Premarin improves memory, prevents scopolamine-induced amnesia and increases number of basal forebrain choline acetyltransferase positive cells in middle-aged surgically menopausal rats

Horm Behav. 2009 Mar;55(3):454-64. doi: 10.1016/j.yhbeh.2008.11.008. Epub 2008 Dec 3.


Conjugated equine estrogen (CEE) is the most commonly prescribed estrogen therapy, and is the estrogen used in the Women's Health Initiative study. While in-vitro studies suggest that CEE is neuroprotective, no study has evaluated CEE's effects on a cognitive battery and brain immunohistochemistry in an animal model. The current experiment tested whether CEE impacted: I) spatial learning, reference memory, working memory and long-term retention, as well as ability to handle mnemonic delay and interference challenges; and, II) the cholinergic system, via pharmacological challenge during memory testing and ChAT-immunoreactive cell counts in the basal forebrain. Middle-aged ovariectomized (Ovx) rats received chronic cyclic injections of either Oil (vehicle), CEE-Low (10 microg), CEE-Medium (20 microg) or CEE-High (30 microg) treatment. Relative to the Oil group, all three CEE groups showed less overnight forgetting on the spatial reference memory task, and the CEE-High group had enhanced platform localization during the probe trial. All CEE groups exhibited enhanced learning on the spatial working memory task, and CEE dose-dependently protected against scopolamine-induced amnesia with every rat receiving the highest CEE dose maintaining zero errors after scopolamine challenge. CEE also increased number of ChAT-immunoreactive neurons in the vertical diagonal band of the basal forebrain. Neither the ability to remember after a delay nor interference, nor long-term retention, was influenced by the CEE regimen used in this study. These findings are similar to those reported previously for 17 beta-estradiol, and suggest that CEE can provide cognitive benefits on spatial learning, reference and working memory, possibly through cholinergic mechanisms.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amnesia / chemically induced*
  • Amnesia / prevention & control*
  • Amnesia / psychology
  • Animals
  • Avoidance Learning / drug effects
  • Choline O-Acetyltransferase / metabolism*
  • Cognition / drug effects
  • Contraceptives, Oral, Hormonal / pharmacology*
  • Discrimination, Psychological / drug effects
  • Estradiol / blood
  • Estrogens, Conjugated (USP) / pharmacology*
  • Estrone / blood
  • Female
  • Maze Learning / drug effects
  • Memory / drug effects*
  • Muscarinic Antagonists*
  • Organ Size
  • Prosencephalon / enzymology*
  • Psychomotor Performance / drug effects
  • Rats
  • Rats, Inbred F344
  • Scopolamine*
  • Sexual Maturation / physiology*
  • Uterus / anatomy & histology
  • Uterus / physiology


  • Contraceptives, Oral, Hormonal
  • Estrogens, Conjugated (USP)
  • Muscarinic Antagonists
  • Estrone
  • Estradiol
  • Scopolamine
  • Choline O-Acetyltransferase