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.
Highlights
IntroductionAntipsychotic drugs are effective in treating positive symptoms of schizophrenia (agitation, psychosis, paranoid delusions and hallucinations), they are less effective in moderating negative symptoms (autism, ambivalence, apathy and social withdrawal) and cognitive deficits, including memory formation, problem solving, sensory gating, illogical joining of thoughts and words.[1,2,3,4,5] The worldwide personal and societal costs of psychotic disorders support the need to develop new pharmacotherapies, those with mechanisms of action outside of the typical and atypical antipsychotics
Antipsychotic drugs are effective in treating positive symptoms of schizophrenia, they are less effective in moderating negative symptoms and cognitive deficits, including memory formation, problem solving, sensory gating, illogical joining of thoughts and words.[1,2,3,4,5] The worldwide personal and societal costs of psychotic disorders support the need to develop new pharmacotherapies, those with mechanisms of action outside of the typical and atypical antipsychotics
The glutamate theory evolved from the observation that open channel NMDA (N-methyl-D-aspartate) receptor antagonists (phencyclidine (PCP), ketamine and dizocilpine (MK-801)) induce schizophrenia-like behaviors in humans and animals, while the dopamine theory is based on the clinical efficacy of dopamine (D2) receptor antagonists and the behaviors induced by dopamine-releasing drugs, including d-amphetamine
Summary
Antipsychotic drugs are effective in treating positive symptoms of schizophrenia (agitation, psychosis, paranoid delusions and hallucinations), they are less effective in moderating negative symptoms (autism, ambivalence, apathy and social withdrawal) and cognitive deficits, including memory formation, problem solving, sensory gating, illogical joining of thoughts and words.[1,2,3,4,5] The worldwide personal and societal costs of psychotic disorders support the need to develop new pharmacotherapies, those with mechanisms of action outside of the typical and atypical antipsychotics. Schizophrenia is modeled by two non-exclusive theories based on disordered dopamine- and glutamate-mediated neurotransmission.[1,12] The glutamate theory evolved from the observation that open channel NMDA (N-methyl-D-aspartate) receptor antagonists (phencyclidine (PCP), ketamine and dizocilpine (MK-801)) induce schizophrenia-like behaviors in humans and animals, while the dopamine theory is based on the clinical efficacy of dopamine (D2) receptor antagonists and the behaviors induced by dopamine-releasing drugs, including d-amphetamine. Responses of animals to treatment with d-amphetamine or these NMDA antagonists, including motor activation, have been widely validated as models for preclinical assessment of antipsychotic drugs.[1,13,14,15,16,17,18,19,20,21,22,23,24,25]
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