Dietary arginine depletion reduces depressive-like responses in male, but not female, mice

Previous behavioral studies have manipulated nitric oxide (NO) production either by pharmacological inhibition of its synthetic enzyme, nitric oxide synthase (NOS), or by deletion of the genes that code for NOS. However manipulation of dietary intake of the NO precursor, l-arginine, has been understudied in regard to behavioral regulation. l-Arginine is a common amino acid present in many mammalian diets and is essential during development. In the brain l-arginine is converted into NO and citrulline by the enzyme, neuronal NOS (nNOS). In Experiment 1, paired mice were fed a diet comprised either of an l-arginine-depleted, l-arginine-supplemented, or standard level of l-arginine during pregnancy. Offspring were continuously fed the same diets and were tested in adulthood in elevated plus maze, forced swim, and resident-intruder aggression tests. l-Arginine depletion reduced depressive-like responses in male, but not female, mice and failed to significantly alter anxiety-like or aggressive behaviors. Arginine depletion throughout life reduced body mass overall and eliminated the sex difference in body mass. Additionally, arginine depletion significantly increased corticosterone concentrations, which negatively correlated with time spent floating. In Experiment 2, adult mice were fed arginine-defined diets two weeks prior to and during behavioral testing, and again tested in the aforementioned tests. Arginine depletion reduced depressive-like responses in the forced swim test, but did not alter behavior in the elevated plus maze or the resident intruder aggression test. Corticosterone concentrations were not altered by arginine diet manipulation in adulthood. These results indicate that arginine depletion throughout development, as well as during a discrete period during adulthood ameliorates depressive-like responses. These results may yield new insights into the etiology and sex differences of depression.

► Arginine is the precursor to nitric oxide and is a conditionally essential amino acid.
► We examined behavioral effects of dietary arginine depletion during development and adulthood.
► Dietary arginine depletion reduced depressive-like responses in male but not female mice.
► This research may reveal may reveal new insights in sex differences in the risk for depression.