On the effect of neonatal nitric oxide synthase inhibition in rats: a potential neurodevelopmental model of schizophrenia

• Published in: Neuropharmacology Vol. 38; no. 9; pp. 1299 - 1306
• Main Authors: Black, Mark D., Selk, David E., Hitchcock, J.M., Wettstein, Joseph G., Sorensen, Stephen M.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01-09-1999; Elsevier
• Subjects: Adult and adolescent clinical studies; Animals; Animals, Newborn; Biological and medical sciences; Disease Models, Animal; Enzyme Inhibitors - pharmacology; Female; L-Nitroarginine; Male; Medical sciences; Motor Activity - drug effects; NADPH Dehydrogenase - antagonists & inhibitors; NADPH-d; Neonatal; Neurodevelopmental; Nitric oxide; Nitric Oxide Synthase - antagonists & inhibitors; Nitroarginine - pharmacology; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Psychoses; Rats; Rats, Sprague-Dawley; Schizophrenia; Schizophrenia - chemically induced; Schizophrenia - enzymology; Sex Characteristics; Sex differences; Schizophrenia; Sex differences; Neonatal; Neurodevelopmental; NADPH-d; Nitric oxide; Animal model; Rat; Sex; Central nervous system; Startle reflex; Psychosis; Phencyclidine; Amfetamine; Subcutaneous administration; Sensitization; Inhibition; Embryonic development; Enzyme; Rodentia; Enzyme inhibitor; Nitric-oxide synthase; Pregnancy; Progeny; Locomotion; Vertebrata; Mammalia; Animal; Oxidoreductases; Brain (vertebrata)
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/S0028-3908(99)00041-6

NADPH-d (nicotinamide-adenine dinucleotide phosphate-diaphorase) neurons are thought to migrate improperly during development in the brains of schizophrenic patients. This enzyme is a nitric oxide synthase (NOS). Nitric oxide (NO) is known to affect neurodevelopmental processes in the CNS. Therefore, we hypothesized that interference of NO generation during development may produce some aspects of schizophrenia symptomatology in a rat model. In these experiments, neonatal rats were challenged with a NOS inhibitor (
l-nitroarginine 1–100 mg/kg s.c.) daily on post-natal days 3–5.
l-Nitroarginine (L-NoArg) treated male rats developed a hypersensitivity to amphetamine in adulthood versus vehicle treated controls, whereas female rats did not. However, L-NoArg treated female rats developed a hypersensitivity to phencyclidine (PCP) at juvenile and adult ages versus vehicle treated controls, whereas male animals did not. L-NoArg treated male rats also had deficits in pre-pulse inhibition of startle whereas adult female rats did not. The results are discussed in terms of a new neurodevelopmental model of schizophrenia and male/female differences inherent in this disease.