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Nitric oxide signaling in the medial prefrontal cortex is involved in the biochemical and behavioral effects of phencyclidine.

Journal article
Authors Kim Fejgin
Erik Pålsson
Caroline Wass
Lennart Svensson
Daniel Klamer
Published in Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
Volume 33
Issue 8
Pages 1874-83
ISSN 0893-133X
Publication year 2008
Published at Institute of Neuroscience and Physiology, Department of Pharmacology
Pages 1874-83
Language en
Links dx.doi.org/10.1038/sj.npp.1301587
Keywords Animals, Behavior, Animal, drug effects, Brain Chemistry, drug effects, Cyclic GMP, metabolism, Double-Blind Method, Electrodes, Implanted, Enzyme Inhibitors, pharmacology, Excitatory Amino Acid Antagonists, pharmacology, Male, Mice, Microdialysis, Motor Activity, drug effects, NG-Nitroarginine Methyl Ester, pharmacology, Nitric Oxide, physiology, Nitric Oxide Synthase Type II, antagonists & inhibitors, Phencyclidine, pharmacology, Prefrontal Cortex, drug effects, metabolism, physiology, Quinoxalines, pharmacology, Radioimmunoassay, Signal Transduction, drug effects, physiology, Startle Reaction, drug effects
Subject categories Pharmacology and Toxicology

Abstract

The prefrontal cortex (PFC) is believed to play an important role in the cognitive impairments observed in schizophrenia and has also been shown to be involved in the modulation of prepulse inhibition (PPI), a measure of preattentive information processing that is impaired in schizophrenic individuals. Phencyclidine (PCP), a noncompetitive inhibitor of the NMDA receptor, exerts psychotomimetic effects in humans, disrupts PPI, and causes hypofrontality in rodents and monkeys. We have previously demonstrated that interfering with the production of nitric oxide (NO) can prevent a wide range of PCP-induced behavioral deficits, including PPI disruption. In the present study, the role of NO signaling for the behavioral and biochemical effects of PCP was further investigated. Dialysate from the medial PFC of mice receiving systemic treatment with PCP and/or the NO synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME, 40 mg/kg), was analyzed for cGMP content. Furthermore, a specific inhibitor of NO-sensitive soluble guanylyl cyclase (sGC), 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one (ODQ, 0.01-1 mM), was administered into the medial PFC of mice in combination with systemic injections of PCP, followed by PPI and locomotor activity testing. PCP (5 mg/kg) caused an increase in prefrontal cGMP that could be attenuated by pretreatment with the NO synthase inhibitor, L-NAME. Moreover, bilateral microinjection of the sGC inhibitor, ODQ, into the medial PFC of mice attenuated the disruption of PPI, but not the hyperlocomotion, caused by PCP. The present study shows that NO/sGC/cGMP signaling pathway in the medial PFC is involved in specific behavioral effects of PCP that may have relevance for the disabling cognitive dysfunction found in patients with schizophrenia.

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