Galanthamine Plus Estradiol Treatment Enhances Cognitive Performance in Aged Ovariectomized Rats

Overview

Journal Horm Behav

Specialties Endocrinology
Psychology
Social Sciences

Date 2011 Sep 6

PMID 21889940

Citations 15

Authors

R B Gibbs

A M Chipman

R Hammond

D Nelson

Affiliations

Soon will be listed here.

Abstract

We hypothesize that beneficial effects of estradiol on cognitive performance diminish with age and time following menopause due to a progressive decline in basal forebrain cholinergic function. This study tested whether galanthamine, a cholinesterase inhibitor used to treat memory impairment associated with Alzheimer's disease, could enhance or restore estradiol effects on cognitive performance in aged rats that had been ovariectomized in middle-age. Rats were ovariectomized at 16-17 months of age. At 21-22 months of age rats began receiving daily injections of galanthamine (5mg/day) or vehicle. After one week, half of each group also received 17ß-estradiol administered subcutaneously. Rats were then trained on a delayed matching to position (DMP) T-maze task, followed by an operant stimulus discrimination/reversal learning task. Treatment with galanthamine+estradiol significantly enhanced the rate of DMP acquisition and improved short-term delay-dependent spatial memory performance. Treatment with galanthamine or estradiol alone was without significant effect. Effects were task-specific in that galanthamine+estradiol treatment did not significantly improve performance on the stimulus discrimination/reversal learning task. In fact, estradiol was associated with a significant increase in incorrect responses on this task after reversal of the stimulus contingency. In addition, treatments did not significantly affect hippocampal choline acetyltransferase activity or acetylcholine release. This may be an effect of age, or possibly is related to compensatory changes associated with long-term cholinesterase inhibitor treatment. The data suggest that treating with a cholinesterase inhibitor can enhance the effects of estradiol on acquisition of a DMP task by old rats following a long period of hormone deprivation. This could be of particular benefit to older women who have not used hormone therapy for many years and are beginning to show signs of mild cognitive impairment. Potential mechanisms for these effects are discussed.

Citing Articles

A Review of the Role of Estrogens in Olfaction, Sleep and Glymphatic Functionality in Relation to Sex Disparity in Alzheimer's Disease.

Ekanayake A, Peiris S, Ahmed B, Kanekar S, Grove C, Kalra D Am J Alzheimers Dis Other Demen. 2024; 39:15333175241272025.

PMID: 39116421 PMC: 11311174. DOI: 10.1177/15333175241272025.

Estradiol treatment in young postmenopausal women with self-reported cognitive complaints: Effects on cholinergic-mediated cognitive performance.

Conley A, Albert K, McDonald B, Saykin A, Dumas J, Newhouse P Hum Psychopharmacol. 2022; 37(5):e2838.

PMID: 35212023 PMC: 9399322. DOI: 10.1002/hup.2838.

Estrogen Deficiency Induces Mitochondrial Damage Prior to Emergence of Cognitive Deficits in a Postmenopausal Mouse Model.

Zhao W, Hou Y, Song X, Wang L, Zhang F, Zhang H Front Aging Neurosci. 2021; 13:713819.

PMID: 34335235 PMC: 8319728. DOI: 10.3389/fnagi.2021.713819.

Structural MRI of the basal forebrain as predictor of cognitive response to galantamine in healthy older adults-A randomized controlled double-blinded crossover study.

Muller P, Vellage A, Schmicker M, Menze I, Grothe M, Teipel S Alzheimers Dement (N Y). 2021; 7(1):e12153.

PMID: 33842683 PMC: 8020325. DOI: 10.1002/trc2.12153.

Characterizing the effects of tonic 17β-estradiol administration on spatial learning and memory in the follicle-deplete middle-aged female rat.

Koebele S, Mennenga S, Poisson M, Hewitt L, Patel S, Mayer L Horm Behav. 2020; 126:104854.

PMID: 32949557 PMC: 8032560. DOI: 10.1016/j.yhbeh.2020.104854.

References

Markowska A, Savonenko A . Effectiveness of estrogen replacement in restoration of cognitive function after long-term estrogen withdrawal in aging rats. J Neurosci. 2002; 22(24):10985-95. PMC: 6758418. View

Daniel J, Bohacek J . The critical period hypothesis of estrogen effects on cognition: Insights from basic research. Biochim Biophys Acta. 2010; 1800(10):1068-76. DOI: 10.1016/j.bbagen.2010.01.007. View

Sakurai T, Mieda M, Tsujino N . The orexin system: roles in sleep/wake regulation. Ann N Y Acad Sci. 2010; 1200:149-61. DOI: 10.1111/j.1749-6632.2010.05513.x. View

Fadel J, Pasumarthi R, Reznikov L . Stimulation of cortical acetylcholine release by orexin A. Neuroscience. 2005; 130(2):541-7. DOI: 10.1016/j.neuroscience.2004.09.050. View

Singh M, Meyer E, Millard W, Simpkins J . Ovarian steroid deprivation results in a reversible learning impairment and compromised cholinergic function in female Sprague-Dawley rats. Brain Res. 1994; 644(2):305-12. DOI: 10.1016/0006-8993(94)91694-2. View

Taly A, Corringer P, Guedin D, Lestage P, Changeux J . Nicotinic receptors: allosteric transitions and therapeutic targets in the nervous system. Nat Rev Drug Discov. 2009; 8(9):733-50. DOI: 10.1038/nrd2927. View

Moore H, Stuckman S, Sarter M, Bruno J . Potassium, but not atropine-stimulated cortical acetylcholine efflux, is reduced in aged rats. Neurobiol Aging. 1996; 17(4):565-71. DOI: 10.1016/0197-4580(96)00075-9. View

Schilstrom B, Ivanov V, Wiker C, Svensson T . Galantamine enhances dopaminergic neurotransmission in vivo via allosteric potentiation of nicotinic acetylcholine receptors. Neuropsychopharmacology. 2006; 32(1):43-53. DOI: 10.1038/sj.npp.1301087. View

Darreh-Shori T, Meurling L, Pettersson T, Hugosson K, Hellstrom-Lindahl E, Andreasen N . Changes in the activity and protein levels of CSF acetylcholinesterases in relation to cognitive function of patients with mild Alzheimer's disease following chronic donepezil treatment. J Neural Transm (Vienna). 2006; 113(11):1791-801. DOI: 10.1007/s00702-006-0526-2. View

10.

Gibbs R, Johnson D . Cholinergic lesions produce task-selective effects on delayed matching to position and configural association learning related to response pattern and strategy. Neurobiol Learn Mem. 2007; 88(1):19-32. PMC: 1991294. DOI: 10.1016/j.nlm.2007.03.007. View

11.

Fischer W, Chen K, Gage F, Bjorklund A . Progressive decline in spatial learning and integrity of forebrain cholinergic neurons in rats during aging. Neurobiol Aging. 1992; 13(1):9-23. DOI: 10.1016/0197-4580(92)90003-g. View

12.

Szekely M, Petervari E, Balasko M . Thermoregulation, energy balance, regulatory peptides: recent developments. Front Biosci (Schol Ed). 2010; 2(3):1009-46. DOI: 10.2741/s116. View

13.

Sandstrom N, Williams C . Spatial memory retention is enhanced by acute and continuous estradiol replacement. Horm Behav. 2004; 45(2):128-35. DOI: 10.1016/j.yhbeh.2003.09.010. View

14.

Daniel J, Hulst J, Berbling J . Estradiol replacement enhances working memory in middle-aged rats when initiated immediately after ovariectomy but not after a long-term period of ovarian hormone deprivation. Endocrinology. 2005; 147(1):607-14. DOI: 10.1210/en.2005-0998. View

15.

McIntyre C, Marriott L, Gold P . Patterns of brain acetylcholine release predict individual differences in preferred learning strategies in rats. Neurobiol Learn Mem. 2003; 79(2):177-83. DOI: 10.1016/s1074-7427(02)00014-x. View

16.

Thakkar M, Ramesh V, Strecker R, McCarley R . Microdialysis perfusion of orexin-A in the basal forebrain increases wakefulness in freely behaving rats. Arch Ital Biol. 2001; 139(3):313-28. View

17.

Talboom J, Williams B, Baxley E, West S, Bimonte-Nelson H . Higher levels of estradiol replacement correlate with better spatial memory in surgically menopausal young and middle-aged rats. Neurobiol Learn Mem. 2008; 90(1):155-63. PMC: 2453224. DOI: 10.1016/j.nlm.2008.04.002. View

18.

Orsetti M, Casamenti F, Pepeu G . Enhanced acetylcholine release in the hippocampus and cortex during acquisition of an operant behavior. Brain Res. 1996; 724(1):89-96. DOI: 10.1016/0006-8993(96)00292-2. View

19.

Davis B, Sadik K . Circadian cholinergic rhythms: implications for cholinesterase inhibitor therapy. Dement Geriatr Cogn Disord. 2006; 21(2):120-9. DOI: 10.1159/000090630. View

20.

Fitz N, Gibbs R, Johnson D . Selective lesion of septal cholinergic neurons in rats impairs acquisition of a delayed matching to position T-maze task by delaying the shift from a response to a place strategy. Brain Res Bull. 2008; 77(6):356-60. PMC: 2649660. DOI: 10.1016/j.brainresbull.2008.08.016. View