Neonatal nitric oxide synthase inhibition: social interaction deficits in adulthood and reversal by antipsychotic drugs.
Nitric oxide synthase (NOS) is thought to migrate improperly during development in the brains of schizophrenic patients. Also it is known that nitric oxide (NO) effects synaptogenesis during development of the CNS. Previously we have shown that neonatal treatment with a NOS inhibitor effects an animal's sensitivity to amphetamine and PCP. In the present study, neonatal rats were challenged with a NOS inhibitor (L-nitroarginine, 10mg/kg, s.c.) daily on post-natal days (PD) three, four and five. L-Nitroarginine (L-NoArg) treated male rats at adulthood (PD56 and older) had a deficit in social interaction (SI) when placed in an environment with another foreign male rat and this deficit was reproducible on a weekly basis for at least five weeks. Haloperidol failed to significantly reverse this deficit before pronounced secondary effects on general behavior were seen at high doses. However, the atypical antipsychotics, clozapine and olanzapine, were able to significantly reverse this deficit at doses which did not effect baseline SI values. In a separate cohort of animals the effect of DOI was investigated, this was done to ascertain if there was a differential sensitivity of serotonergic pathways in this model. There was no difference in the behavioral score elicited from control or NoArg-treated rats. It is suggested that the SI deficits seen here may be more sensitive to atypical antipsychotics rather than haloperidol.
Black
M D
MD
Aventis Pharmaceuticals, CNS Pharmacology, Route 202-206, PO Box 6800, Bridgewater, NJ 08807, USA. mark.black@aventis.com
Simmonds
J
J
Senyah
Y
Y
Wettstein
J G
JG
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn / Q000378:metabolism*; D014150:Antipsychotic Agents / Q000008:administration & dosage*; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D008297:Male; D008959:Models, Neurological; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D019335:Nitroarginine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017366:Serotonin Receptor Agonists / Q000494:pharmacology
D014150:Antipsychotic Agents; D004791:Enzyme Inhibitors; D017366:Serotonin Receptor Agonists; D019335:Nitroarginine; D019001:Nitric Oxide Synthase