BACKGROUND: The prevalence of depression in women is approximately twice that in men. Differences in androgens levels between men and women, due to gonadal differences, may be associated with the development of depression, although the underlying mechanisms are not well understood. METHODS: We evaluated the depressive phenotypes of female mice following low-dose androgen treatment using a variety of behavioral and in vivo electrophysiological experiments. The mRNA profile of hippocampal tissues from female mice treated with dehydroepiandrosterone (DHEA) was constructed through RNA sequencing (RNA-seq). GO and KEGG pathway analyses were performed on the differentially expressed genes. The expression changes of candidate differential genes were verified in hippocampal tissues by quantitative real-time PCR and western blotting. Moreover, the mechanism of action of the DHEA-regulated differential gene (Avpr1a), which is involved in the neuroactive ligand-receptor interaction pathway, was determined in vitro. RESULTS: Chronic DHEA treatment resulted in a distinct antidepressant phenotype and significantly enhanced neuronal excitability of the ventral hippocampal region of female mice. RNA-seq identified the crucial differentially expressed gene, Avpr1a. In vitro experiments showed that DHEA reduced levels of the AVP system. Additionally, ChIP-PCR experiments revealed that Avpr1a directly targets androgen receptor (AR). Cell function experiments demonstrated that DHEA can inhibit AVPR1a expression through AR in a dose-dependent manner, and this effect can be reversed by the androgen receptor antagonist (Flutamide). CONCLUSION: Androgens (DHEA) exert antidepressant effects by inhibiting the binding of Avpr1a to AR. The Avpr1a gene may serve as a new target for the treatment of depression in women.