Original article| Volume 54, ISSUE 1, P59-69, July 01, 2003

Influence of estradiol, stress, and 5-HT2A agonist treatment on Brain-Derived Neurotrophic Factor expression in female rats

  • Idil Cavus
    Address reprint requests to Idil Cavus, M.D., Ph.D., Yale University, Psychiatry Department, Connecticut Mental Health Center, Room S-309, 34 Park St, New Haven CT 06511, USA.
    Division of Molecular Psychiatry, Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, Yale University School of Medicine, New Haven, Connecticut, USA
    Search for articles by this author
  • Ronald S. Duman
    Division of Molecular Psychiatry, Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, Yale University School of Medicine, New Haven, Connecticut, USA
    Search for articles by this author



      Estradiol affects neuronal plasticity, mood, and cognition. We examined the effects of the estrous cycle, acute and chronic estradiol treatments on BDNF mRNA expression in the hippocampus and cortex of female rats. The roles of 5-HT2A receptors and of stress on the BDNF mRNA regulation were also explored.


      BDNF mRNA levels were measured using in situ hybridization at proestrus and estrus, and following acute and chronic estradiol treatment of acutely and chronically ovariectomized (OVX) female rats. Some rats were pretreated with 5-HT2A agonist and antagonist, and another group was subjected to two-hour immobilization stress.


      BDNF mRNA levels in the dentate gyrus and the medial prefrontal cortex were decreased during estrus, when estradiol levels are highest. Acute estradiol treatment decreased hippocampal BDNF mRNA in acutely OVX rats, but neither acute nor chronic estradiol had effect in chronically OVX rats. Estradiol pretreatment reduced the 5-HT2A receptor-mediated cortical upregulation in BDNF mRNA and did not effect the stress-induced down-regulation of BDNF mRNA in the dentate gyrus.


      The duration of the estradiol treatment and the duration of the ovarian hormone deprivation are important factors in the regulation of BDNF synthesis and possibly in the functional outcome of estrogen treatment.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Adams M.M.
        • Oung T.
        • Morrison J.H.
        • Gore A.C.
        Length of postovariectomy interval and age, but not estrogen replacement, regulate N-methyl-D-aspartate receptor mRNA levels in the hippocampus of female rats.
        Exp Neurol. 2001; 170: 345-356
        • Ahokas A.
        • Aito M.
        • Rimon R.
        Positive treatment effect of estradiol in postpartum psychosis.
        J Clin Psychiatry. 2000; 61: 166-169
        • Ahokas A.
        • Kaukoranta J.
        • Wahlbeck K.
        • Aito M.
        Estrogen deficiency in severe postpartum depression.
        J Clin Psychiatry. 2001; 62: 332-336
        • Altar C.A.
        Neurotrophins and depression.
        Trends Pharmacol Sci. 1999; 20: 59-61
        • Angelucci F.
        • Mathe A.A.
        • Aloe L.
        Brain-derived neurotrophic factor and tyrosine kinase receptor TrkB in rat brain are significantly altered after haloperidol and risperidone administration.
        J Neurosci Res. 2000; 60: 783-794
        • Behl C.
        Oestrogen as a neuroprotective hormone.
        Nat Rev Neurosci. 2002; 3: 433-442
        • Berchtold N.C.
        • Kesslak J.P.
        • Pike C.J.
        • Adlard P.A.
        • Cotman C.W.
        Estrogen and exercise interact to regulate brain-derived neurotrophic factor mRNA and protein expression in the hippocampus.
        Eur J Neurosci. 2001; 14: 1992-2002
        • Berendsen H.H.
        Interactions between 5-hydroxytryptamine receptor subtypes.
        Pharmacol Ther. 1995; 66: 17-37
        • Bethea C.L.
        • Mirkes S.J.
        • Shively C.A.
        • Adams M.R.
        Steroid regulation of tryptophan hydroxylase protein in the dorsal raphe of macaques.
        Biol Psychiatry. 2000; 47: 562-576
        • Biegon A.
        • McEwen B.S.
        Modulation by estradiol of serotonin receptors in brain.
        J Neurosci. 1982; 2: 199-205
        • Bremner J.D.
        • Randall P.
        • Scott T.M.
        • Bronen R.A.
        • Seibyl J.P.
        • Southwick S.M.
        • et al.
        MRI-based measurement of hippocampal volume in patients with combat-related posttraumatic stress disorder.
        Am J Psychiatry. 1995; 152: 973-981
        • Chen B.
        • Dowlatshahi D.
        • MacQueen G.M.
        • Wang J.F.
        • Young L.T.
        Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant medication.
        Biol Psychiatry. 2001; 50: 260-265
        • Cyr M.
        • Bosse R.
        • Di Paolo T.
        Gonadal hormones modulate 5-hydroxytryptamine2A receptors.
        Neuroscience. 1998; 83: 829-836
        • Cyr M.
        • Landry M.
        • Di Paolo T.
        Modulation by estrogen-receptor directed drugs of 5-hydroxytryptamine-2A receptors in rat brain.
        Neuropsychopharmacology. 2000; 23: 69-78
        • Cyr M.
        • Ghribi O.
        • Di Paolo T.
        Regional and selective effects of oestradiol and progesterone on NMDA and AMPA receptors in the rat brain.
        J Neuroendocrinol. 2000; 12: 445-452
        • Dudley M.W.
        • Wiech N.L.
        • Miller F.P.
        • Carr A.A.
        • Cheng H.C.
        • Roebel L.E.
        • et al.
        Pharmacological effects of MDL 11 939.
        Drug Dev Res. 1988; 13: 29-43
        • Duman R.S.
        Novel therapeutic approaches beyond the serotonin receptor.
        Biol Psychiatry. 1998; 44: 324-335
        • Duman R.S.
        • Malberg J.
        • Nakagawa S.
        • D’Sa C.
        Neuronal plasticity and survival in mood disorders.
        Biol Psychiatry. 2000; 48: 732-739
        • Galea L.A.
        • McEwen B.S.
        • Tanapat P.
        • Deak T.
        • Spencer R.L.
        • Dhabhar F.S.
        Sex differences in dendritic atrophy of CA3 pyramidal neurons in response to chronic restraint stress.
        Neuroscience. 1997; 81: 689-697
        • Galea L.A.
        • Wide J.K.
        • Barr A.M.
        Estradiol alleviates depressive-like symptoms in a novel animal model of post-partum depression.
        Behav Brain Res. 2001; 122: 1-9
        • Galea L.A.
        • Wide J.K.
        • Paine T.A.
        • Holmes M.M.
        • Ormerod B.K.
        • Floresco S.B.
        High levels of estradiol disrupt conditioned place preference learning, stimulus response learning and reference memory but have limited effects on working memory.
        Behav Brain Res. 2001; 126: 115-126
        • Garey L.J.
        • Ong W.Y.
        • Patel T.S.
        • Kanani M.
        • Davis A.
        • Mortimer A.M.
        • et al.
        Reduced dendritic spine density on cerebral cortical pyramidal neurons in schizophrenia.
        J Neurol Neurosurg Psychiatry. 1998; 65: 446-453
        • Gellman R.L.
        • Aghajanian G.K.
        Serotonin2 receptor-mediated excitation of interneurons in piriform cortex.
        Neuroscience. 1994; 58: 515-525
        • Gibbs R.B.
        Levels of trkA and BDNF mRNA, but not NGF mRNA, fluctuate across the estrous cycle and increase in response to acute hormone replacement.
        Brain Res. 1998; 787: 259-268
        • Gibbs R.B.
        Treatment with estrogen and progesterone affects relative levels of brain-derived neurotrophic factor mRNA and protein in different regions of the adult rat brain.
        Brain Res. 1999; 844: 20-27
        • Gibbs R.B.
        • Aggarwal P.
        Estrogen and basal forebrain cholinergic neurons.
        Horm Behav. 1998; 34: 98-111
        • Glantz L.A.
        • Lewis D.A.
        Decreased dendritic spine density on prefrontal cortical pyramidal neurons in schizophrenia.
        Arch Gen Psychiatry. 2000; 57: 65-73
        • Hogervorst E.
        • Williams J.
        • Budge M.
        • Riedel W.
        • Jolles J.
        The nature of the effect of female gonadal hormone replacement therapy on cognitive function in post-menopausal women.
        Neuroscience. 2000; 101: 485-512
        • Horch H.W.
        • Kruttgen A.
        • Portbury S.D.
        • Katz L.C.
        Destabilization of cortical dendrites and spines by BDNF.
        Neuron. 1999; 23: 353-364
        • Jezierski M.K.
        • Sohrabji F.
        Region- and peptide-specific regulation of the neurotrophins by estrogen.
        Brain Res Mol Brain Res. 2000; 85: 77-84
        • Joffe H.
        • Cohen L.S.
        Estrogen, serotonin, and mood disturbance.
        Biol Psychiatry. 1998; 44: 798-811
        • Kessler R.C.
        • McGonagle K.A.
        • Nelson C.B.
        • Hughes M.
        • Swartz M.
        • Blazer D.G.
        Sex and depression in the National Comorbidity Survey. II.
        J Affect Disord. 1994; 30: 15-26
        • Kuroda Y.
        • McEwen B.S.
        Effect of chronic restraint stress and tianeptine on growth factors, growth-associated protein-43 and microtubule-associated protein 2 mRNA expression in the rat hippocampus.
        Brain Res Mol Brain Res. 1998; 59: 35-39
        • LeBlanc E.S.
        • Janowsky J.
        • Chan B.K.
        • Nelson H.D.
        Hormone replacement therapy and cognition.
        JAMA. 2001; 285: 1489-1499
        • Levy A.D.
        • Van de Kar L.D.
        Endocrine and receptor pharmacology of serotonergic anxiolytics, antipsychotics and antidepressants.
        Life Sci. 1992; 51: 83-94
        • Lu B.
        • Chow A.
        Neurotrophins and hippocampal synaptic transmission and plasticity.
        J Neurosci Res. 1999; 58: 76-87
        • Luine V.N.
        • Richards S.T.
        • Wu V.Y.
        • Beck K.D.
        Estradiol enhances learning and memory in a spatial memory task and effects levels of monoaminergic neurotransmitters.
        Horm Behav. 1998; 34: 149-162
        • Mamounas L.A.
        • Altar C.A.
        • Blue M.E.
        • Kaplan D.R.
        • Tessarollo L.
        • Lyons W.E.
        BDNF promotes the regenerative sprouting, but not survival, of injured serotonergic axons in the adult rat brain.
        J Neurosci. 2000; 20: 771-782
        • Mamounas L.A.
        • Blue M.E.
        • Siuciak J.A.
        • Altar C.A.
        Brain-derived neurotrophic factor promotes the survival and sprouting of serotonergic axons in rat brain.
        J Neurosci. 1995; 15: 7929-7939
        • McEwen B.S.
        Estrogens effects on the brain.
        J Appl Physiol. 2001; 91: 2785-2801
        • McQueen J.K.
        • Wilson H.
        • Fink G.
        Estradiol-17 beta increases serotonin transporter (SERT) mRNA levels and the density of SERT-binding sites in female rat brain.
        Brain Res Mol Brain Res. 1997; 45: 13-23
        • Miranda P.
        • Williams C.L.
        • Einstein G.
        Granule cells in aging rats are sexually dimorphic in their response to estradiol.
        J Neurosci. 1999; 19: 3316-3325
        • Mulnard R.A.
        • Cotman C.W.
        • Kawas C.
        • van Dyck C.H.
        • Sano M.
        • Doody R.
        • et al.
        Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease.
        JAMA. 2000; 283: 1007-1015
        • Murer M.G.
        • Yan Q.
        • Raisman-Vozari R.
        Brain-derived neurotrophic factor in the control human brain, and in Alzheimer’s disease and Parkinson’s disease.
        Prog Neurobiol. 2001; 63: 71-124
        • Murphy D.D.
        • Cole N.B.
        • Greenberger V.
        • Segal M.
        Estradiol increases dendritic spine density by reducing GABA neurotransmission in hippocampal neurons.
        J Neurosci. 1998; 18: 2550-2559
        • Murphy D.D.
        • Cole N.B.
        • Segal M.
        Brain-derived neurotrophic factor mediates estradiol-induced dendritic spine formation in hippocampal neurons.
        Proc Natl Acad Sci U S A. 1998; 95: 11412-11417
        • Nibuya M.
        • Morinobu S.
        • Duman R.S.
        Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments.
        J Neurosci. 1995; 15: 753-7547
        • Nitta A.
        • Ohmiya M.
        • Sometani A.
        • Itoh M.
        • Nomoto H.
        • Furukawa Y.
        • et al.
        Brain-derived neurotrophic factor prevents neuronal cell death induced by corticosterone.
        J Neurosci Res. 1999; 57: 227-235
        • Osterlund M.K.
        • Halldin C.
        • Hurd Y.L.
        Effects of chronic 17 beta-estradiol treatment on the serotonin 5-HT1A receptor mRNA and binding levels in the rat brain.
        Synapse. 2000; 35: 39-44
        • Pecins-Thompson M.
        • Brown N.A.
        • Kohama S.G.
        • Bethea C.L.
        Ovarian steroid regulation of tryptophan hydroxylase mRNA expression in rhesus macaques.
        J Neurosci. 1996; 16: 7021-7029
        • Rosoklija G.
        • Toomayan G.
        • Ellis S.P.
        • Kelip J.
        • Mann J.J.
        • Latov N.
        • et al.
        Structural abnormalities of subicular dendrites in subjects with schizophrenia and mood disorders.
        Arch Gen Psychiatry. 2000; 57: 349-356
        • Rudick C.N.
        • Woolley C.S.
        Estrogen regulates functional inhibition of hippocampal CA1 pyramidal cells in the adult female rat.
        Neuroscience. 2001; 21: 6532-6543
        • Rutherford L.C.
        • Nelson S.B.
        • Turrigiano G.G.
        BDNF has opposite effects on the quantal amplitude of pyramidal neuron and interneuron excitatory synapses.
        Neuron. 1998; 21: 521-530
        • Shirayama Y.
        • Chen A.C.
        • Nakagawa S.
        • Russell D.S.
        • Duman R.S.
        Brain-derived neurotrophic factor produces antidepressant effects in behavioral models of depression.
        J Neurosci. 2002; 22: 3251-3261
        • Shors T.J.
        • Chua C.
        • Falduto J.
        Sex differences and opposite effects of stress on dendritic spine density in the male versus female hippocampus.
        J Neurosci. 2001; 21: 6292-6297
        • Singh M.
        • Meyer E.M.
        • Simpkins J.W.
        The effect of ovariectomy and estradiol replacement on brain-derived neurotrophic factor messenger ribonucleic acid expression in cortical and hippocampal brain regions of female Sprague-Dawley rats.
        Endocrinology. 1995; 136: 2320-2324
        • Siuciak J.A.
        • Clark M.S.
        • Rind H.B.
        • Whittemore S.R.
        • Russo A.F.
        BDNF induction of tryptophan hydroxylase mRNA levels in the rat brain.
        J Neurosci Res. 1998; 52: 149-158
        • Smith M.S.
        • Freeman M.E.
        • Neill J.D.
        The control of progesterone secretion during the estrous cycle and early pseudopregnancy in the rat.
        Endocrinology. 1975; 96: 219-226
        • Smith M.A.
        • Makino S.
        • Kvetnansky R.
        • Post R.M.
        Stress and glucocorticoids affect the expression of brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus.
        J Neurosci. 1995; 15: 1768-1777
        • Sohrabji F.
        • Miranda R.C.
        • Toran-Allerand C.D.
        Identification of a putative estrogen response element in the gene encoding brain-derived neurotrophic factor.
        Proc Natl Acad Sci U S A. 1995; 92: 11110-11114
        • Sumner B.E.
        • Fink G.
        Estrogen increases the density of 5-hydroxytryptamine(2A) receptors in cerebral cortex and nucleus accumbens in the female rat.
        J Steroid Biochem Mol Biol. 1995; 54: 15-20
        • Sumner B.E.
        • Fink G.
        Testosterone as well as estrogen increases serotonin2A receptor mRNA and binding site densities in the male rat brain.
        Brain Res Mol Brain Res. 1998; 59: 205-214
        • Sumner B.E.
        • Grant K.E.
        • Rosie R.
        • Hegele-Hartung C.
        • Fritzemeier K.H.
        • Fink G.
        Effects of tamoxifen on serotonin transporter and 5-hydroxytryptamine(2A) receptor binding sites and mRNA levels in the brain of OVX rats with or without acute estradiol replacement.
        Mol Brain Res. 1999; 73: 119-128
        • Sunanda
        • Rao M.S.
        • Raju T.R.
        Effect of chronic restraint stress on dendritic spines and excrescences of hippocampal CA3 pyramidal neurons-a quantitative study.
        Brain Res. 1995; 694: 312-317
        • Takahashi M.
        • Shirakawa O.
        • Toyooka K.
        • Kitamura N.
        • Hashimoto T.
        • Maeda K.
        • et al.
        Abnormal expression of brain-derived neurotrophic factor and its receptor in the corticolimbic system of schizophrenic patients.
        Mol Psychiatry. 2000; 5: 293-300
        • Thoenen H.
        Neurotrophins and activity-dependent plasticity.
        Prog Brain Res. 2000; 128: 183-191
        • Titeler M.
        • Lyon R.A.
        • Glennon R.A.
        Radioligand binding evidence implicates the brain 5-HT2 receptor as a site of action for LSD and phenylisopropylamine hallucinogens.
        Psychopharmacology (Berl). 1988; 94: 213-216
        • Turrigiano G.G.
        Homeostatic plasticity in neuronal networks.
        Trends Neurosci. 1999; 22: 221-227
        • Vaidya V.A.
        • Marek G.J.
        • Aghajanian G.K.
        • Duman R.S.
        5-HT2A receptor-mediated regulation of brain-derived neurotrophic factor mRNA in the hippocampus and the neocortex.
        J Neurosci. 1997; 17: 2785-2795
        • Vaidya V.A.
        • Terwilliger R.M.
        • Duman R.S.
        Role of 5-HT2A receptors in the stress-induced down-regulation of brain-derived neurotrophic factor expression in rat hippocampus.
        Neurosci Lett. 1999; 262: 1-4
        • Watanabe Y.
        • Gould E.
        • McEwen B.S.
        Stress induces atrophy of apical dendrites of hippocampal CA3 pyramidal neurons.
        Brain Res. 1992; 588: 341-345
        • Woolley C.S.
        • Gould E.
        • Frankfurt M.
        • McEwen B.S.
        Naturally occurring fluctuation in dendritic spine density on adult hippocampal pyramidal neurons.
        J Neurosci. 1990; 10: 4035-4039
        • Woolley C.S.
        • Gould E.
        • McEwen B.S.
        Exposure to excess glucocorticoids alters dendritic morphology of adult hippocampal pyramidal neurons.
        Brain Res. 1990; 531: 22-231
        • Woolley C.S.
        • McEwen B.S.
        Estradiol mediates fluctuation in hippocampal synapse density during the estrous cycle in the adult rat.
        J Neurosci. 1992; 12: 2549-2554
        • Woolley C.S.
        • McEwen B.S.
        Roles of estradiol and progesterone in regulation of hippocampal dendritic spine density during the estrous cycle in the rat.
        J Comp Neurol. 1993; 336: 293-306
        • Yamada K.
        • Mizuno M.
        • Nabeshima T.
        Role for brain-derived neurotrophic factor in learning and memory.
        Life Sci. 2002; 70: 735-744
        • Young E.
        • Korszun A.
        Psychoneuroendocrinology of depression. Hypothalamic-pituitary-gonadal axis.
        Psychiatr Clin North Am. 1998; 21: 309-323
        • Young E.A.
        • Altemus M.
        • Parkison V.
        • Shastry S.
        Effects of estrogen antagonists and agonists on the ACTH response to restraint stress in female rats.
        Neuropsychopharmacology. 2001; 25: 881-891
        • Zafra F.
        • Castren E.
        • Thoenen H.
        • Lindholm D.
        Interplay between glutamate and gamma-aminobutyric acid transmitter systems in the physiological regulation of brain-derived neurotrophic factor and nerve growth factor synthesis in hippocampal neurons.
        Proc Natl Acad Sci U S A. 1991; 88: 10037-10041
        • Zetterstrom T.S.
        • Pei Q.
        • Madhav T.R.
        • Coppell A.L.
        • Lewis L.
        • Grahame-Smith D.G.
        Manipulations of brain 5-HT levels affect gene expression for BDNF in rat brain.
        Neuropharmacology. 1999; 38: 1063-1073
        • Zhang J.Q.
        • Cai W.Q.
        • Zhou S.
        • Su B.Y.
        Distribution and differences of estrogen receptor beta immunoreactivity in the brain of adult male and female rats.
        Brain Res. 2002; 935: 73-80
        • Zweifel J.E.
        • O’Brien W.H.
        A meta-analysis of the effect of hormone replacement therapy upon depressed mood.
        Psychoneuroendocrinology. 1997; 22: 189-212