Research Article| Volume 50, ISSUE 4, P260-265, August 15, 2001

Download started.


Increased hippocampal bdnf immunoreactivity in subjects treated with antidepressant medication


      Background: The cAMP signaling pathway, and its downstream neurotrophic factor BDNF, are major targets of antidepressant medications. Abnormalities in this pathway have previously been reported in postmortem brain of subjects with mood disorders. This study was designed to test whether the diagnosis of a mood disorder, or treatment with an antidepressant or mood stabilizer was associated with changes in hippocampal BDNF in postmortem brain
      Methods: Frozen postmortem anterior hippocampus sections were obtained from the Stanley Foundation Neuropathology Consortium. Tissue from subjects with major depression, bipolar disorder, schizophrenia and nonpsychiatric control subjects were stained for BDNF using immunohistochemistry
      Results: Increased BDNF expression was found in dentate gyrus, hilus and supragranular regions in subjects treated with antidepressant medications at the time of death, compared with antidepressant-untreated subjects. Furthermore, there was a trend toward increased BDNF expression in hilar and supragranular regions in depressed subjects treated with antidepressants, compared with the subjects not on these medications at the time of death
      Conclusions: These findings are consistent with recent studies measuring CREB levels in this same subject sample, and support current animal and cellular models of antidepressant function.


      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


        • Bayer T.
        • Schramm M.
        • Feldmann N.
        • Knable M.
        • Falkai P.
        Antidepressant drug exposure is associated with mRNA levels of tyrosine receptor kinase B in major depressive disorder.
        Prog Neuropsychopharm Biol Psych. 2000; 24: 881-888
        • Bremner J.D.
        • Narayan M.
        • Anderson E.R.
        • Staib L.H.
        • Miller H.L.
        • Charney D.S.
        Hippocampal volume reduction in major depression.
        Am J Psychiatry. 2000; 157: 115-118
        • Cowburn R.F.
        • Marcusson J.O.
        • Eriksson A.
        • Wiehager B.
        • O’Neill C.
        Adenylyl cyclase activity and G-protein subunit levels in postmortem frontal cortex of suicide victims.
        Brain Res. 1994; 633: 297-304
        • Dowlatshahi D.
        • MacQueen G.M.
        • Wang J.F.
        • Young L.T.
        Increased temporal cortex CREB concentrations and antidepressant treatment in major depression.
        Lancet. 1998; 352: 1754-1755
        • Dowlatshahi D.
        • MacQueen G.M.
        • Wang J.F.
        • Reiach J.S.
        • Young L.T.
        G Protein-coupled cyclic AMP signaling in postmortem brain of subjects with mood disorders.
        J Neurochem. 1999; 73: 1121-1126
        • Duman R.S.
        • Heninger G.R.
        • Nestler E.J.
        A molecular and cellular theory of depression.
        Arch Gen Psychiatry. 1997; 54: 597-606
        • Earnest D.J.
        • Liang F.Q.
        • Ratcliff M.
        • Cassone V.M.
        Immortal time.
        Science. 1999; 283: 693-695
        • Fitzgerald L.R.
        • Vaidya V.A.
        • Terwilliger R.Z.
        • Duman R.S.
        Electroconvulsive seizure increases the expression of CREM (cyclic AMP response element modulator) and ICER (inducible cyclic AMP early repressor) in rat brain.
        J Neurochem. 1996; 66: 429-432
        • Fujimaki K.
        • Morinobu S.
        • Duman R.S.
        Administration of a cAMP phosphodiesterase 4 inhibitor enhances antidepressant-induction of BDNF mRNA in rat hippocampus.
        Neuropsychopharmacology. 2000; 22: 42-51
        • Hock C.
        • Heese K.
        • Hulette C.
        • Rosenberg C.
        • Otten U.
        Region-specific neurotrophin imbalances in Alzheimer disease.
        Arch Neurol. 2000; 57: 846-851
        • Jensen J.B.
        • Mikkelsen J.D.
        • Mork A.
        Increased adenylyl cyclase type 1 mRNA, but not adenylyl cyclase type 2 in the rat hippocampus following antidepressant treatment.
        Eur Neuropsychopharmacol. 2000; 10: 105-111
        • Jeon S.H.
        • Seong Y.S.
        • Juhnn Y.S.
        • Kang U.G.
        • Ha K.S.
        • Kim Y.S.
        • et al.
        Electroconvulsive shock increases the phosphorylation of cyclic AMP response element binding protein at Ser-133 in rat hippocampus but not in cerebellum.
        Neuropharmacology. 1997; 36: 411-414
        • Kerschenstainer M.
        • Gallmeier E.
        • Behrens L.
        • Leal V.V.
        • Misgeld T.
        • Klinkert W.E.F.
        • et al.
        Activated human T cells, B cells, and monocytes produce BDNF in vitro and in inflammatory brain lesions.
        J Exp Med. 1999; 189: 865-870
        • Lowther S.
        • Katona C.L.
        • Crompton M.R.
        • Horton R.W.
        Brain [3H]cAMP binding sites are unaltered in depressed suicides, but decreased by antidepressants.
        Brain Res. 1997; 758: 223-228
        • Mori S.
        • Zanardi R.
        • Popoli M.
        • Garbini S.
        • Brunello N.
        • Smeraldi E.
        • et al.
        CAMP-dependent phosphorylation system after short and long-term administration of moclobemide.
        J Psychiatr Res. 1998; 32: 111-115
        • Murer M.G.
        • Boissiere F.
        • Yan Q.
        • Hunot S.
        • Villares J.
        An immunohistochemical study of the distribution of brain-derived neurotrophic factor in the adult human brain, with particular reference to Alzheimer’s disease.
        Neuroscience. 1999; 88: 1015-1032
        • 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: 7539-7547
        • Nibuya M.
        • Nestler E.J.
        • Duman R.S.
        Chronic antidepressant administration increases the expression of cAMP response element binding protein (CREB) in rat hippocampus.
        J Neurosci. 1996; 16: 2365-2372
        • Pilc A.
        • Legutko B.
        Antidepressant treatment influences cyclic AMP accumulation induced by excitatory amino acids in rat brain.
        Pol J Pharmacol. 1995; 47: 359-361
        • Pilc A.
        • Legutko B.
        The influence of prolonged antidepressant treatment on the changes in cyclic AMP accumulation induced by excitatory amino acids in rat cerebral cortical slices.
        Neuroreport. 1995; 7: 85-88
        • Reiach J.S.
        • Li P.P.
        • Warsh J.J.
        • Kish S.J.
        • Young L.T.
        Reduced adenylyl cyclase immunolabeling and activity in postmortem temporal cortex of depressed suicide victims.
        J Affect Disord. 1999; 56: 141-151
        • Sheline Y.I.
        • Wang P.W.
        • Gado M.H.
        • Csernansky J.G.
        • Vannier M.W.
        Hippocampal atrophy in recurrent major depression.
        Proc Natl Acad Sci USA. 1996; 93: 3908-3913
        • Sheline Y.I.
        • Sanghavi M.
        • Mintun M.A.
        • Gado M.H.
        Depression duration but not age predicts hippocampal volume loss in medically healthy women with recurrent major depression.
        J Neurosci. 1999; 19: 5034-5043
        • Shimizu M.
        • Nishida A.
        • Fukuda H.
        • Saito H.
        • Yamawaki S.
        Enhancement of cyclic AMP accumulation mediated by 5-HT after chronic amitriptyline treatment in NG 108–15 cells.
        Br J Pharmacol. 1995; 114: 1282-1288
        • Takahashi M.
        • Terwilliger R.
        • Lane C.
        • Mezes P.S.
        • Conti M.
        • Duman R.S.
        Chronic antidepressant administration increases the expression of cAMP-specific phosphodiesterase 4A and 4B isoforms.
        J Neurosci. 1999; 19: 610-618
        • Thome J.
        • Sakai N.
        • Shin K.
        • Steffen C.
        • Zhang Y.J.
        • Impey S.
        • Storm D.
        • Duman R.S.
        Cyclic AMP response element-mediated gene transcription is upregulated by chronic antidepressant treatment.
        J Neurosci. 2000; 20: 4030-4036
        • Wang J.F.
        • Bown C.
        • Young L.T.
        Differential display PCR reveals novel targets for the mood stabilizing drug valproate including the molecular chaperone GRP78.
        Molec Pharmacol. 1999; 55: 521-527