Behavioural, neurochemical and neuroanatomical effects of chronic postnatal N-nitro-L-arginine methyl ester treatment in neonatal and adult rats.
In the present study we evaluated the consequences of interference with nitric oxide synthesis during development on brain function and behaviour in later life. Rat pups received a daily injection of the nitric oxide synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME, 25 mg/kg, s.c.) from postnatal day 0 to 24. At postnatal day 8 L-NAME-treated rats had enlarged and heavier stomachs, while body weights appeared to be reduced. The stomachs were not affected in size and weight anymore at postnatal day 24, whereas the body weights were still reduced by the L-NAME treatment, although they soon recovered after termination of the treatment. At four months-of-age, rats were tested in non-cognitive (open field) and cognitive (Morris water escape, two-way active avoidance) tasks. Open field behaviour of adult rats postnatally treated with L-NAME was not affected. In the water escape task there were no differences between the saline and L-NAME-treated rats in spatial discrimination learning and spatial reversal learning. Furthermore, postnatal L-NAME treatment did not have an effect on the acquisition of the two-way active avoidance task. Subsequently, we tested rat pups during the L-NAME treatment at postnatal day 19 through 24 in the open field and the two-way active avoidance task. L-NAME treatment appeared to increase the behavioural activity in the open field. There was no difference in behaviour in the active avoidance task between saline and L-NAME-treated rats. Biochemical and immunocytochemical studies showed that at postnatal day 8 the basal cyclic GMP level was reduced, while the cyclic GMP formation due to incubation with the nitric oxide donor sodium nitroprusside appeared to be increased in the hippocampus, striatum and frontal cortex of L-NAME-treated rats. Hence, nitric oxide synthase was inhibited whereas the soluble guanylyl cyclase activity may be increased in sensitivity. At postnatal day 24 basal cyclic GMP levels and nitric oxide-mediated cyclic GMP formation in the brain structures of L-NAME-treated rats had normal values again. Taken together, the findings of this study suggest that postnatal inhibition of nitric oxide synthase has profound neurochemical effects during development and may have short-lasting effects on non-cognitive behaviour, but it does not affect behaviour and brain function in later life.
European Graduate School of Neuroscience EURON, Department of Psychiatry and Neuropsychology, Maastricht University, The Netherlands.
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J
Prickaerts
J
J
De Vente
M
M
Markerink-Van Ittersum
H W
HW
Steinbusch
D000818:Animals; D000831:Animals, Newborn; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects*; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000033:anatomy & histology / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D006152:Cyclic GMP / Q000096:biosynthesis / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004924:Escape Reaction / Q000187:drug effects; D005260:Female; D006162:Guanylate Cyclase / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009249:NADP / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D011863:Radioimmunoassay; D051381:Rats; D012995:Solubility
D004791:Enzyme Inhibitors; D009569:Nitric Oxide; D009249:NADP; D019001:Nitric Oxide Synthase; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D019331:NG-Nitroarginine Methyl Ester