Effects of Estrogen Therapy on the Serotonergic System in an Animal Model of Perimenopause Induced by 4-Vinylcyclohexen Diepoxide (VCD)

eNeuro. 2018 Jan 22;5(1):ENEURO.0247-17.2017. doi: 10.1523/ENEURO.0247-17.2017. eCollection Jan-Feb 2018.


Chronic exposure to 4-vinylcycloxene diepoxide (VCD) in rodents accelerates the natural process of ovarian follicular atresia modelling perimenopause in women. We investigated why estrogen therapy is beneficial for symptomatic women despite normal or high estrogen levels during perimenopause. Female rats (28 d) were injected daily with VCD or oil for 15 d; 55-65 d after the first injection, pellets of 17β-estradiol or oil were inserted subcutaneously. Around 20 d after, the rats were euthanized (control rats on diestrus and estradiol-treated 21 d after pellets implants). Blood was collected for hormone measurement, the brains were removed and dorsal raphe nucleus (DRN), hippocampus (HPC), and amygdala (AMY) punched out for serotonin (5-HT), estrogen receptor β (ERβ), and progesterone receptor (PR) mRNA level measurements. Another set of rats was perfused for tryptophan hydroxylase (TPH) immunohistochemistry in the DRN. Periestropausal rats exhibited estradiol levels similar to controls and a lower progesterone level, which was restored by estradiol. The DRN of periestropausal rats exhibited lower expression of PR and ERβ mRNA and a lower number of TPH cells. Estradiol restored the ERβ mRNA levels and number of serotonergic cells in the DRN caudal subregion. The 5-HT levels were lower in the AMY and HPC in peristropausal rats, and estradiol treatment increased the 5-HT levels in the HPC and also increased ERβ expression in this area. In conclusion, estradiol may improve perimenopause symptoms by increasing progesterone and boosting serotonin pathway from the caudal DRN to the dorsal HPC potentially through an increment in ERβ expression in the DRN.

Keywords: amygdala; dorsal raphe nucleus; estrogen; estrogen receptor β; hippocampus; progesterone receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / cytology
  • Brain / drug effects*
  • Brain / metabolism
  • Cyclohexenes
  • Estradiol / metabolism
  • Estradiol / pharmacology*
  • Estrogen Receptor beta / metabolism
  • Estrogens / metabolism
  • Estrogens / pharmacology*
  • Female
  • Hormone Replacement Therapy*
  • Models, Animal
  • Perimenopause / drug effects*
  • Perimenopause / metabolism
  • RNA, Messenger / metabolism
  • Rats, Wistar
  • Receptors, Progesterone / metabolism
  • Serotonin / metabolism*
  • Tryptophan Hydroxylase / metabolism
  • Vinyl Compounds


  • Cyclohexenes
  • Estrogen Receptor beta
  • Estrogens
  • RNA, Messenger
  • Receptors, Progesterone
  • Vinyl Compounds
  • Serotonin
  • Estradiol
  • 4-vinyl-1-cyclohexene dioxide
  • Tryptophan Hydroxylase