Long-Term Imipramine Treatment Increases Nitrate Levels in the Rat Hypothalamus

1. Animal experiments have shown nitric oxide synthase inhibitors to have antidepressant-like properties. However, the effects of clinically available antidepressants on nitric oxide production in the brain remain unclear. In the present study, we examined whether imipramine, a conventional antidepressant, changes the levels of type-II nitric oxide synthase mRNA and nitrate, a final nitric-oxide-oxidation product measurable in vivo, in the rat brain. 2. Type-II nitric oxide synthase mRNA was detected using a reverse transcription-polymerase chain reaction method and nitrate was measured with a combination of high-performance liquid chromatography and the Griess reaction. 3. In untreated rats, type-II nitric oxide synthase mRNA was not detected in the hypothalamus, hippocampus, cerebral cortex, brain stem, or cerebellum. However, after 28-day oral administration of imipramine, it was detected in every brain region tested. Nitrate levels in the hypothalamus and cerebral cortex increased after 28-day treatment. In the hypothalamus, nitrate levels increased dose-dependently. These dose-dependent nitrate level changes were prevented by pretreatment with a nitric oxide synthase inhibitor. Moreover, the preventive effect of N^G-nitro-L-arginine methyl ester was reversed by coadministration of L-arginine, a nitric oxide substrate. 4. These results suggest that chronic imipramine treatment induces nitric oxide synthase gene expression in the brain, followed by augmented NO production.