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology*; D012999:Soman / Q000031:analogs & derivatives; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C402107:2-(phosphonomethyl)pentanedioic acid; D014150:Antipsychotic Agents; D018691:Excitatory Amino Acid Antagonists; D009943:Organophosphorus Compounds; D018094:Receptors, Metabotropic Glutamate; C486211:ZJ43; C046573:pinacolyl methylphosphonic acid; D014508:Urea; D012999:Soman; D043425:Glutamate Carboxypeptidase II; D018967:Risperidone; D003913:Dextroamphetamine