Editors' ChoicePsychiatry

Depression: Just Say NO

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Science Translational Medicine  12 Sep 2012:
Vol. 4, Issue 151, pp. 151ec165
DOI: 10.1126/scitranslmed.3004902

Depression is a common psychiatric disorder that has a twofold higher prevalence in women compared with men. The underlying mechanism of this “gender gap” in depression remains elusive. Now, Hu and colleagues provide new insight into the role of the signaling molecule nitric oxide (NO) in pathways leading to affective disorders. They focused on NO production in the hippocampus, a brain structure important for memory formation.

Hu et al. investigated NO in the hippocampus of male and female rodents, in conjunction with behavioral tests that are thought to detect depression-like symptoms in animals. They found reduced basal concentrations of neuronal NO in females compared with males, a difference that correlated with an increase in depressive-like behavior. Importantly, this behavior was reversed by pharmacologically increasing NO concentrations in the hippocampus of females. The relative decrease in NO production in the female hippocampus was related to decreased concentrations of estrogen in the hippocampus of females compared with males (8 nM for males compared with 0.5 to 2 nM for females). Delivering an estrogen-receptor agonist into the hippocampus of females increased NO production and reduced depressive behavior. Hu and colleagues then investigated the effects of chronic mild stress on male and female rats, revealing an opposite response in the expression of NO synthase, the enzyme that generates NO. Male rats showed increased NO synthase expression in response to stress, whereas females showed a reduction in expression of this enzyme in response to stress. These divergent responses were mediated by decreased estrogen in female rats and increased glucocorticoid concentrations in males, leading to a shortage and an excess, respectively, of NO. Dysregulation of NO in either direction was associated with depression-like behavior.

Working in rats, Hu and colleagues have elucidated a critical role for NO that may account for the observed sex differences regarding susceptibility to affective disorders like depression. The divergent stress responses observed in male and female rats also point to distinct hormonal pathways leading to a shortage (females) or excess (males) of NO, both of which cause depressive behavior in rodents. One must interpret data in animals with caution, and confirmation in humans is required. Nonetheless, these findings represent the potential for sex-specific therapy in men and women that will help us “just say NO” to depression.

Y. Hu et al. Hippocampal nitric oxide contributes to sex difference in affective behaviors. Proc. Natl. Acad. Sci. U.S.A. 109, 14224–14229 (2012). [Abstract]

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