Evidence that nitric oxide production increases gamma-amino butyric acid permeability of blood-brain barrier

Blood-brain barrier permeability (BBB) to the inhibitory neurotransmitter gamma-amino butyric acid (GABA) was studied in rats following intraperitoneal (i.p) injections of GABA alone and in combination with L-Arginine (L-Arg). Administration of GABA (600 mg/kg body weight [b. wt.]) alone increased brain GABA concentration (33%, p < 0.01), when compared to untreated rats and administration of L-Arg (2000 mg/kg b. wt.) alone also increased GABA concentration (65%, p < 0.01) in the brain. Moreover, GABA + L-Arg treated brains showed a fourfold increase in GABA level (383.3%, p < 0.01) when compared to controls. Dose-dependent increase in nitric oxide production was observed 10 min after i.p injections of L-Arg (400, 800, 1000, and 2000 mg/kg b. wt.) and a peak nitric oxide (NO) production was observed at the dose level of 2000 mg/kg b. wt. On the other hand, administration of GABA failed to increase NO production in the brain. Rats pretreated (10 min) with a nonspecific nitric oxide synthase (NOS) inhibitor N(omega)-nitro-L-Arginine methyl ester (L-NAME, 50 mg/kg b. wt.) completely blocked the production of NO induced by L-Arg. In addition, L-NAME attenuated GABA entry into the brain after the administration of GABA alone or in combination with L-Arg. We conclude that high NO concentrations in the brain following L-Arg administration may increase the permeability of BBB to peripheral GABA.