Medroxyprogesterone acetate impairs memory and alters the GABAergic system in aged surgically menopausal rats

Neurobiology of Learning and Memory

Volumn 93, Issue 3, 2010, Pages 444-453

  Braden, B Blair ^a,d   Talboom, Joshua S ^a,d   Crain, Ian D ^a   Simard, Alain R ^b   Lukas, Ronald J ^b,d   Prokai, Laszlo ^c   Scheldrup, Melissa R ^a   Bowman, Bronson L ^a   Bimonte Nelson, Heather A ^a,d  

^a ARIZONA STATE UNIVERSITY   (United States)

^b BARROW NEUROLOGICAL INSTITUTE   (United States)

^c UNIVERSITY OF NORTH TEXAS HEALTH SCIENCE CENTER   (United States)

^d ARIZONA ALZHEIMER S CONSORTIUM   (United States)

Author keywords

Aging; Cognition; Hormone therapy; Learning and memory; Menopause; Progestins

Indexed keywords

GLUTAMATE DECARBOXYLASE; MEDROXYPROGESTERONE ACETATE; NEUROTROPHIN; PROGESTERONE;

AGED; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; BRAIN FUNCTION; BRAIN LEVEL; BRAIN REGION; COGNITION; CONTROLLED STUDY; DRUG DOSE COMPARISON; DRUG MEGADOSE; ENTORHINAL CORTEX; FEMALE; GABAERGIC SYSTEM; HIPPOCAMPUS; LEARNING DISORDER; LOW DRUG DOSE; MAZE TEST; MEMORY CONSOLIDATION; MEMORY DISORDER; MENOPAUSAL SYNDROME; MENTAL HEALTH; NEUROBIOLOGY; NONHUMAN; OVARIECTOMY; PROTEIN ANALYSIS; RAT; UTERUS WEIGHT;

ANIMALS; CONTRACEPTIVE AGENTS, FEMALE; FEMALE; GAMMA-AMINOBUTYRIC ACID; HIPPOCAMPUS; MEDROXYPROGESTERONE ACETATE; MEMORY DISORDERS; MENOPAUSE; OVARIECTOMY; RATS; RATS, INBRED F344;

EID: 77950691298     PISSN: 10747427     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.nlm.2010.01.002     Document Type: Article

References (77)

1. Acosta J.I., Mayer L., Talboom J.S., Zay C., Scheldrup M., Castillo J., et al. Premarin improves memory, prevents scopolamine-induced amnesia and increases number of basal forebrain choline acetyltransferase positive cells in middle-aged surgically menopausal rats. Hormones and Behavior 2009, 55:454-464.
2. Aguirre C.C., Baudry M. Progesterone reverses 17beta-estradiol-mediated neuroprotection and BDNF induction in cultured hippocampal slices. European Journal of Neuroscience 2009, 29:447-454.
3. Backman C., Rose G.M., Hoffer B.J., Henry M.A., Bartus R.T., Friden P., et al. Systemic administration of a nerve growth factor conjugate reverses age-related cognitive dysfunction and prevents cholinergic neuron atrophy. Journal of Neuroscience 1996, 16:5437-5442.
4. Bauer C.A., Brozoski T.J., Holder T.M., Caspary D.M. Effects of chronic salicylate on GABAergic activity in rat inferior colliculus. Hearing Research 2000, 147:175-182.
5. Belelli D., Herd M.B. The contraceptive agent Provera enhances GABA(A) receptor-mediated inhibitory neurotransmission in the rat hippocampus: Evidence for endogenous neurosteroids?. Journal of Neuroscience 2003, 23:10013-10020.
6. Bimonte H.A., Denenberg V.H. Estradiol facilitates performance as working memory load increases. Psychoneuroendocrinology 1999, 24:161-173.
7. Bimonte H.A., Denenberg V.H. Sex differences in vicarious trial-and-error behavior during radial arm maze learning. Physiology & Behavior 2000, 68:495-499.
8. Bimonte H.A., Granholm A.C., Seo H., Isacson O. Spatial memory testing decreases hippocampal amyloid precursor protein in young, but not aged, female rats. Neuroscience Letters 2002, 328:50-54.
9. Bimonte H.A., Hyde L.A., Hoplight B.J., Denenberg V.H. In two species, females exhibit superior working memory and inferior reference memory on the water radial-arm maze. Physiology & Behavior 2000, 70:311-317.
10. Bimonte H.A., Nelson M.E., Granholm A.C. Age-related deficits as working memory load increases: Relationships with growth factors. Neurobiology of Aging 2003, 24:37-48.
11. Bimonte-Nelson H.A., Francis K.R., Umphlet C.D., Granholm A.C. Progesterone reverses the spatial memory enhancements initiated by tonic and cyclic oestrogen therapy in middle-aged ovariectomized female rats. European Journal of Neuroscience 2006, 24:229-242.
12. Bimonte-Nelson H.A., Nelson M.E., Granholm A.C. Progesterone counteracts estrogen-induced increases in neurotrophins in the aged female rat brain. NeuroReport 2004, 15:2659-2663.
13. Bimonte-Nelson H.A., Singleton R.S., Hunter C.L., Price K.L., Moore A.B., Granholm A.C. Ovarian hormones and cognition in the aged female rat: I. Long-term, but not short-term, ovariectomy enhances spatial performance. Behavioral Neuroscience 2003, 117:1395-1406.
14. Bimonte-Nelson H.A., Singleton R.S., Williams B.J., Granholm A.C. Ovarian hormones and cognition in the aged female rat: II. Progesterone supplementation reverses the cognitive enhancing effects of ovariectomy. Behavioral Neuroscience 2004, 118:707-714.
15. Brett M., Baxendale S. Motherhood and memory: A review. Psychoneuroendocrinology 2001, 26:339-362.
16. Brun V.H., Leutgeb S., Wu H.Q., Schwarcz R., Witter M.P., Moser E.I., et al. Impaired spatial representation in CA1 after lesion of direct input from entorhinal cortex. Neuron 2008, 57:290-302.
17. Campbell S., Whitehead M. Oestrogens for menopausal flushing. British Medical Journal 1977, 1:104-105.
18. Duka T., Tasker R., McGowan J.F. The effects of 3-week estrogen hormone replacement on cognition in elderly healthy females. Psychopharmacology (Berl) 2000, 149:129-139.
19. Engler-Chiurazzi, E., Tsang, C., Nonnenmacher, S., Liang, W. S., Corneveaux, J. J. Prokai, L., et al. (2009). Tonic premarin dose-dependently enhances memory, affects neurotrophin protein levels and alters gene expression in middle-aged rats. Neurobiology of Aging.
20. Erlander M.G., Tobin A.J. The structural and functional heterogeneity of glutamic acid decarboxylase: A review. Neurochemical Research 1991, 16:215-226.
21. Ferreira M.B., Da Silva R.C., Medina J.H., Izquierdo I. Late posttraining memory processing by entorhinal cortex: Involvement of NMDA and GABAergic receptors. Pharmacology, Biochemistry and Behavior 1992, 41:767-771.
22. Freedman M.A. Quality of life and menopause: The role of estrogen. Journal of Women's Health (Larchmt) 2002, 11:703-718.
23. Freeman E.W., Weinstock L., Rickels K., Sondheimer S.J., Coutifaris C. A placebo-controlled study of effects of oral progesterone on performance and mood. British Journal of Clinical Pharmacology 1992, 33:293-298.
24. Frye C.A., Sturgis J.D. Neurosteroids affect spatial/reference, working, and long-term memory of female rats. Neurobiology of Learning and Memory 1995, 64:83-96.
25. Gabriel A., Fahim G. Do depot medroxyprogesterone acetate contraceptive injections cause mood changes and memory impairment?. Primary Psychiatry 2005, 12:59-60.
26. Gibbs R.B. Long-term treatment with estrogen and progesterone enhances acquisition of a spatial memory task by ovariectomized aged rats. Neurobiology of Aging 2000, 21:107-116.
27. Goldman J.M., Murr A.S., Cooper R.L. The rodent estrous cycle: Characterization of vaginal cytology and its utility in toxicological studies. British Defects Research Part B - Developmental and Reproductive Toxicology 2007, 80:84-97.
28. Harburger L.L., Bennett J.C., Frick K.M. Effects of estrogen and progesterone on spatial memory consolidation in aged females. Neurobiol Aging 2007, 28:602-610.
29. Hersh A.L., Stefanick M.L., Stafford R.S. National use of postmenopausal hormone therapy: Annual trends and response to recent evidence. JAMA 2004, 291:47-53.
30. Hyde L.A., Hoplight B.J., Denenberg V.H. Water version of the radial-arm maze: Learning in three inbred strains of mice. Brain Research 1998, 785:236-244.
31. Hyde L.A., Sherman G.F., Denenberg V.H. Non-spatial water radial-arm maze learning in mice. Brain Research 2000, 863:151-159.
32. Izquierdo I., Medina J.H., Bianchin M., Walz R., Zanatta M.S., Da Silva R.C., et al. Memory processing by the limbic system: Role of specific neurotransmitter systems. Behavioural Brain Research 1993, 58:91-98.
33. Jarrard L.E., Okaichi H., Steward O., Goldschmidt R.B. On the role of hippocampal connections in the performance of place and cue tasks: Comparisons with damage to hippocampus. Behavioral Neuroscience 1984, 98:946-954.
34. Johansson I.M., Birzniece V., Lindblad C., Olsson T., Backstrom T. Allopregnanolone inhibits learning in the Morris water maze. Brain Research 2002, 934:125-131.
35. Kantor H.I., Michael C.M., Shore H. Estrogen for older women. American Journal of Obstetrics and Gynecology 1973, 116:115-118.
36. Kask K., Backstrom T., Nilsson L.G., Sundstrom-Poromaa I. Allopregnanolone impairs episodic memory in healthy women. Psychopharmacology (Berl) 2008, 199:161-168.
37. Kaur P., Jodhka P.K., Underwood W.A., Bowles C.A., de Fiebre N.C., de Fiebre C.M., et al. Progesterone increases brain-derived neuroptrophic factor expression and protects against glutamate toxicity in a mitogen-activated protein kinase- and phosphoinositide-3 kinase-dependent manner in cerebral cortical explants. Journal of Neuroscience Research 2007, 85:2441-2449.
38. Keppel G., Wickens T.D. Design and analysis: A researcher's handbook 2004, Pearson Prentice Hall, Upper Saddle River, NJ. 4th ed.
39. Kim S.M., Kim D.H. Quantitative determination of medroxyprogesterone acetate in plasma by liquid chromatography/electrospray ion trap mass spectrometry. Rapid Communications in Mass Spectrometry 2001, 15:2041-2045.
40. Knowles W.D. Normal anatomy and neurophysiology of the hippocampal formation. Journal of Clinical Neurophysiology 1992, 9:252-263.
41. Lu K.H., Hopper B.R., Vargo T.M., Yen S.S. Chronological changes in sex steroid, gonadotropin and prolactin secretions in aging female rats displaying different reproductive states. Biology of Reproduction 1979, 21:193-203.
42. Markham J.A., Pych J.C., Juraska J.M. Ovarian hormone replacement to aged ovariectomized female rats benefits acquisition of the morris water maze. Hormones and Behavior 2002, 42:284-293.
43. Markowska A.L., Savonenko A.V. Effectiveness of estrogen replacement in restoration of cognitive function after long-term estrogen withdrawal in aging rats. Journal of Neuroscience 2002, 22:10985-10995.
44. McAuley J.W., Kroboth P.D., Stiff D.D., Reynolds I.J. Modulation of [3H]flunitrazepam binding by natural and synthetic progestational agents. Pharmacology, Biochemistry and Behavior 1993, 45:77-83.
45. Milbrandt J.C., Holder T.M., Wilson M.C., Salvi R.J., Caspary D.M. GAD levels and muscimol binding in rat inferior colliculus following acoustic trauma. Hearing Research 2000, 147:251-260.
46. Mora F., Segovia G., del Arco A. Aging, plasticity and environmental enrichment: Structural changes and neurotransmitter dynamics in several areas of the brain. Brain Research Reviews 2007, 55:78-88.
47. Morris R.G., Garrud P., Rawlins J.N., O'Keefe J. Place navigation impaired in rats with hippocampal lesions. Nature 1982, 297:681-683.
48. Mosher W.D., Martinez G.M., Chandra A., Abma J.C., Willson S.J. Use of contraception and use of family planning services in the United States: 1982-2002. Advance Data 2004, 1:36.
49. Nappi R.E., Sinforiani E., Mauri M., Bono G., Polatti F., Nappi G. Memory functioning at menopause: Impact of age in ovariectomized women. Gynecologic and Obstetric Investigation 1999, 47:29-36.
50. Nilsen J., Brinton R.D. Impact of progestins on estradiol potentiation of the glutamate calcium response. NeuroReport 2002, 13:825-830.
51. Nilsen J., Brinton R.D. Impact of progestins on estrogen-induced neuroprotection: Synergy by progesterone and 19-norprogesterone and antagonism by medroxyprogesterone acetate. Endocrinology 2002, 143:205-212.
52. Nilsen J., Morales A., Brinton R.D. Medroxyprogesterone acetate exacerbates glutamate excitotoxicity. Gynecological Endocrinology 2006, 22:355-361.
53. Ohkura T., Isse K., Akazawa K., Hamamoto M., Yaoi Y., Hagino N. Long-term estrogen replacement therapy in female patients with dementia of the Alzheimer type: 7 case reports. Dementia 1995, 6:99-107.
54. Pandey S.C., Zhang D., Mittal N., Nayyar D. Potential role of the gene transcription factor cyclic AMP-responsive element binding protein in ethanol withdrawal-related anxiety. Journal of Pharmacology and Experimental Therapeutics 1999, 288:866-878.
55. Paul S.M., Purdy R.H. Neuroactive steroids. FASEB Journal 1992, 6:2311-2322.
56. Paxinos G., Watson C. The rat brain in stereotaxic coordinates 1998, Academic Press, New York. 4th ed.
57. Pazol K., Northcutt K.V., Patisaul H.B., Wallen K., Wilson M.E. Progesterone and medroxyprogesterone acetate differentially regulate alpha4 subunit expression of GABA(A) receptors in the CA1 hippocampus of female rats. Physiology & Behavior 2009, 97:58-61.
58. Penning T.M., Sharp R.B., Krieger N.R. Purification and properties of 3 alpha-hydroxysteroid dehydrogenase from rat brain cytosol. Inhibition by nonsteroidal anti-inflammatory drugs and progestins. Journal of Biological Chemistry 1985, 260:15266-15272.
59. Phillips S.M., Sherwin B.B. Effects of estrogen on memory function in surgically menopausal women. Psychoneuroendocrinology 1992, 17:485-495.
60. Pluchino N., Luisi M., Lenzi E., Centofanti M., Begliuomini S., Freschi L., et al. Progesterone and progestins: Effects on brain, allopregnanolone and beta-endorphin. Journal of Steroid Biochemistry and Molecular Biology 2006, 102:205-213.
61. Prempro Prescribing Information, (2009). <> Retrieved on November 23 2009. http://www.wyeth.com/content/showlabeling.asp?id=133.
62. Pridjian G., Schmit V., Schreiber J. Medroxyprogesterone acetate: Receptor binding and correlated effects on steroidogenesis in rat granulosa cells. Journal of Steroid Biochemistry 1987, 26:313-319.
63. Raol Y.H., Zhang G., Budreck E.C., Brooks-Kayal A.R. Long-term effects of diazepam and phenobarbital treatment during development on GABA receptors, transporters and glutamic acid decarboxylase. Neuroscience 2005, 132:399-407.
64. Rasband, W. (1997-2004). ImageJ Bethesda, National Institute of Health, Maryland, USA. <>. http://rsb.info.nih.gov/ij/.
65. Sherwin B.B. Estrogen and/or androgen replacement therapy and cognitive functioning in surgically menopausal women. Psychoneuroendocrinology 1988, 13:345-357.
66. Sherwin B.B. Estrogen and memory in women: How can we reconcile the findings?. Hormones and Behavior 2005, 47:371-375.
67. Shumaker S.A., Legault C., Kuller L., Rapp S.R., Thal L., Lane D.S., et al. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women's health initiative memory study. JAMA 2004, 291:2947-2958.
68. Shumaker S.A., Legault C., Rapp S.R., Thal L., Wallace R.B., Ockene J.K., et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: The Women's health initiative memory study: A randomized controlled trial. JAMA 2003, 289:2651-2662.
69. Smith D.C., Prentice R., Thompson D.J., Herrmann W.L. Association of exogenous estrogen and endometrial carcinoma. New England Journal of Medicine 1975, 293:1164-1167.
70. Hormones and aging 1995, CRC Press, Boca Raton, NY, London, Tokyo. P. Timaras, W. Quay, A. Vernadakis (Eds.).
71. Stavnezer A.J., Hyde L.A., Bimonte H.A., Armstrong C.M., Denenberg V.H. Differential learning strategies in spatial and nonspatial versions of the Morris water maze in the C57BL/6J inbred mouse strain. Behavioural Brain Research 2002, 133:261-270.
72. US Census Bureau, (2007). Word population information. <> Retrieved on April 21 2007. http://www.census.gov/ipc/www/world.html.
73. Wallis C.J., Luttge W.G. Influence of estrogen and progesterone on glutamic acid decarboxylase activity in discrete regions of rat brain. Journal of Neurochemistry 1980, 34:609-613.
74. Weiland N.G. Glutamic acid decarboxylase messenger ribonucleic acid is regulated by estradiol and progesterone in the hippocampus. Endocrinology 1992, 131:2697-2702.
75. Wolf O.T., Kudielka B.M., Hellhammer D.H., Torber S., McEwen B.S., Kirschbaum C. Two weeks of transdermal estradiol treatment in postmenopausal elderly women and its effect on memory and mood: Verbal memory changes are associated with the treatment induced estradiol levels. Psychoneuroendocrinology 1999, 24:727-741.
76. Zhang L., Fishman M.C., Huang P.L. Estrogen mediates the protective effects of pregnancy and chorionic gonadotropin in a mouse model of vascular injury. Arteriosclerosis, Thrombosis, and Vascular Biology 1999, 19:2059-2065.
77. Ziel H.K., Finkle W.D. Increased risk of endometrial carcinoma among users of conjugated estrogens. New England Journal of Medicine 1975, 293:1167-1170.