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Pharmacopsychiatry 2010; 43(5): 174-178
DOI: 10.1055/s-0030-1249095
Original Paper

© Georg Thieme Verlag KG Stuttgart · New York

Finasteride Treatment Inhibits Adult Hippocampal Neurogenesis in Male Mice

B. Römer1 , N. Pfeiffer1 , S. Lewicka2 , N. Ben-Abdallah1 , M. A. Vogt1 , M. Deuschle1 , B. Vollmayr1 , P. Gass1
  • 1RG Behavioural Biology, Central Institute of Mental Health, Mannheim, University of Heidelberg, Germany
  • 2Department of Pharmacology, University of Heidelberg, Germany
Further Information

Publication History

received 02.06.2009 revised 27.01.2010

accepted 29.01.2010

Publication Date:
18 May 2010 (online)

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Abstract

Introduction: The 5-alpha-reductase inhibitor finasteride is used for the treatment of androgenic alopecia, benign prostate hyperplasia and prostate cancer. Besides inhibiting the conversion of testosterone to the biologically more active 5α-dihydrotestosterone, it also inhibits the production of neurosteroids. Decreased neurosteroid levels are postulated to be involved in the pathophysiology of psychiatric disorders such as depression. As neurosteroids metabolized by 5-alpha-reductase influence neural plasticity, we investigated whether finasteride treatment alters adult hippocampal neurogenesis, implicated in the pathophysiology of depression.

Methods: Male C57BL/6N mice were treated subchronically (7 days) with finasteride or vehicle. Adult neurogenesis was assessed at two different time points after treatment (day 1; day 35) using immunohistochemistry.

Results: Finasteride treatment led to a significant decrease in brain 5α-dihydrotestosterone levels and induced a reversible reduction in the number of newborn cells and young neurons in the hippocampus. 35 days after the last finasteride injection, neurogenesis had returned to normal.

Discussion: These data indicate that inhibition of 5-alpha-reductase activity by finasteride treatment influences neuronal plasticity on a structural level. These changes might contribute to the pathophysiology of depressive episodes observed after finasteride treatment.

References

  • 1 Agis-Balboa RC, Pinna G, Pibiri F. et al . Down-regulation of neurosteroid biosynthesis in corticolimbic circuits mediates social isolation-induced behavior in mice.  Proc Natl Acad Sci USA. 2007;  104 18736-18741
    CrossrefPubMedGoogle Scholar
  • 2 Agis-Balboa RC, Pinna G, Zhubi A. et al . Characterization of brain neurons that express enzymes mediating neurosteroid biosynthesis.  Proc Natl Acad Sci USA. 2006;  103 14602-14607
    CrossrefPubMedGoogle Scholar
  • 3 Altomare G, Capella GL. Depression circumstantially related to the administration of finasteride for androgenetic alopecia.  J Dermatol. 2002;  29 665-669
    PubMedGoogle Scholar
  • 4 Bartsch G, Rittmaster RS, Klocker H. Dihydrotestosterone and the concept of 5alpha-reductase inhibition in human benign prostatic hyperplasia.  World J Urol. 2002;  19 413-425
    PubMedGoogle Scholar
  • 5 Brinton RD, Wang JM. Preclinical analyses of the therapeutic potential of allopregnanolone to promote neurogenesis in vitro and in vivo in transgenic mouse model of Alzheimer's disease.  Curr Alzheimer Res. 2006;  3 11-17
    CrossrefPubMedGoogle Scholar
  • 6 Charalampopoulos I, Alexaki VI, Tsatsanis C. et al . Neurosteroids as endogenous inhibitors of neuronal cell apoptosis in aging.  Ann N Y Acad Sci. 2006;  1088 139-152
    CrossrefPubMedGoogle Scholar
  • 7 Charalampopoulos I, Remboutsika E, Margioris AN. et al . Neurosteroids as modulators of neurogenesis and neuronal survival.  Trends Endocrinol Metab. 2008;  19 300-307
    CrossrefPubMedGoogle Scholar
  • 8 Ciriza I, Carrero P, Frye CA. et al . Reduced metabolites mediate neuroprotective effects of progesterone in the adult rat hippocampus. The synthetic progestin medroxyprogesterone acetate (Provera) is not neuroprotective.  J Neurobiol. 2006;  66 916-928
    CrossrefPubMedGoogle Scholar
  • 9 Couillard-Despres S, Winner B, Schaubeck S. et al . Doublecortin expression levels in adult brain reflect neurogenesis.  Eur J Neurosci. 2005;  21 1-14
    CrossrefPubMedGoogle Scholar
  • 10 Djebaili M, Guo Q, Pettus EH. et al . The neurosteroids progesterone and allopregnanolone reduce cell death, gliosis, and functional deficits after traumatic brain injury in rats.  J Neurotrauma. 2005;  22 106-118
    CrossrefPubMedGoogle Scholar
  • 11 Djebaili M, Hoffman SW, Stein DG. Allopregnanolone and progesterone decrease cell death and cognitive deficits after a contusion of the rat pre-frontal cortex.  Neuroscience. 2004;  123 349-359
    CrossrefPubMedGoogle Scholar
  • 12 Duskova M, Hill M, Hanus M. et al . Finasteride treatment and neuroactive steroid formation.  Prague Med Rep. 2009;  110 222-230
    PubMedGoogle Scholar
  • 13 Eser D, Baghai TC, Schule C. et al . Neuroactive steroids as endogenous modulators of anxiety.  Curr Pharm Des. 2008;  14 3525-3533
    CrossrefPubMedGoogle Scholar
  • 14 Eser D, Schule C, Baghai TC. et al . Neuroactive steroids and affective disorders.  Pharmacol Biochem Behav. 2006;  84 656-666
    CrossrefPubMedGoogle Scholar
  • 15 Eser D, Schule C, Baghai TC. et al . Neuroactive steroids in depression and anxiety disorders: clinical studies.  Neuroendocrinology. 2006;  84 244-254
    CrossrefPubMedGoogle Scholar
  • 16 Finn DA, Beadles-Bohling AS, Beckley EH. et al . A new look at the 5alpha-reductase inhibitor finasteride.  CNS Drug Rev. 2006;  12 53-76
    CrossrefPubMedGoogle Scholar
  • 17 Frank C, Giammarioli AM, Pepponi R. et al . Cholesterol perturbing agents inhibit NMDA-dependent calcium influx in rat hippocampal primary culture.  FEBS Lett. 2004;  566 25-29
    CrossrefPubMedGoogle Scholar
  • 18 Frank C, Rufini S, Tancredi V. et al . Cholesterol depletion inhibits synaptic transmission and synaptic plasticity in rat hippocampus.  Exp Neurol. 2008;  212 407-414
    CrossrefPubMedGoogle Scholar
  • 19 Frye CA. Neurosteroids’ effects and mechanisms for social, cognitive, emotional, and physical functions.  Psychoneuroendocrinology. 2009;  34 (S 01) S143-S161
    CrossrefPubMedGoogle Scholar
  • 20 Frye CA, Walf AA, Rhodes ME. et al . Progesterone enhances motor, anxiolytic, analgesic, and antidepressive behavior of wild-type mice, but not those deficient in type 1 5 alpha-reductase.  Brain Res. 2004;  1004 116-124
    CrossrefPubMedGoogle Scholar
  • 21 Galea LA, Uban KA, Epp JR. et al . Endocrine regulation of cognition and neuroplasticity: our pursuit to unveil the complex interaction between hormones, the brain, and behaviour.  Can J Exp Psychol. 2008;  62 247-260
    PubMedGoogle Scholar
  • 22 Gass P, Riva MA. CREB, neurogenesis and depression.  Bioessays. 2007;  29 957-961
    CrossrefPubMedGoogle Scholar
  • 23 Ge S, Goh EL, Sailor KA. et al . GABA regulates synaptic integration of newly generated neurons in the adult brain.  Nature. 2006;  439 589-593
    CrossrefPubMedGoogle Scholar
  • 24 Ge S, Sailor KA, Ming GL. et al . Synaptic integration and plasticity of new neurons in the adult hippocampus.  J Physiol. 2008;  586 3759-3765
    CrossrefPubMedGoogle Scholar
  • 25 Ge S, Yang CH, Hsu KS. et al . A critical period for enhanced synaptic plasticity in newly generated neurons of the adult brain.  Neuron. 2007;  54 559-566
    CrossrefPubMedGoogle Scholar
  • 26 Griffin LD, Mellon SH. Selective serotonin reuptake inhibitors directly alter activity of neurosteroidogenic enzymes.  Proc Natl Acad Sci USA. 1999;  96 13512-13517
    CrossrefPubMedGoogle Scholar
  • 27 Guo J, Chi S, Xu H. et al . Effects of cholesterol levels on the excitability of rat hippocampal neurons.  Mol Membr Biol. 2008;  25 216-223
    CrossrefPubMedGoogle Scholar
  • 28 Janowsky JS. Thinking with your gonads: testosterone and cognition.  Trends Cogn Sci. 2006;  10 77-82
    CrossrefPubMedGoogle Scholar
  • 29 Kempermann G. The neurogenic reserve hypothesis: what is adult hippocampal neurogenesis good for?.  Trends Neurosci. 2008;  31 163-169
    CrossrefPubMedGoogle Scholar
  • 30 Kempermann G, Gage FH. Experience-dependent regulation of adult hippocampal neurogenesis: effects of long-term stimulation and stimulus withdrawal.  Hippocampus. 1999;  9 321-332
    CrossrefPubMedGoogle Scholar
  • 31 Kempermann G, Jessberger S, Steiner B. et al . Milestones of neuronal development in the adult hippocampus.  Trends Neurosci. 2004;  27 447-452
    CrossrefPubMedGoogle Scholar
  • 32 Kokate TG, Banks MK, Magee T. et al . Finasteride, a 5alpha-reductase inhibitor, blocks the anticonvulsant activity of progesterone in mice.  J Pharmacol Exp Ther. 1999;  288 679-684
    PubMedGoogle Scholar
  • 33 Kuhn HG, Dickinson-Anson H, Gage FH. Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation.  J Neurosci. 1996;  16 2027-2033
    PubMedGoogle Scholar
  • 34 Lambert JJ, Cooper MA, Simmons RD. et al . Neurosteroids: Endogenous allosteric modulators of GABA(A) receptors.  Psychoneuroendocrinology. 2009;  34 (S 01) S48-S58
    CrossrefPubMedGoogle Scholar
  • 35 Laplagne DA, Kamienkowski JE, Esposito MS. et al . Similar GABAergic inputs in dentate granule cells born during embryonic and adult neurogenesis.  Eur J Neurosci. 2007;  25 2973-2981
    CrossrefPubMedGoogle Scholar
  • 36 Locchi F, Dall’olio R, Gandolfi O. et al . Olanzapine counteracts stress-induced anxiety-like behavior in rats.  Neurosci Lett. 2008;  438 146-149
    CrossrefPubMedGoogle Scholar
  • 37 Marx CE, Stevens RD, Shampine LJ. et al . Neuroactive steroids are altered in schizophrenia and bipolar disorder: relevance to pathophysiology and therapeutics.  Neuropsychopharmacology. 2006;  31 1249-1263
    PubMedGoogle Scholar
  • 38 Marx CE, Trost WT, Shampine LJ. et al . The neurosteroid allopregnanolone is reduced in prefrontal cortex in Alzheimer's disease.  Biol Psychiatry. 2006;  60 1287-1294
    CrossrefPubMedGoogle Scholar
  • 39 Marx CE, VanDoren MJ, Duncan GE. et al . Olanzapine and clozapine increase the GABAergic neuroactive steroid allopregnanolone in rodents.  Neuropsychopharmacology. 2003;  28 1-13
    CrossrefPubMedGoogle Scholar
  • 40 Marx CE, Yuan P, Kilts JD. et al . Neuroactive steroids, mood stabilizers, and neuroplasticity: alterations following lithium and changes in Bcl-2 knockout mice.  Int J Neuropsychopharmacol. 2008;  11 547-552
    PubMedGoogle Scholar
  • 41 Mellon SH. Neurosteroid regulation of central nervous system development.  Pharmacol Ther. 2007;  116 107-124
    CrossrefPubMedGoogle Scholar
  • 42 Mirescu C, Gould E. Stress and adult neurogenesis.  Hippocampus. 2006;  16 233-238
    CrossrefPubMedGoogle Scholar
  • 43 Moffat SD, Zonderman AB, Metter EJ. et al . Longitudinal assessment of serum free testosterone concentration predicts memory performance and cognitive status in elderly men.  J Clin Endocrinol Metab. 2002;  87 5001-5007
    CrossrefPubMedGoogle Scholar
  • 44 Molina-Hernandez M, Tellez-Alcantara NP, Olivera-Lopez JI. et al . Olanzapine plus 17-beta estradiol produce antidepressant-like actions in rats forced to swim.  Pharmacol Biochem Behav. 2009;  93 491-497
    CrossrefPubMedGoogle Scholar
  • 45 Mukai Y, Higashi T, Nagura Y. et al . Studies on neurosteroids XXV. Influence of a 5alpha-reductase inhibitor, finasteride, on rat brain neurosteroid levels and metabolism.  Biol Pharm Bull. 2008;  31 1646-1650
    CrossrefPubMedGoogle Scholar
  • 46 Pibiri F, Nelson M, Guidotti A. et al . Decreased corticolimbic allopregnanolone expression during social isolation enhances contextual fear: A model relevant for posttraumatic stress disorder.  Proc Natl Acad Sci USA. 2008;  105 5567-5572
    CrossrefPubMedGoogle Scholar
  • 47 Pinna G, Costa E, Guidotti A. Fluoxetine and norfluoxetine stereospecifically and selectively increase brain neurosteroid content at doses that are inactive on 5-HT reuptake.  Psychopharmacology (Berl). 2006;  186 362-372
    CrossrefPubMedGoogle Scholar
  • 48 Rahimi-Ardabili B, Pourandarjani R, Habibollahi P. et al . Finasteride induced depression: a prospective study.  BMC Clin Pharmacol. 2006;  6 7
    CrossrefPubMedGoogle Scholar
  • 49 Romeo E, Strohle A, Spalletta G. et al . Effects of antidepressant treatment on neuroactive steroids in major depression.  Am J Psychiatry. 1998;  155 910-913
    PubMedGoogle Scholar
  • 50 Romer B, Lewicka S, Kopf D. et al . Cortisol metabolism in depressed patients and healthy controls.  Neuroendocrinology. 2009;  90 301-306
    CrossrefPubMedGoogle Scholar
  • 51 Romer B, Sartorius A, Inta D. et al . Imaging new neurons in vivo: a pioneering tool to study the cellular biology of depression?.  Bioessays. 2008;  30 806-810
    CrossrefPubMedGoogle Scholar
  • 52 Rubinow DR, Schmidt PJ. Androgens, brain, and behavior.  Am J Psychiatry. 1996;  153 974-984
    PubMedGoogle Scholar
  • 53 Schule C, Romeo E, Uzunov DP. et al . Influence of mirtazapine on plasma concentrations of neuroactive steroids in major depression and on 3alpha-hydroxysteroid dehydrogenase activity.  Mol Psychiatry. 2006;  11 261-272
    CrossrefPubMedGoogle Scholar
  • 54 Singh S, Hota D, Prakash A. et al . Allopregnanolone, the active metabolite of progesterone protects against neuronal damage in picrotoxin-induced seizure model in mice.  Pharmacol Biochem Behav. 2010;  94 416-422
    CrossrefPubMedGoogle Scholar
  • 55 Spritzer MD, Galea LA. Testosterone and dihydrotestosterone, but not estradiol, enhance survival of new hippocampal neurons in adult male rats.  Dev Neurobiol. 2007;  67 1321-1333
    CrossrefPubMedGoogle Scholar
  • 56 Thompson IM, Goodman PJ, Tangen CM. et al . The influence of finasteride on the development of prostate cancer.  N Engl J Med. 2003;  349 215-224
    CrossrefPubMedGoogle Scholar
  • 57 Uzunova V, Sheline Y, Davis JM. et al . Increase in the cerebrospinal fluid content of neurosteroids in patients with unipolar major depression who are receiving fluoxetine or fluvoxamine.  Proc Natl Acad Sci USA. 1998;  95 3239-3244
    CrossrefPubMedGoogle Scholar
  • 58 Walf AA, Sumida K, Frye CA. Inhibiting 5alpha-reductase in the amygdala attenuates antianxiety and antidepressive behavior of naturally receptive and hormone-primed ovariectomized rats.  Psychopharmacology (Berl). 2006;  186 302-311
    CrossrefPubMedGoogle Scholar
  • 59 Wang JM, Johnston PB, Ball BG. et al . The neurosteroid allopregnanolone promotes proliferation of rodent and human neural progenitor cells and regulates cell-cycle gene and protein expression.  J Neurosci. 2005;  25 4706-4718
    CrossrefPubMedGoogle Scholar
  • 60 Wang JM, Irwin RW, Liu L. et al . Regeneration in a degenerating brain: potential of allopregnanolone as a neuroregenerative agent.  Curr Alzheimer Res. 2007;  4 510-517
    CrossrefPubMedGoogle Scholar
  • 61 Wang JM, Liu L, Irwin RW. et al . Regenerative potential of allopregnanolone.  Brain Res Rev. 2008;  57 398-409
    CrossrefPubMedGoogle Scholar
  • 62 Zhao C, Deng W, Gage FH. Mechanisms and functional implications of adult neurogenesis.  Cell. 2008;  132 645-660
    CrossrefPubMedGoogle Scholar

Correspondence

B. RömerMD 

Central Institute of

Mental Health

J5

68159 Mannheim

Germany

Phone: +49/621/17 030

Email: benedikt.roemer@zi-mannheim.de

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