ABSTRACT
Systemic administration of NMDA receptor antagonists elevates extracellular glutamate within prefrontal cortex. The cognitive and behavioral effects of NMDA receptor blockade have direct relevance to symptoms of schizophrenia, and recent studies demonstrate an important role for nitric oxide and GABA(B) receptors in mediating the effects of NMDA receptor blockade on these behaviors. We sought to extend those observations by directly measuring the effects of nitric oxide and GABA(B) receptor mechanisms on MK-801-induced glutamate release in the prefrontal cortex. Systemic MK-801 injection (0.3 mg/kg) to male Sprague-Dawley rats significantly increased extracellular glutamate levels in prefrontal cortex, as determined by microdialysis. This effect was blocked by pre-treatment with the nitric oxide synthase inhibitor L-NAME (60 mg/kg). Reverse dialysis of the nitric oxide donor SNAP (0.5-5 mM) directly into prefrontal cortex mimicked the effect of systemic MK-801, dose-dependently elevating cortical extracellular glutamate. The effect of MK-801 was also blocked by systemic treatment with the GABA(B) receptor agonist baclofen (5 mg/kg). In combination, these data suggest increased nitric oxide formation is necessary for NMDA antagonist-induced elevations of extracellular glutamate in the prefrontal cortex. Additionally, the data suggest GABA(B) receptor activation can modulate the NMDA antagonist-induced increase in cortical glutamate release.
Subject(s)
Dizocilpine Maleate/pharmacology , Glutamic Acid/metabolism , Nerve Tissue Proteins/metabolism , Nitric Oxide/metabolism , Prefrontal Cortex/drug effects , Receptors, GABA-B/metabolism , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Animals , Disease Models, Animal , Dizocilpine Maleate/toxicity , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Excitatory Amino Acid Antagonists/pharmacology , Excitatory Amino Acid Antagonists/toxicity , Extracellular Fluid/drug effects , Extracellular Fluid/metabolism , GABA-B Receptor Agonists/pharmacology , GABA-B Receptor Agonists/therapeutic use , Male , Nerve Tissue Proteins/agonists , Nerve Tissue Proteins/antagonists & inhibitors , Neurons/drug effects , Neurons/metabolism , Neurotoxicity Syndromes/metabolism , Neurotoxicity Syndromes/prevention & control , Nitric Oxide Donors/pharmacology , Nitric Oxide Donors/toxicity , Nitric Oxide Synthase/antagonists & inhibitors , Nitric Oxide Synthase/metabolism , Prefrontal Cortex/metabolism , Rats , Rats, Sprague-Dawley , Receptors, GABA-B/chemistry , Schizophrenia/metabolism , Schizophrenia/prevention & controlABSTRACT
The NMDA glutamate hypofunction model of schizophrenia is based in part upon acute effects of NMDA receptor blockade in humans and rodents. Several laboratories have reported glutamate system abnormalities following prenatal exposure to immune challenge, a known environmental risk factor for schizophrenia. Here we report indices of NMDA glutamate receptor hypofunction following prenatal immune activation, as well as the effects of treatment during periadolescence with the atypical antipsychotic medications risperidone and paliperidone. Pregnant Sprague-Dawley rats were injected with polyinosinic:polycytidylic acid (poly I:C) or saline on gestational day 14. Male offspring were treated orally via drinking water with vehicle, risperidone (0.01mg/kg/day), or paliperidone (0.01mg/kg/day) between postnatal days 35 and 56 (periadolescence) and extracellular glutamate levels in the prefrontal cortex were determined by microdialysis at PD 56. Consistent with decreased NMDA receptor function, MK-801-induced increases in extracellular glutamate concentration were markedly blunted following prenatal immune activation. Further suggesting NMDA receptor hypofunction, prefrontal cortex basal extracellular glutamate was significantly elevated (p<0.05) in offspring of poly I:C treated dams. Pretreatment with low dose paliperidone or risperidone (0.01mg/kg/day postnatal days 35-56) normalized prefrontal cortical basal extracellular glutamate (p<0.05 vs. poly I:C vehicle-treatment). Pretreatment with paliperidone and risperidone also prevented the acute MK-801-induced increase in extracellular glutamate. These observations demonstrate decreased NMDA receptor function and elevated extracellular glutamate, two key features of the NMDA glutamate receptor hypofunction model of schizophrenia, during periadolescence following prenatal immune activation. Treatment with the atypical antipsychotic medications paliperidone and risperidone normalized basal extracellular glutamate. Demonstration of glutamatergic abnormalities consistent with the NMDA glutamate receptor hypofunction model of schizophrenia as an early developmental consequence of prenatal immune action provides a model to identify novel early interventions targeting glutamatergic systems which play an important role in both positive and negative symptoms of schizophrenia.
