Estrogen treatment alleviates NMDA-antagonist induced hippocampal LTP blockade and cognitive deficits in ovariectomized mice

Neurobiol Learn Mem. 2003 Jan;79(1):72-80. doi: 10.1016/s1074-7427(02)00012-6.


Estrogen is implicated in hippocampus-dependent spatial learning as well as structural organization and electrophysiological properties of the rat hippocampus but little is known about its mechanisms of action in mice. In this study, we investigated pharmacologically whether estrogen interacts with the hippocampal N-methyl-D-aspartate (NMDA) receptors in ovariectomized mice as postulated for rats. Female C57BL/6J mice were ovariectomized at 5 months, and 2 weeks before testing at 12 months, half of them received subcutaneous estrogen pellets containing 0.18 mg of 17 beta-estradiol. The competitive NMDA-antagonist, 3-((+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), was administered at 5.0 and 10.0 microM to block induction of long-term potentiation (LTP) in the hippocampal slice and intraperitoneally at 0.5, 2.0, and 5.0 mg/kg to impair spatial learning in the water maze. Estrogen treatment shifted the dose-response curve to CPP in both experiments. First, 10 microM CPP blocked the initiation of LTP in all mice, but 5 microM only in ovariectomized non-estrogen-treated mice. Second, final level of acquisition and probe trial performance in the water maze were less affected by high doses of CPP in the estrogen-treated ovariectomized mice than in non-treated group. In control tests for motor side effects, estrogen treatment did not reduce the tendency of CPP to decrease locomotor activity in the open field and impair balance on a rotating rod, and estrogen by itself decreased swimming speed as did CPP, but these effects did not interact. Our findings support the notion that estrogen treatment increases the number of active NMDA-receptors in the mouse hippocampus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cognition / drug effects*
  • Cognition / physiology
  • Dose-Response Relationship, Drug
  • Estradiol / pharmacology*
  • Excitatory Amino Acid Antagonists / pharmacology*
  • Female
  • Hippocampus / drug effects*
  • Hippocampus / physiology
  • In Vitro Techniques
  • Learning / drug effects
  • Learning / physiology
  • Long-Term Potentiation / drug effects*
  • Memory / drug effects
  • Memory / physiology
  • Mice
  • Mice, Inbred C57BL
  • Motor Activity / drug effects
  • Motor Activity / physiology
  • Ovariectomy
  • Piperazines / pharmacology
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
  • Spatial Behavior / drug effects
  • Spatial Behavior / physiology


  • Excitatory Amino Acid Antagonists
  • Piperazines
  • Receptors, N-Methyl-D-Aspartate
  • Estradiol
  • 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid