phenobarbital-sodium and Schizophrenia

Topics: Animals; Antipsychotic Agents; Disease Models, Animal; Excitatory Amino Acid Antagonists; Exploratory Behavior; Glutamate Carboxypeptidase II; Mice; Mice, Knockout; Motor Activity; Organophosphorus Compounds; Phencyclidine; Receptors, Metabotropic Glutamate; Schizophrenia

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.

Topics: Analysis of Variance; Animals; Antipsychotic Agents; Dextroamphetamine; Disease Models, Animal; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Exploratory Behavior; Glutamate Carboxypeptidase II; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Organophosphorus Compounds; Rats; Rats, Sprague-Dawley; Receptors, Metabotropic Glutamate; Recognition, Psychology; Risperidone; Schizophrenia; Soman; Urea

Group II metabotropic glutamate receptor (mGluR) agonists represent a novel approach to the treatment of schizophrenia. Inasmuch as the peptide neurotransmitter N-acetylaspartylglutamate (NAAG) activates these receptors, NAAG peptidase inhibitors conceptually represent a parallel path toward development of new antipsychotic drugs. While group II agonists are effective in several animal models of schizophrenia, they are reported to lack efficacy in moderating the effects of phencyclidine (PCP) on prepulse inhibition of acoustic startle in animal models of sensory processing deficits found in this disorder.. The objective of this study was to re-examine the efficacy of a group II metabotropic glutamate agonist and NAAG peptidase inhibitors in prepulse inhibition models of schizophrenia across two strains of mice.. The method used was an assay to determine the efficacy of these drugs in moderating the reduction in prepulse inhibition of acoustic startle in mice treated with PCP and D: -amphetamine.. The group II agonist LY354740 (5 and 10 mg/kg) moderated the effects of PCP on prepulse inhibition of acoustic startle in DBA/2 but not C57BL/6 mice. In contrast, two NAAG peptidase inhibitors, ZJ43 (150 mg/kg) and 2-PMPA (50, 100, and 150 mg/kg), did not significantly affect the PCP-induced reduction in prepulse inhibition in either strain.. These data demonstrate that the efficacy of group II agonists in this model of sensory motor processing is strain-specific in mice. The difference between the effects of the group II agonist and the peptidase inhibitors in the DBA/2 mice may relate to the difference in efficacy of NAAG and the agonist at mGluR2.

Topics: Animals; Bridged Bicyclo Compounds; Dextroamphetamine; Disease Models, Animal; Dose-Response Relationship, Drug; Excitatory Amino Acid Agonists; Glutamate Carboxypeptidase II; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Organophosphorus Compounds; Phencyclidine; Receptors, Metabotropic Glutamate; Reflex, Startle; Schizophrenia; Species Specificity; Urea