Estrogen Treatment Effects on Anticholinergic-Induced Cognitive Dysfunction in Normal Postmenopausal Women

Estrogen has been shown to interact with the cholinergic system and influence cognition in animal models. This study investigated the interaction of estrogen and cholinergic system functioning and the effects of this interaction on cognitive task performance in healthy older women. Fifteen post-menopausal women were randomly and blindly placed on 1 mg of 17-β estradiol or placebo for 3 months after which they participated in five anticholinergic challenge sessions, where they were administered one of two doses of the antimuscarinic drug scopolamine (SCOP) or the antinicotinic drug mecamylamine (MECA) or placebo. After the first challenge phase, they were crossed over to the other hormone treatment for another 3 months and repeated the challenges. Performance in multiple domains of cognition was assessed during anticholinergic drug challenge, including attention and verbal and nonverbal learning and memory. Results showed that estrogen pretreatment attenuated the anticholinergic drug-induced impairments on tests of attention and tasks with speed components. This study is the first to demonstrate the interaction of estrogen and the cholinergic system and the effects on cognitive performance in humans. The results suggest that estrogen status may affect cholinergic system tone and may be important for cholinergic system integrity.

[1]  B. McEwen,et al.  Effect of gonadal steroids on activities of monoamine oxidase and choline acetylase in rat brain , 1975, Brain Research.

[2]  D. Drachman,et al.  Human memory and the cholinergic system. A relationship to aging? , 1974, Archives of neurology.

[3]  David A. Johnson,et al.  Estrogen Replacement Attenuates Effects of Scopolamine and Lorazepam on Memory Acquisition and Retention , 1998, Hormones and Behavior.

[4]  H. Critchley,et al.  Prolactin response to d-fenfluramine in postmenopausal women on and off ERT: comparison with young women , 2001, Psychoneuroendocrinology.

[5]  Herman Buschke,et al.  Selective reminding for analysis of memory and learning , 1973 .

[6]  K. Marder,et al.  Cognitive function in nondemented older women who took estrogen after menopause , 1998, Neurology.

[7]  W. Dement,et al.  Quantification of sleepiness: a new approach. , 1973, Psychophysiology.

[8]  K. Yaffe.  Hormone therapy and the brain: déjà vu all over again? , 2003, JAMA.

[9]  R. R. Abidin.  Psychological Assessment Resources , 1995 .

[10]  J. Manson,et al.  Effect of estrogen plus progestin on global cognitive function in postmenopausal women: the Women's Health Initiative Memory Study: a randomized controlled trial. , 2003, JAMA.

[11]  W. Banks,et al.  Estradiol potentiates acetylcholine and glutamate-mediated post-trial memory processing in the hippocampus , 2000, Brain Research.

[12]  M. Voytko,et al.  Estrogen and the cholinergic system modulate visuospatial attention in monkeys (Macaca fascicularis). , 2002, Behavioral neuroscience.

[13]  B. Sherwin,et al.  Estrogen and/or androgen replacement therapy and cognitive functioning in surgically menopausal women , 1988, Psychoneuroendocrinology.

[14]  M. Sarter,et al.  Attentional functions of cortical cholinergic inputs: What does it mean for learning and memory? , 2003, Neurobiology of Learning and Memory.

[15]  T. Duka,et al.  The effects of 3-week estrogen hormone replacement on cognition in elderly healthy females , 2000, Psychopharmacology.

[16]  Martin Sarter,et al.  Developmental origins of the age-related decline in cortical cholinergic function and associated cognitive abilities , 2004, Neurobiology of Aging.

[17]  M. Kritzer,et al.  Ovarian hormones differentially influence immunoreactivity for dopamine β‐ hydroxylase, choline acetyltransferase, and serotonin in the dorsolateral prefrontal cortex of adult rhesus monkeys , 1999, The Journal of comparative neurology.

[18]  A. Mirsky,et al.  The Continuous Performance Test. , 1963 .

[19]  A. Baddeley,et al.  Dual‐Task Paradigm: A Means To Examine the Central Executive , 1995, Annals of the New York Academy of Sciences.

[20]  R. Bartus,et al.  The cholinergic hypothesis of geriatric memory dysfunction. , 1982, Science.

[21]  Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women's Health Initiative Memory Study , 2004 .

[22]  T. Salthouse,et al.  Meta-analyses of age-cognition relations in adulthood: estimates of linear and nonlinear age effects and structural models. , 1997, Psychological bulletin.

[23]  C. Conners.  The computerized continuous performance test. , 1985, Psychopharmacology bulletin.

[24]  D. Pfaff,et al.  Effects of estrogen and fimbria/fornix transection on p75NGFR and ChAT expression in the medial septum and diagonal band of Broca , 1992, Experimental Neurology.

[25]  M. Voytko,et al.  Estrogen modulates cognitive and cholinergic processes in surgically menopausal monkeys , 2005, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[26]  Michael E. Hasselmo,et al.  Unraveling the attentional functions of cortical cholinergic inputs: interactions between signal-driven and cognitive modulation of signal detection , 2005, Brain Research Reviews.

[27]  I Hindmarch,et al.  Psychological performance models as indicators of the effects of hypnotic drugs on sleep. , 1984, Psychopharmacology. Supplementum.

[28]  M. M. Ghoneim,et al.  STUDIES ON HUMAN MEMORY THE INTERACTIONS OF DIAZEPAM, SCOPOLAMINE AND PHYSOSTIGMINE , 1978 .

[29]  J. Corwin,et al.  Nicotinic treatment of Alzheimer’s disease , 2001, Biological Psychiatry.

[30]  J. Zubieta,et al.  The Journal of Clinical Endocrinology & Metabolism Printed in U.S.A. Copyright © 2001 by The Endocrine Society Effects of Long-Term Hormone Therapy on Cholinergic Synaptic Concentrations in Healthy , 2022 .

[31]  E. Barrett-Connor,et al.  Effect of postmenopausal hormone therapy on cognitive function: the Heart and Estrogen/progestin Replacement Study. , 2002, The American journal of medicine.

[32]  T. Salthouse.  The processing-speed theory of adult age differences in cognition. , 1996, Psychological review.

[33]  Estrogen Replacement Therapy and Cognitive Function in Older Women , 1993 .

[34]  R. Lobo,et al.  Estrogen Improves Psychological Function in Asymptomatic Postmenopausal Women , 1991, Obstetrics and gynecology.

[35]  B. McEwen,et al.  Sex-dependent differences in estrogen regulation of choline acetyltransferase are altered by neonatal treatments. , 1986, Endocrinology.

[36]  C. Woolley,et al.  Roles of estradiol and progesterone in regulation of hippocampal dendritic spine density during the estrous cycle in the rat , 1993, The Journal of comparative neurology.

[37]  Leslie Carol Botha.  Estrogen Plus Progestin and the Incidence of Dementia and Mild Cognitive Impairment in Postmenopausal Women , 2003 .

[38]  P. Tariot,et al.  The effects of acute scopolamine in geriatric depression. , 1988, Archives of general psychiatry.

[39]  G. Dohanich,et al.  Acetylcholine Mediates the Estrogen-Induced Increase in NMDA Receptor Binding in CA1 of the Hippocampus and the Associated Improvement in Working Memory , 2001, The Journal of Neuroscience.

[40]  R. Dolan,et al.  Effects of Cholinergic Enhancement on Visual Stimulation, Spatial Attention, and Spatial Working Memory , 2004, Neuron.

[41]  T. Kupke,et al.  Relative influence of subject variables and neurological parameters on neuropsychological performance of adult seizure patients. , 1989, Archives of clinical neuropsychology : the official journal of the National Academy of Neuropsychologists.

[42]  L. Thal,et al.  Conjugated equine estrogens and global cognitive function in postmenopausal women: Women's Health Initiative Memory Study , 2004, JAMA.

[43]  B. Sherwin,et al.  Effects of estrogen on memory function in surgically menopausal women , 1992, Psychoneuroendocrinology.

[44]  F. Gengo,et al.  Possible acceleration of age effects on cognition following menopause. , 1995, Journal of psychiatric research.

[45]  P. Tariot,et al.  Scopolamine challenges in Alzheimer's disease , 2004, Psychopharmacology.

[46]  F. Sohrabji,et al.  Estrogen differentially regulates estrogen and nerve growth factor receptor mRNAs in adult sensory neurons. , 1994, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[47]  E. Cudahy,et al.  Qualitative analysis of scopolamine-induced amnesia , 2004, Psychopharmacology.

[48]  C. Reynolds,et al.  Wechsler memory scale-revised , 1988 .

[49]  M. Voytko,et al.  Cognitive function and its neural mechanisms in nonhuman primate models of aging, Alzheimer disease, and menopause. , 2004, Frontiers in bioscience : a journal and virtual library.

[50]  Toran-Allerand Cd.  The Estrogen/Neurotrophin Connection during Neural Development: Is Co-Localization of Estrogen Receptors with the Neurotrophins and Their Receptors Biologically Relevant? , 1996 .

[51]  D. B. Williams,et al.  Effects of hormone replacement therapy on cognitive performance in elderly women. , 2001, Maturitas.

[52]  B. McEwen,et al.  Neurotrophic and neuroprotective actions of estrogens and their therapeutic implications. , 2001, Annual review of pharmacology and toxicology.

[53]  J. Corwin,et al.  Acute nicotinic blockade produces cognitive impairment in normal humans , 2005, Psychopharmacology.

[54]  Robert B. Wallace,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. , 2003 .

[55]  J. Henningfield,et al.  Effects of atropine on the repeated acquisition and performance of response sequences in humans. , 1989, Journal of the experimental analysis of behavior.

[56]  R. Gibbs.  Expression of estrogen receptor-like immunoreactivity by different subgroups of basal forebrain cholinergic neurons in gonadectomized male and female rats , 1996, Brain Research.

[57]  B. Reisberg,et al.  Global Deterioration Scale (GDS). , 1988, Psychopharmacology bulletin.

[58]  D. Drachman,et al.  Memory and cognitive function in man , 1977, Neurology.

[59]  J. Simpkins,et al.  Role of estrogen replacement therapy in memory enhancement and the prevention of neuronal loss associated with Alzheimer's disease. , 1997, The American journal of medicine.

[60]  P. Tariot,et al.  Differential responsivity of mood, behavior and cognition to cholinergic agents in elderly neuropsychiatric populations , 1988, Brain Research Reviews.

[61]  Patrik Vuilleumier,et al.  Effects of attention and emotion on repetition priming and their modulation by cholinergic enhancement. , 2003, Journal of neurophysiology.

[62]  D. Panidis,et al.  The role of estrogen replacement therapy in Alzheimer's disease. , 2001, European journal of obstetrics, gynecology, and reproductive biology.

[63]  C. Toran-Allerand.  The estrogen/neurotrophin connection during neural development: is co-localization of estrogen receptors with the neurotrophins and their receptors biologically relevant? , 1996, Developmental neuroscience.

[64]  J. Overall,et al.  The Brief Psychiatric Rating Scale , 1962 .

[65]  M. Voytko,et al.  Effects of two years of estrogen loss or replacement on nucleus basalis cholinergic neurons and cholinergic fibers to the dorsolateral prefrontal and inferior parietal cortex of monkeys , 2004, The Journal of comparative neurology.

[66]  H Helenius,et al.  The Effect of Short‐Term Estrogen Replacement Therapy on Cognition: A Randomized, Double‐Blind, Cross‐Over Trial in Postmenopausal Women , 1998, Obstetrics and gynecology.

[67]  A. Hofman,et al.  Silent brain infarcts and the risk of dementia and cognitive decline. , 2003, The New England journal of medicine.

[68]  V. Henderson,et al.  Estrogen deficiency and risk of Alzheimer's disease in women. , 1994, American journal of epidemiology.

[69]  H. Weingartner,et al.  Human serial learning: enhancement with arecholine and choline impairment with scopolamine. , 1978, Science.

[70]  J. Zubieta,et al.  Long-term estrogen replacement is associated with improved nonverbal memory and attentional measures in postmenopausal women. , 2001, Fertility and sterility.

[71]  M. Packard.  Posttraining Estrogen and Memory Modulation , 1998, Hormones and Behavior.

[72]  Richard F. Thompson,et al.  Cyclic changes in estradiol regulate synaptic plasticity through the MAP kinase pathway , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[73]  H. Buschke,et al.  Cognitive performance in surgically menopausal women on estrogen , 2000, Neurology.

[74]  M. Sarter,et al.  Effects of ovariectomy, 192 IgG-saporin-induced cortical cholinergic deafferentation, and administration of estradiol on sustained attention performance in rats. , 1999, Behavioral neuroscience.

[75]  D. Pfaff,et al.  Effects of Estrogen Replacement on the Relative Levels of Choline Acetyltransferase, trkA, and Nerve Growth Factor Messenger RNAs in the Basal Forebrain and Hippocampal Formation of Adult Rats , 1994, Experimental Neurology.

[76]  M. Lorr,et al.  Profile of mood states , 1971 .

[77]  L. Greene,et al.  Reciprocal regulation of estrogen and NGF receptors by their ligands in PC12 cells. , 1994, Journal of neurobiology.

[78]  Yaakov Stern,et al.  Effect of oestrogen during menopause on risk and age at onset of Alzheimer's disease , 1996, The Lancet.

[79]  R. Petersen,et al.  Scopolamine induced learning failures in man , 1977, Psychopharmacology.

[80]  Brenda L Plassman,et al.  Hormone replacement therapy and incidence of Alzheimer disease in older women: the Cache County Study. , 2002, JAMA.

[81]  C. Singer,et al.  The effects of ovariectomy and estrogen replacement on trkA and choline acetyltransferase mRNA expression in the basal forebrain of the adult female Sprague-Dawley rat , 1996, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[82]  S. Folstein,et al.  "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. , 1975, Journal of psychiatric research.

[83]  J. Corwin,et al.  Age-Related Effects of the Nicotinic Antagonist Mecamylamine on Cognition and Behavior , 1994, Neuropsychopharmacology.

[84]  D. Wechsler.  Wechsler Adult Intelligence Scale , 2021, Encyclopedia of Evolutionary Psychological Science.

[85]  David Wechsler,et al.  Wechsler Memory scale. , 2005 .

[86]  L. Mozley,et al.  Pilot study on the effect of estrogen replacement therapy on brain dopamine transporter availability in healthy, postmenopausal women. , 2004, The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry.

[87]  S. Resnick,et al.  Estrogen replacement therapy and longitudinal decline in visual memory , 1997, Neurology.