Endothelial nitric oxide synthase in rat brain is downregulated by sub-chronic antidepressant treatment.

BACKGROUND: Nitric oxide (NO) is a neurotransmitter that may be related to major depressive disorder (MDD) because the selective neuronal NO synthase (NOS) inhibitor, 7-nitroindazole, induces a dose-dependent antidepressant-like effect. NO modulates major neurotransmitters involved in the neurobiology of MDD, such as norepinephrine, serotonin, dopamine, and glutamate. In this study, we investigated the effects of antidepressants as NO modulators in acute and sub-chronic treatments.

METHODS: Rats were injected with the SSRI paroxetine (PAR, 10 mg/kg), the SNRI milnacipran (MIL, 30 mg/kg), or the NaSSA mirtazapine (MIR, 10 mg/kg) for acute (1 h) or sub-chronic (3 weeks) treatment prior to analysis of nine brain regions (frontal cortex, temporal cortex, striatum, thalamus, hippocampus, midbrain, pons, cerebellum, and olfactory bulb). The mRNA expression levels of three NOS subtypes (neuronal: nNOS, inducible: iNOS, and endothelial: eNOS) were analyzed using real-time PCR with Taqman probes.

RESULTS: Acute MIR treatment significantly increased nNOS mRNA expression in the hippocampus, midbrain, cerebellum and olfactory bulb, and iNOS mRNA expression in the frontal cortex and midbrain. Acute PAR and MIR treatments significantly increased eNOS mRNA expression in most brain regions. Conversely, sub-chronic treatment with all types of antidepressants resulted in significant decreases of eNOS mRNA expression in most brain regions.

CONCLUSIONS: Sub-chronic treatment with the three types of antidepressants consistently decreased eNOS mRNA expression levels in the rat brain. These effects may be associated with the involvement of the NO system in the mechanism of action of antidepressants.