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.
Published by Elsevier Ltd.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Disease Models, Animal
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Dizocilpine Maleate / pharmacology*
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Dizocilpine Maleate / toxicity
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Enzyme Inhibitors / pharmacology
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Enzyme Inhibitors / therapeutic use
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Excitatory Amino Acid Antagonists / pharmacology
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Excitatory Amino Acid Antagonists / toxicity
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Extracellular Fluid / drug effects
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Extracellular Fluid / metabolism
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GABA-B Receptor Agonists / pharmacology
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GABA-B Receptor Agonists / therapeutic use
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Glutamic Acid / metabolism*
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Male
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Nerve Tissue Proteins / agonists
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Nerve Tissue Proteins / antagonists & inhibitors
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Nerve Tissue Proteins / metabolism*
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Neurons / drug effects
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Neurons / metabolism
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Neurotoxicity Syndromes / metabolism
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Neurotoxicity Syndromes / prevention & control
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Nitric Oxide / metabolism*
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Nitric Oxide Donors / pharmacology
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Nitric Oxide Donors / toxicity
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Nitric Oxide Synthase / antagonists & inhibitors
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Nitric Oxide Synthase / metabolism
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Prefrontal Cortex / drug effects*
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Prefrontal Cortex / metabolism
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Rats
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Rats, Sprague-Dawley
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Receptors, GABA-B / chemistry
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Receptors, GABA-B / metabolism*
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Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
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Schizophrenia / metabolism
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Schizophrenia / prevention & control
Substances
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Enzyme Inhibitors
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Excitatory Amino Acid Antagonists
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GABA-B Receptor Agonists
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Nerve Tissue Proteins
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Nitric Oxide Donors
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Receptors, GABA-B
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Receptors, N-Methyl-D-Aspartate
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Nitric Oxide
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Glutamic Acid
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Dizocilpine Maleate
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Nitric Oxide Synthase