In the present study, we have investigated the effects of prolonged inhibition of nitric oxide synthase (NOS) by infusion of NOS inhibitor, l -nitroarginine, to examine the pentobarbital-induced sleep, modulation of GABA A receptor binding, and GABA A receptor subunit mRNA level in rat brain. Pre-treatment with l -nitroarginine 30 min before pentobarbital treatment (60 mg/kg, i.p.) significantly increased the duration of sleep in rats. However, the duration of pentobarbital-induced sleep was shortened by the prolonged infusion of l -nitroarginine into ventricle. We have investigated the effect of NOS inhibitor on GABA A receptor binding characteristics in discrete areas of brain regions by using autoradiographic and in situ hybridization techniques. Rats were infused with l -nitroarginine (10, 100 pmol/10 μl/h, i.c.v.) for 7 days, through pre-implanted cannula by osmotic minipumps. The levels of ( 3 H)muscimol and ( 3 H)flunitrazepam binding were markedly elevated in almost all of brain regions including cortex, caudate putamen, thalamus, hippocampus, and cerebellum. However, there was no change in the level of ( 35 S)TBPS binding. The levels of β2-subunit were elevated in the cortex, brainstem, and cerebellar granule layers. By contrast, the levels of β3-subunit were significantly decreased in the cortex, hippocampus, and cerebellar granule layers in l -nitroarginine-infused rats. Following l -nitroarginine treatment, the levels of α6- and δ-subunits which were strictly localized to the cerebellum, were not changed in the cerebellar granule layer. These results show that the prolonged inhibition of NOS by l -nitroarginine-infusion markedly elevates ( 3 H)muscimol and ( 3 H)flunitrazepam binding throughout the brain, and alters GABA A receptor subunit mRNA levels in different directions. Chronic inhibition of NO generation has differential effects on the various expressions of GABA A receptor subunits. These suggest the involvement of different regulatory mechanisms for the NO-induced expression of GABA A receptor.
Brain Research – Elsevier
Published: Oct 18, 2002
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