Effects of estrogen and progesterone treatment on rat hippocampal NMDA receptors: Relationship to Morris water maze performance

Abstract

Ovarian hormones have several effects on the nervous system that extend beyond regulation of the reproductive functions. Estrogen is believed to have a neuroprotective effect, both in human [1] and animal models [2]. Estrogen protects the neurons from injury of different insults like β-amyloid and glutamate toxicity [3], oxidative stress [4] and ischemia [5]. Moreover, it enhances neuronal repair after injury [6] and neurite plasticity by regulating the number of synaptic inputs in pyramidal cells of the CA1 region in the hippocampus [7,8] AbstractEstrogen modulates NMDA receptors function in the brain. It increases both dendritic spine density and synapse number in the hippocampus, an effect that can be blocked by NMDA antagonist. In this study, we investigated the effect of 17β-estradiol and progesterone treatment on NMDA receptors in ovariectomized rats. Two different doses were used for 10 weeks. Receptor autoradiography was done on brain sections using [ 3 H] MK-801 as a ligand. Our results showed a significant increase in [ 3 H] MK-801 binding in the dentate gyrus, CA3 and CA4 areas of the hippocampus of ovariectomized compared to sham operated rats. In addition, we observed similar changes in CA1. 17β-estradiol treatment in both doses reduced the binding back to the normal level while progesterone treatment did not show any effect. Spatial reference memory was tested on Morris water maze task. Ovariectomy severely impaired spatial reference memory. Estradiol but not progesterone treatment significantly improved the memory performance of the ovariectomized rats. Low dose treatment showed better learning than high dose estrogen treatment. The decrease in the antagonist sites by estradiol treatment could result in an increase in the sensitivity of the hippocampus to the excitatory stimulation by glutamate system and hence the effect of estradiol on learning and memory. The changes of NMDA receptors in the hippocampus support the concept that estrogen-enhancing effect on spatial reference memory could be through the enhancing of NMDA function.

β-Estradiol Increases Dentate Gyrus Inhibition in Female Rats via Augmentation of Hilar Neuropeptide Y

“…The decline of hippocampal NPY attributable to the lack of ␤-estradiol may be involved in learning and memory disturbances and changes in mood, including increased anxiety states in women after menopause (medical or natural) (Hattiangady et al, 2005;Osterlund et al, 2005). These clinical observations are supported by animal studies, which also show that ovariectomy leads to decline in learning and memory and to increased anxiety in females, all of which can be corrected by ␤-estradiol replacement (El-Bakri et al, 2004;Imwalle et al, 2005). Similarly, changes in the NPY system are associated with disturbances in learning and memory as well as anxiety behaviors (Heilig, 2004;Redrobe et al, 2004).…”

Assessment of estradiol influence on spatial tasks and hippocampal CA1 spines: Evidence that the duration of hormone deprivation after ovariectomy compromises 17β-estradiol effectiveness in altering CA1 spines

“…While the 5E group displayed slower swim speeds during day 2 of testing compared to 10E, differences in motivation and motor ability are unlikely because distance covered was consistent with latency to escape. This nonlinear effect for the 5E rats to outperform the 10E and vehicle groups on spatial acquisition is consistent with other reports using a different treatment regimen with estradiol benzoate (Xu and Zhang, 2006) or low-dose tonic or cyclic estradiol treatment in young (El-Bakri et al, 2004) and middle-aged OVX female rats (Bimonte-Nelson et al, 2006;Fernandez and Frick, 2004). At the end of the training session in our study, we gave a probe trial to assess navigation strategies, which showed that all treatment groups learned the platform location.…”

The impact of using different doses of progesterone on memory performance

“…Moreover, ElBakri et al (2004) indicated that low-dose estrogen usage showed better learning and memory than high-dose estradiol administration. Treatment with high doses of female sex hormones can decrease the dendritic spine and synapse in CA1 hippocampus (25). The current study indicated that doses of 1.5 and 2 μg of progesterone were effectively able to increase memory in a passive avoidance task.…”