Neurosteroids reduce social isolation-induced behavioral deficits: A proposed link with neurosteroid-mediated upregulation of BDNF expression

Frontiers in Endocrinology

Volumn 2, Issue NOV, 2011, Pages

  Nin, Mauricio Schüler ^a,b   Martinez, Luis A ^a   Pibiri, Fabio ^a   Nelson, Marianela ^a   Pinna, Graziano ^a  

^a UNIVERSITY OF ILLINOIS   (United States)

^b Ministry of Education Brazil   (Brazil)

Author keywords

5 reductase type I; Aggressive behavior; Allopregnanolone; Anxiety; Bdnf; GABAA receptors; Ptsd; selective brain steroidogenic stimulants

Indexed keywords

EID: 84874347452     PISSN: None     EISSN: 16642392     Source Type: Journal    
DOI: 10.3389/fendo.2011.00073     Document Type: Review

References (154)

1. Acheson, D. T., Gresack, J. E., and Risbrough, V. B. (2011). Hip-pocampal dysfunction effects on context memory: possible etiology for posttraumatic stress disorder. Neuropharmacology. doi: 10.1016/j.neuropharm.2011.04.029. [Epub ahead of print].
2. Agis-Balboa, R. C., Guidotti, A., Whit-field, H., and Pinna, G. (2010). Allo-pregnanolone biosynthesis is down-regulated in the prefrontal cor-tex/Brodmann's area 9 (BA9) of depressed patients. 2010 Neuro-science Meeting, Abstr. 881.15.
3. Agis-Balboa, R. C., Pinna, G., Kadriu, B., Costa, E., and Guidotti, A. (2007). Down-regulation of neuros-teroid biosynthesis in corticolimbic circuits mediates social isolation-induced behavior in mice. Proc. Natl. Acad. Sci. U.S.A. 104, 18736-18741.
4. Agis-Balboa, R. C., Pinna, G., Zhubi, A., Maloku, E., Veldic, M., Costa, E., and Guidotti, A. (2006). Characterization of brain neurons that express enzymes mediating neurosteroid biosynthesis. Proc. Natl. Acad. Sci. U.S.A. 103, 14602-14607.
5. Akk, G., Shu, H. J., Wang, C., Steinbach, J. H., Zorumski, C. F., Covey, D. F., and Mennerick, S. (2005). Neurosteroid access to the GABAa receptor. J. Neurosci. 25, 11605-11613.
6. Alfonso, J., Frick, L. R., Silberman, D. M., Palumbo, M. L., Genaro, A. M., and Frasch, A. C. (2006). Regulation of hippocampal gene expression is conserved in two species subjected to different stressors and antidepres-sant treatments. Biol Psychiatry 59, 244-251.
7. Altar, C. A., Whitehead, R. E., Chen, R., Wörtwein, G., and Madsen, T. M. (2003). Effects of electroconvulsive seizures and antidepressant drugs on brain-derived neurotrophic factor protein in rat brain. Biol Psychiatry 54, 703-709.
8. Amin,Z., Mason, G. F., Cavus, I., Krystal, J. H., Rothman, D. L., and Epperson, C. N. (2007). The interaction of neuroactive steroids and GABA in the development of neuropsychi-atric disorders in women. J. Psy-chopharmacol (Oxford) 21,414-420.
9. Aydemir, O., Deveci, A., and Taneli, F. (2005). The effect of chronic antidepressant treatment on serum brain-derived neurotrophic factor levels in depressed patients: a preliminary study. Prog. Neuropsychopharmacol. Biol Psychiatry 29, 261-265.
10. Bäckström, T., Andreen, L., Birzniece, V., Björn, I., Johansson, I. M., Nordenstam-Haghjo, M., Nyberg, S., Sundström-Poromaa, I., Wahlström, G., Wang, M., and Zhu, D. (2003). The role of hormones and hormonal treatments in premenstrual syndrome. CNS Drugs 17, 325-342.
11. Baulieu, E. E. (1981). "Steroid hormones in the brain: several mechanisms," in Steroid Hormone Regulation of the Brain, eds K. Fuxe, J. A. Gustafson, and L. Wettenberg (Elmsford, NY: Pergamon), 3-14.
12. Baulieu, E. E., Robel, P., and Schumacher, M. (2001). Neurosteroids: beginning of the story. Int. Rev. Neurobiol. 46, 1-32.
13. Belelli, D., and Lambert, J. J. (2005). Neurosteroids: endogenous regulators of the GABAa receptor. Nat. Rev. Neurosci. 6, 565-575.
14. Berry, A., Bellisario, V., Capoccia, S., Tirassa, P., Calza, A., Alleva, E., and Cirulli, F. (2011). Social deprivation stress is a triggering factor for the emergence of anxiety-and depression-like behaviours and leads to reduced brain BDNF levels in C57BL/6J mice. Psychoneu-roendocrinology. PMID: 21974975. [Epub ahead of print].
15. Bitran, D., Hilvers, R. J., and Kellogg, C. K. (1991). Anxiolytic effects of 3 alpha-hydroxy-5 alpha[beta]- pregnan-20-one: endogenous metabolites of progesterone that are active at the GABAa receptor. Brain Res. 561, 157-161.
16. Bloch, M., Schmidt, P. J., Danaceau, M., Murphy, J., Nieman, L., and Rubi-now, D. R. (2000). Effects of gonadal steroids in women with a history of postpartum depression. Am. J. Psychiatry 157, 924-930.
17. Bocchio-Chiavetto, L., Zanardini, R., Bortolomasi, M., Abate, M., Segala, M., Giacopuzzi, M., Riva, M. A., Marchina, E., Pasqualetti, P., Perez, J., and Gennarelli, M. (2006). Electroconvulsive therapy (ECT) increases serum brain derived neurotrophic factor (BDNF) in drug resistant depressed patients. Eur. Neuropsychopharmacol. 16, 620-624.
18. Boldrini, M., Underwood, M. D., Hen, R., Rosoklija, G. B., Dwork, A. J., John Mann, J., and Arango, V. (2009). Antidepressants increase neural progenitor cells in the human hippocampus. Neuropsychopharma-cology 34, 2376-2389.
19. Bortolato, M., Devoto, P., Roncada, P., Frau, R., Flore, G., Saba, P., Pistritto, G., Soggiu, A., Pisanu, S., Zappala, A., Ristaldi, M. S., Tattoli, M., Cuomo, V., Marrosu, E, and Barbaccia, M. L. (2011). Isolation rearing induced reduction of brain 5α-reductase expression: relevance to dopaminergic impairments. Neuropharmacology 60, 1301-1308.
20. Bredy, T. W., Wu, H., Crego, C., Zell-hoefer, J., Sun, Y. E., and Barad, M. (2007). Histone modifications around individual BDNF gene promoters in prefrontal cortex are associated with extinction of conditioned fear. Learn. Mem. 14, 268-276.
21. Breslau, N., Chase, G. A., and Anthony, J. C. (2002). The uniqueness of the DSM definition of posttraumatic stress disorder: implications for research. Psychol Med. 32, 573-576.
22. Brewer, G. J., Espinosa, J., McIlhaney, M. P., Pencek, T. P., Kesslak, J. P., Cotman, C., Viel, J., and McManus, D. C. (2001). Culture and regeneration of human neurons after brain surgery. J. Neurosci. Methods 107, 15-23.
23. Brinton, R. D., and Wang, J. M. (2006). 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. 3, 11-17.
24. Brunoni, A. R., Lopes, M., and Fregni, F.(2008). A systematic review and meta-analysis of clinical studies on depression and BDNF levels: impli cations for the role of neuroplastic- ity in depression. Int. J. Neuropsy chopharmacol. 11,1169-1180.
25. Castro, J. E., Varea, E., Márquez, C., Cordero, M. I., Poirier, G., and Sandi, C. (2010). Role of the amygdala in antidepressant effects on hippocampal cell proliferation and survival and on depression-like behavior in the rat. PLoS ONE 5, e8618. doi:10.1371/journal.pone.0008618
26. Chen, B., Dowlatshahi, D., MacQueen, G.M., Wang, J. F., and Young, L. T. (2001). Increased hippocam pal BDNF immunoreactivity in subjects treated with antidepres sant medication. Biol. Psychiatry 50, 260-265.
27. Cheney, D. L., Uzunov, D., Costa, E., and Guidotti, A. (1995). Gas chromatographic-mass frag-mentographic quantitation of 3α-hydroxy-5α-pregnan-20-one (allopregnanolone) and its precursors in blood and brain of adrenalectomized and castrated rats. J. Neurosci. 15,4641-4650.
28. Cowansage, K. K., LeDoux, J. E., and Monfils, M. H. (2010). Brain-derived neurotrophic factor: a dynamic gatekeeper of neural plasticity. Curr. Mol. Pharmacol. 3, 12-29.
29. Coyle, J. T., and Duman, R. S. (2003). Finding the intracellular signaling pathways affected by mood disorder treatments. Neuron 38, 157-160.
30. D'Aquila, P. S., Canu, S., Sardella, M., Spanu, C., Serra, G., and Franconi, F. (2010). Dopamine is involved in the antidepressant-like effect of allo-pregnanolone in the forced swimming test in female rats. Behav. Pharmacol. 21, 21-28.
31. David, D. J., Samuels, B. A., Rainer, Q., Wang, J. W., Marsteller, D., Mendez, I., Drew, M., Craig, D. A., Guiard, B. P., Guilloux, J. P., Artymyshyn, R. P., Gardier, A. M., Gerald, C., Antonijevic, I. A., Leonardo, E. D., and Hen, R. (2009). Neurogenesis-dependent and -independent effects of fluoxetine in an animal model of anxiety/depression. Neuron 62, 479-493.
32. Davidson, J. R. (2004). Use of ben-zodiazepines in social anxiety disorder, generalized anxiety disorder, and posttraumatic stress disorder. J. Clin. Psychiatry 65, 29-33.
33. Deng, W., Aimone, J. B., and Gage, F. H. (2010). New neurons and newmem-ories: how does adult hippocam-pal neurogenesis affect learning and memory? Nat. Rev. Neurosci. 11, 339-350.
34. Deo, G. S., Dandekar, M. P., Upad-hya, M. A., Kokare, D. M., and Sub-hedar, N. K. (2010). NeuropeptideY Y1 receptors in the central nucleus of amygdala mediate the anxiolytic-like effect of allopregnanolone in mice: behavioral and immunocyto-chemical evidences. Brain Res. 1318, 77-86.
35. Désarnaud, F., Do Thi, A. N., Brown, A. M., Lemke, G., Suter, U., Baulieu, E. E., and Schumacher, M. (1998). Progesterone stimulates the activity of the promoters of peripheral myelin protein-22 and protein zero genes in Schwann cells. J. Neu-rochem. 71, 1765-1768.
36. Dong, E., Matsumoto, K., Uzunova, V., Sugaya, I., Costa, E., and Guidotti, A. (2001). Brain 5α-dihydroprogesterone and allopregnanolone synthesis in a mouse model of protracted social isolation. Proc. Natl. Acad. Sci. U.S.A. 98, 2849-2854.
37. Dranovsky, A., and Hen, R. (2006). Hip-pocampal neurogenesis: regulation by stress and antidepressants. Biol. Psychiatry 59, 1136-1143.
38. Dranovsky, A., Picchini, A. M., Moadel, T., Sisti, A. C., Yamada, A., Kimura, S., Leonardo, E. D., and Hen, R. (2011). Experience dictates stem cell fate in the adult hippocampus. Neuron 70, 908-923.
39. Duman, R. S. (2004). Depression: a case of neuronal life and death? Biol. Psychiatry 56,140-145.
40. Egan, M. F., Kojima, M., Callicott, J. H., Goldberg, T. E., Kolachana, B. S., Bertolino, A., Zaitsev, E., Gold, B., Goldman, D., Dean, M., Lu, B., and Weinberger, D. R. (2003). The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 112, 257-269.
41. Ehninger, D., Wang, L. P., Klempin, E, Romer, B., Kettenmann, H., and Kempermann, G. (2011). Enriched environment and physical activity reduce microglia and influence the fate of NG2 cells in the amygdala of adult mice. Cell Tissue Res. 345, 69-86.
42. Engin, E., and Treit, D. (2007). The anxiolytic-like effects of allopregnanolone vary as a function of intracerebral microinfusion site: the amygdala, medial prefrontal cortex, or hippocampus. Behav. Pharmacol. 18,461-470.
43. Frye, C. A., Paris, J. J., and Rhodes, M. E. (2009). Increasing 3alpha,5alpha-THP following inhibition of neu-rosteroid biosynthesis in the ventral tegmental area reinstates anti-anxiety, social, and sexual behavior of naturally receptive rats. Reproduction 137,119-128.
44. Frye, C. A., and Rhodes, M. E. (2006). Infusions of 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP) to the ventral tegmental area, but not the substantia nigra, enhance exploratory, antianxiety, social and sexual behaviours and concomi-tantly increase 3alpha,5alpha-THP concentrations in the hippocampus, diencephalon and cortex of ovariec-tomised oestrogen primed rats. J. Neuroendocrinol. 18, 960-975.
45. Gelpin, E., Bonne, O., Peri, T., Brandes, D., and Shalev, A. Y. (1996). Treatment of recent trauma survivors with benzodiazepines: a prospective study. J. Clin. Psychiatry 57, 390-394.
46. Gonul, A. S., Akdeniz, F., Taneli, F., Donat, O., Eker, C., and Vahip, S. (2005). Effect of treatment on serum brain-derived neurotrophic factor levels in depressed patients. Eur. Arch. Psychiatry Clin. Neurosci. 255, 381-386.
47. Griffin, L. D., and Mellon, S. H. (1999). Selective serotonin reup-take inhibitors directly alter activity of neurosteroidogenic enzymes. Proc. Natl. Acad. Sci. U.S.A. 96, 13512-13517.
48. Guennoun, R., Benmessahel, Y., Dele-spierre, B., Gouézou, M., Rajkowski, K. M., Baulieu, E. E., and Schumacher, M. (2001). Progesterone stimulates Krox-20 gene expression in Schwann cells. Brain Res. Mol. Brain Res. 90, 75-82.
49. Guidotti, A., Dong, E., Matsumoto, K., Pinna, G., Rasmusson, A. M., and Costa, E. (2001). The socially-isolated mouse: a model to study the putative role of allopregnanolone and 5α-dihydroprogesterone in psychiatric disorders. Brain Res. Rev. 37, 110-115.
50. Holsboer, F., and Barden, N. (1996). Antidepressants and hypothalamic-pituitary-adrenocortical regulation. Endocr. Rev. 17, 187-205.
51. Hosie, A. M., Wilkins, M. E., da Silva, H. M., and Smart, T. G. (2006). Endogenous neurosteroids regulate GABAa receptors through two discrete transmembrane sites. Nature 444, 486-489.
52. Ito, W., Chehab, M., Thakur, S., Li, J., and Morozov, A. (2011). BDNF-restricted knockout mice as an animal model for aggression. Genes Brain Behav. 10, 365-374.
53. Jain, N. S., Hirani, K., and Chopde, C. T. (2005). Reversal of caffeine-induced anxiety by neurosteroid 3-alpha-hydroxy-5-alpha-pregnane-20-one in rats. Neuropharmacology 48, 627-638.
54. Karege, F., Bondolfi, G., Gervasoni, N., Schwald, M., Aubry, J. M., and Bertschy, G. (2005). Low brain-derived neurotrophic factor (BDNF) levels in serum of depressed patients probably results from lowered platelet BDNF release unrelated to platelet reactivity. Biol. Psychiatry 57, 1068-1072.
55. Karege, F., Perret, G., Bondolfi, G., Schwald, M., Bertschy, G., and Aubry, J. M. (2002). Decreased serum brain-derived neurotrophic factor levels in major depressed patients. Psychiatry Res. 109, 143-148.
56. Karishma, K. K., and Herbert, J. (2002). Dehydroepiandrosterone (DHEA) stimulates neurogenesis in the hippocampus of the rat, promotes survival of newly formed neurons and prevents corticosterone-induced suppression. Eur. J. Neurosci. 16,445-453.
57. Kaur, P., Jodhka, P. K., Underwood, W A., Bowles, C. A., de Fiebre, N. C., de Fiebre, C. M., and Singh, M. (2007). Progesterone increases brain-derived neurotrophic factor expression and protects against glutamate toxic-ity in a mitogen-activated protein kinase- and phosphoinositide-3 kinase-dependent manner in cerebral cortical explants. J. Neurosci. Res. 85,2441-2449.
58. Keller, E. A., Zamparini, A., Borodinsky, L. N., Gravielle, M. C., and Fisz-man, M. L. (2004). Role of allopregnanolone on cerebellar granule cells neurogenesis. Brain Res. Dev. Brain Res. 153,13-17.
59. Kempermann, G., and Gage, F. H. (1998). Closer to neurogenesis in adult humans. Nat. Med. 4,555-557.
60. Kempermann, G., and Kronenberg, G. (2003). Depressed new neurons-adult hippocampal neurogenesis and a cellular plasticity hypothesis of major depression. Biol. Psychiatry 54, 499-503.
61. Kita, A., and Furukawa, K. (2008). Involvement of neurosteroids in the anxiolytic-like effects of AC-5216 in mice. Pharmacol. Biochem. Behav. 89, 171-178.
62. Koshimizu, H., Hazama, S., Hara, T., Ogura, A., and Kojima, M. (2010). Distinct signaling pathways of precursor BDNF and mature BDNF in cultured cerebellar granule neurons. Neurosci. Lett. 473, 229-232.
63. Lambert, J. J., Belelli, D., Peden, D. R., Vardy, A. W., and Peters, J. A. (2003). Neurosteroidmodulation of GABAa receptors. Prog. Neurobiol. 71, 67-80.
64. Lambert, J. J., Cooper, M. A., Simmons, R. D., Weir, C. J., and Belelli, D. (2009). Neurosteroids: endogenous allosteric modulators of GABAa receptors. Psychoneuroendocrinology 34, S48-S58.
65. Lang, U. E., Bajbouj, M., Galli-nat, J., and Hellweg, R. (2006). Brain-derived neurotrophic factor serum concentrations in depressive patients during vagus nerve stimulation and repetitive transcranial magnetic stimulation. Psychopharmacol-ogy(Berl.) 187,156-159.
66. Leuner, B., Mendolia-Loffredo, S., Kozorovitskiy, Y., Samburg, D., Gould, E., and Shors, T. J. (2004). Learning enhances the survival of new neurons beyond the time when the hippocampus is required for memory. J. Neurosci. 24, 7477-7481.
67. Lu, B., Buck, C. R., Dreyfus, C. F., and Black, I. B. (1989). Expression of NGF and NGF receptor mRNAs in the developing brain: evidence for local delivery and action of NGF. Exp. Neurol. 104, 191-199.
68. Majewska, M. D. (1992). Neurosteroids: endogenous bimodal modulators of the GABAa receptor. Mechanism of action and physiological significance. Prog. Neurobiol. 38, 379-395.
69. Martinez, L. A., Pibiri, F., Nelson, M., Nin, M. S., and Pinna, G. (2011). Selective brain steroidogenic stimulant (SBSS)-induced neuros-teroid upregulation facilitates fear extinction and reinstatement of fear memory by a BDNF-mediated mechanism in a mouse model of PTSD. Society for Neuroscience 2011 Abstract, Washington, DC.
70. Martin-Garcia, E., and Pallares, M. (2005). The intrahippocampal administration of the neurosteroid allopregnanolone blocks the audio-genic seizures induced by nicotine. Brain Res. 1062, 144-150.
71. Marx, C. E., Keefe, R. S., Buchanan, R. W., Hamer, R. M., Kilts, J. D., Bradford, D. W., Strauss, J. L., Naylor, J. C., Payne, V. M., Lieberman, J. A., Savitz, A. J., Leimone, L. A., Dunn, L., Porcu, P., Morrow, A. L., and Shampine, L. J. (2009). Proof-of concept trial with the neurosteroid pregnenolone targeting cognitive and negative symptoms in schizophrenia. Neuropsy-chopharmacology 34, 1885-1903.
72. Mason, B. L., and Pariante, C. M. (2006). The effects of antide-pressants on the hypothalamic-pituitary-adrenal axis. Drug News Perspect. 19, 603-608.
73. Matrisciano, F., Bonaccorso, S., Riccia-rdi, A., Scaccianoce, S., Panaccione, I., Wang, L., Ruberto, A., Tatarelli, R., Nicoletti, F., Girardi, P., and Shel-ton, R. C. (2009). Changes in BDNF serum levels in patients with depression disorder (MDD) after 6 months treatment with sertraline, escitalo-pram, or venlafaxine. J. Psychiatr. Res. 43, 247-254.
74. Matsumoto, K., Nomura, H., Murakami, Y., Taki, K., Taka-hata, H., and Watanabe, H. (2003). Long-term social isolation enhances picrotoxin seizure susceptibility in mice: up-regulatory role of endogenous brain allopregnanolone in GABAergic systems. Pharmacol. Biochem. Behav. 75, 831-835.
75. Matsumoto, K., Puia, G., Dong, E., and Pinna, G. (2007). GABAa receptor neurotransmission dysfunction in a mouse model of social isolation-induced stress: possible insights into a nonserotonergic mechanism of action of SSRIs in mood and anxiety disorders. Stress 10, 3-12.
76. Matsumoto, K., Uzunova, V., Pinna, G., Taki, K., Uzunov, D. P., Watanabe, H., Mienvielle, J.-M., Guidotti, A., and Costa, E. (1999). Permissive role of brain allopregnanolone content in the regulation of pentobarbital-induced righting reflex loss. Neu-ropharmacology 38, 955-963.
77. Matsumoto, T, Rauskolb, S., Polack, M., Klose, J., Kolbeck, R., Korte, M., and Barde, Y. A. (2008). Biosynthesis and processing of endogenous BDNF: CNS neurons store and secrete BDNF, not pro-BDNF. Nat. Neurosci. 11,131-133.
78. McEwen, B. S., Magarinos, A. M., and Reagan, L. P. (2002). Structural plasticity and tianeptine: cellular and molecular targets. Eur. Psychiatry 17, 318-330.
79. Melcangi, R. C., Magnaghi, V., Cavar-retta, I., Martini, L., and Piva, E (1998). Age-induced decrease of glycoprotein Po and myelin basic protein gene expression in the rat sciatic nerve. Repair by steroid derivatives. Neuroscience 85, 569-578.
80. Melcangi, R. C., Magnaghi, V., Cavar-retta, I., Zucchi, I., Bovolin, P., D'Urso, D., and Martini, L. (1999). Progesterone derivatives are able to influence peripheral myelin protein 22 and P0 gene expression: possible mechanisms of action. J. Neurosci. Res. 56, 349-357.
81. Mellon, S. H. (2007). Neurosteroid regulation of central nervous system development. Pharmacol. Ther. 116, 107-124.
82. Monteggia, L. M., Barrot, M., Powell, C. M., Berton, O., Galanis, V., Gemelli, T., Meuth, S., Nagy, A., Greene, R. W., and Nestler, E. J. (2004). Essential role of brain-derived neurotrophic factor in adult hippocampal function. Proc. Natl. Acad. Sci. U.S.A. 101, 10827-10832.
83. Mowla, S. J., Pareek, S., Farhadi, H. F., Petrecca, K., Fawcett, J. P., Seidah, N. G., Morris, S. J., Sossin, W S., and Murphy, R. A. (1999). Differential sorting of nerve growth factor and brain-derived neurotrophic factor in hippocampal neurons. J. Neurosci. 19,2069-2080.
84. Naert, G., Maurice, T., Tapia-Arancibia, L., and Givalois, L. (2007). Neu- roactive steroids modulate HPA axis activity and cerebral brain-derived neurotrophic factor (BDNF) pro tein levels in adult male rats. Psychoneuroendocrinology 32, 1062-1078.
85. Nagahara, A. H., and Tuszynski, M. H. (2011). Potential therapeutic uses of BDNF in neurological and psychiatric disorders. Nat. Rev. Drug Discov. 10,209-219.
86. Nappi, R. E., Petraglia, F., Luisi, S., Polatti, F., Farina, C., and Genaz-zani, A. R. (2001). Serum allopregnanolone in women with postpar-tum "blues". Obstet. Gynecol. 97, 77-80.
87. Nelson, M., Pibiri, F., and Pinna, G. (2010). Relationship between allopregnanolone (Allo) and reduced brain BDNF and reelin expression in a mouse model of posttraumatic stress disorders (PTSD). Soc. Neurosci. 2010 Abstr. 666.22.
88. Nelson, M., and Pinna, G. (2011). S-norfluoxetine infused into the basolateral amygdala increases allopregnanolone levels and reduces aggression in socially isolated mice. Neuropharmacology 60, 1154-1159.
89. Nibuya, M., Morinobu, S., and Duman, R. S. (1995). Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments. J.Neurosci. 15,7539-7547.
90. Nin, M. S., Salles, E B., Azeredo, L. A., Frazon, A. P., Gomez, R., and Barros, H. M. (2008). Anti-depressant effect and changes of GABAa receptor gamma2 subunit mRNA after hippocampal administration of allopregnanolone in rats. J. Psychopharmacol (Oxford) 22, 477-485.
91. Nin M. S., Martinez, L. A., Thomas, R., Nelson, M., and Pinna, G. (2011). Allopregnanolone and S-norfluoxetine decrease anxiety-like behavior in a mouse model of anxiety/depression. Trab. Inst. Cajal 83, 215-216.
92. Notterpek, L., Snipes, G. J., and Shooter, E. M. (1999). Temporal expression pattern of peripheral myelin protein 22 during in vivo and in vitro myelination. Glia 25, 358-369.
93. Pearlstein, T. (2010). Premenstrual dys-phoric disorder: out of the appendix. Arch. Womens Ment. Health 13, 21-23.
94. Peters, J., Dieppa-Perea, L. M., Melen-dez, L. M., and Quirk, G. J. (2010). Induction of fear extinction with hippocampal-infralimbic BDNF. Science 328, 1288-1290.
95. Pibiri, F., Nelson, M., Guidotti, A., Costa, E., and Pinna, G. (2008). Decreased allopregnanolone content during social isolation enhances contextual fear: a model relevant for posttraumatic stress disorder. Proc. Natl Acad. Sci. U.S.A. 105, 5567-5572.
96. Piccinni, A., Marazziti, D., Catena, M., Domenici, L., Del Debbio, A., Bianchi, C., Mannari, C., Martini, C., Da Pozzo, E., Schiavi, E., Mariotti, A., Roncaglia, I., Palla, A., Consoli, G., Giovannini, L., Massimetti, G., and Dell'Osso, L. (2008). Plasma and serum brain-derived neurotrophic factor (BDNF) in depressed patients during 1 year of antidepressant treatments. J. Affect. Disord. 105, 279-283.
97. Pinna, G. (2010). In a mouse model relevant for post-traumatic stress disorder, selective brain steroidogenic stimulants (SBSS) improve behavioral deficits by normalizing allopregnanolone biosynthesis. Behav. Pharmacol. 21,438-450.
98. Pinna, G., Agis-Balboa, R., Pibiri, F., Nelson, M., Guidotti, A., and Costa, E. (2008). Neurosteroid biosynthesis regulates sexually dimorphic fear and aggressive behavior in mice. Neurochem. Res. 33, 1990-2007.
99. Pinna, G., Costa, E., and Guidotti, A. (2004). Fluoxetine and norfluoxe-tine stereospecifically facilitate pen-tobarbital sedation by increasing neurosteroids. Proc. Natl Acad. Sci. U.S.A. 101,6222-6225.
100. Pinna, G., Costa, E., and Guidotti, A. (2006). Fluoxetine and norfluoxe-tine stereospecifically and selectively increase brain neurosteroid content at doses that are inactive on 5-HT reuptake. Psychopharmacology (Berl.) 186, 362-372.
101. Pinna, G., Costa, E., and Guidotti, A. (2009). SSRIs act as selective brain steroidogenic stimulants (SBSSs) at low doses that are inactive on 5-HT reuptake. Curr. Opin. Pharmacol. 9, 24-30.
102. Pinna, G., Dong, E., Matsumoto, K., Costa, E., and Guidotti, A. (2003). In socially isolated mice, the reversal of brain allopregnanolone down-regulation mediates the anti-aggressive action of fluoxetine. Proc. Natl Acad. Sci. U.S.A. 100, 2035-2040.
103. Pinna, G., Uzunova, V., Matsumoto, K., Puia, G., Mienville, J.-M., Costa, E., and Guidotti, A. (2000). Brain allopregnanolone regulates the potency of the GABAa receptor agonist muscimol. Neuropharmacology 39, 440-448.
104. Pinnock, S. B., Lazic, S. E., Wong, H. T., Wong, I. H., and Herbert, J. (2009). Synergistic effects of dehy-droepiandrosterone and fluoxetine on proliferation of progenitor cells in the dentate gyrus of the adult male rat. Neuroscience 158, 1644-1651.
105. Pisu, M. G., Dore, R., Mostallino, M. C., Loi, M., Pibiri, F., Mameli, R., Cadeddu, R., Secci, P. P., and Serra, M. (2011). Down-regulation of hippocampal BDNF and Arc associated with improvement in aversive spatial memory performance in socially isolated rats. Behav. Brain Res. 222, 73-80.
106. Puia, G., Mienville, J.-M., Matsumoto, K., Takahata, H., Watanabe, H., Costa, E., and Guidotti, A. (2003). On the putative physiological role of allopregnanolone on GABAa receptor function. Neuropharmacology 44, 49-55.
107. Puia, G., Santi, M. R., Vicini, S., Pritch-ett, D. B., Purdy, R. H., Paul, S. M., Seeburg, P. H., and Costa, E. (1990). Neurosteroids act on recombinant human GABAa receptors. Neuron 4, 759-765.
108. Puia, G., Vicini, S., Seeburg, P. H., and Costa, E. (1991). Influence of recombinant gamma-aminobutyric acid - a receptor subunit composition on the action of allosteric modulators of gammaaminobutyricacid-gated Cl-currents. Mol. Pharmacol. 39,691-696.
109. Quirk, G. J., and Milad, M. R. (2010). Neuroscience: editing out fear. Nature 463, 36-37.
110. Rapkin, A. J., Morgan, M., Goldman, L., Brann, D. W., Simone, D., and Mahesh, V. B. (1997). Progesterone metabolite allopregnanolone in women with premenstrual syndrome. Obstet. Gynecol. 90,709-714.
111. Rasmusson, A. M., Pinna, G., Pali-wal, P., Weisman, D., Gottschalk, C., Charney, D., Krystal, J., and Guidotti, A. (2006). Decreased cere-brospinal fluid allopregnanolone levels in women with posttraumatic stress disorder. Biol Psychiatry 60, 704-713.
112. Rauskolb, S, Zagrebelsky, M., Drezn-jak, A., Deogracias, R., Matsumoto, T., Wiese, S., Erne, B., Sendtner, M., Schaeren-Wiemers, N., Korte, M., and Barde, Y. A. (2010). Global deprivation of brain-derived neu-rotrophic factor in the CNS reveals an area-specific requirement for dendritic growth. J. Neurosci. 30, 1739-1749.
113. Rios, M., Fan, G., Fekete, C., Kelly, J., Bates, B., Kuehn, R., Lechan, R. M., and Jaenisch, R. (2001). Conditional deletion of brain-derived neurotrophic factor in the postnatal brain leads to obesity and hyperactivity. Mol. Endocrinol. 15, 1748-1757.
114. Rodgers, R. J., and Johnson, N. J. (1998). Behaviorally selective effects of neu-roactive steroids on plus-maze anxiety in mice. Pharmacol. Biochem. Behav. 59,221-232.
115. Romeo, E., Ströhle, A., Spalletta, G., di Michele, F., Hermann, B., Hols-boer, F., Pasini, A., and Rupprecht, R. (1998). Effects of antidepressant treatment on neuroactive steroids in major depression. Am. J. Psychiatry 155,910-913.
116. Rupprecht, R., Papadopoulos, V., Rammes, G., Baghai, T. C., Fan, J., Akula, N., Groyer, G., Adams, D., and Schumacher, M. (2010). Translocator protein (18 kDa) (TSPO) as a therapeutic target for neurological and psychiatric disorders. Nat. Rev. Drug Discov. 9, 971-988.
117. Rupprecht, R., Rammes, G., Eser, D., Baghai, T. C., Schüle, C., Noth-durfter, C., Troxler, T., Gentsch, C., Kalkman, H. O., Chaperon, E, Uzunov, V., McAllister, K. H., Bertaina-Anglade, V., La Rochelle, C. D., Tuerck, D., Floesser, A., Kiese, B., Schumacher, M., Land-graf, R., Holsboer, F., and Kucher, K. (2009). Translocator protein (18 kD) as target for anxiolytics without benzodiazepine-like side effects. Science 325, 490-493.
118. Russo-Neustadt, A. A., Alejandre, H., Garcia, C., Ivy, A. S., and Chen, M. J. (2004). Hippocampal brain-derived neurotrophic factor expression following treatment with rebox-etine, citalopram, and physical exercise. Neuropsychopharmacology 29, 2189-2199.
119. Santarelli, L., Saxe, M., Gross, C., Surget, A., Battaglia, F., Dulawa, S., Weis-staub, N., Lee, J., Duman, R., Aran-cio, O., Belzung, C., and Hen, R. (2003). Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 301,805-809.
120. Sapolsky, R. M. (2000). Glucocorticoids and hippocampal atrophy in neu-ropsychiatric disorders. Arch. Gen. Psychiatry 57, 925-935.
121. Scaccianoce, S., Del Bianco, P., Paolone, G., Caprioli, D., Modafferi, A. M., Nencini, P., and Badiani, A. (2006). Social isolation selectively reduces hippocampal brain-derived neurotrophic factor without altering plasma corticosterone. Behav. Brain Res. 168, 323-325.
122. Schmahl, C., Berne, K., Krause, A., Kleindienst, N., Valerius, G., Vermet-ten, E., and Bohus, M. (2009). Hippocampus and amygdala volumes in patients with borderline personality disorder with or without posttraumatic stress disorder. J. Psychiatry Neurosci. 34,289-295.
123. Schüle, C., Eser, D., Baghai, T. C., Nothdurfter, C., Kessler, J. S., and Rupprecht, R. (2011). Neuroactive steroids in affective disorders: target for novel antidepressant or anxiolytic drugs? Neuroscience 191, 55-77.
124. Sen, S., Duman, R., and Sanacora, G. (2008). Serum brain-derived neurotrophic factor, depression, and antidepressant medications: meta-analyses and implications. Biol. Psychiatry 64,527-532.
125. Serra, M., Madau, P., Chessa, M. F., Caddeo, M., Sanna, E., Trapani, G., Franco, M., Liso, G., Purdy, R. H., Barbaccia, M. L., and Biggio, G. (1999). 2-Phenyl-imidazo[1,2-a]pyridine derivatives as ligands for peripheral benzodiazepine receptors: stimulation of neurosteroid synthesis and anticonflict action in rats. Br. J. Pharmacol. 127, 177-187.
126. Serra, M., Pisu, M. G., Littera, M., Papi, G., Sanna, E., Tuveri, F., Usala, L., Purdy, R. H., and Biggio, G. (2000). Social isolation-induced decreases in both the abundance of neuroactive steroids and GABA(A) receptor function in rat brain. J. Neurochem. 75, 732-740.
127. Sheline, Y. I., Mittler, B. L., and Mintun, M. A. (2002). The hippocampus and depression. Eur. Psychiatry 17, 300-305.
128. Sheline, Y. I., Wang, P. W., Gado, M. H., Csernansky, J. G., and Vannier, M. W. (1996). Hippocampal atrophy in recurrent major depression. Proc. Natl. Acad. Sci. U.S.A. 93, 3908-3913.
129. Shimizu, E., Hashimoto, K., Oka-mura, N., Koike, K., Komatsu, N., Kumakiri, C., Nakazato, M., Watanabe, H., Shinoda, N., Okada, S., and Iyo, M. (2003). Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants. Biol. Psychiatry 54, 70-75.
130. Shirayama, Y, Chen, A. C., Nakagawa, S., Russell, D. S., and Duman, R. S. (2002). Brain-derived neurotrophic factor produces antidepressant effects in behavioral models of depression. J. Neurosci. 22, 3251-3261.
131. Smith, M. A., Makino, S., Kvetnansky, R., and Post, R. M. (1995). Stress and glucocorticoids affect the expression of brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus. J. Neurosci. 15, 1768-1777.
132. Soppet, D, Escandon, E., Maragos, J., Middlemas, D. S., Reid, S. W., Blair, J., Burton, L. E., Stanton, B. R., Kaplan, D. R., Hunter, T., Nikolics, K.,andParada,L.F. (1991).The neurotrophic factors brain-derived neurotrophic factor and neurotrophin-3 are ligands for the trkB tyrosine kinase receptor. Cell 65, 895-903.
133. Stoffel-Wagner, B. (2001). Neurosteroid metabolism in the human brain. Eur. J. Endocrinol. 145, 669-679.
134. Ströhle, A., Romeo, E., di Michele, F., Pasini, A., Yassouridis, A., Hols boer, F., and Rupprecht, R. (2002). GABAa receptor-modulationg neuroactive steroid composition in patients with panic disorder before and during paroxetine treatment. Am. J. Psychiatry 159, 145-147.
135. Tapia-Arancibia, L, Rage, F., Givalois, L., and Arancibia, S. (2004). Physiology of BDNF: focus on hypothalamic function. Front. Neuroendocrinol. 25, 77-107.
136. Tsankova, N. M., Berton, O., Renthal, W., Kumar, A., Neve, R. L., and Nestler, E. J. (2006). Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action. Nat. Neurosci. 9,519-525.
137. Tueting, P., and Pinna, G. (2002). Behavior associated with an enriched environment and with social isolation in mice. Soc. Neurosci. 2002 Abstr. 106.12.
138. Ueyama, T., Kawai, Y., Nemoto, K., Sekimoto, M., Toné, S., and Senba, E. (1997). Immobilization stress reduced the expression of neu-rotrophins and their receptors in the rat brain. Neurosci. Res. 28, 103-110.
139. Uzunov, D. P., Cooper, T. B., Costa, E., and Guidotti, A. (1996). Flu-oxetine elicited changes in brain neurosteroid content measured by negative ion mass fragmentography. Proc. Natl. Acad. Sci. U.S.A. 93, 12599-12604.
140. Uzunova, V., Sampson, L., and Uzunov, D. P. (2006). Relevance of endogenous 3alpha-reduced neurosteroids to depression and antidepressant action. Psychopharmacology (Berl.) 186,351-361.
141. Uzunova, V., Sheline, Y., Davis, J. M., Rasmusson, A., Uzunov, D. P., Costa, E., and Guidotti, A. (1998). Increase in the cerebrospinal fluid content of neurosteroids in patients with unipolar major depression who are receiving fluoxetine or fluvoxam-ine. Proc. Natl. Acad. Sci. U.S.A. 95, 3239-3244.
142. Uzunova, V., Wrynn, A. S., Kin-nunen, A., Ceci, M., Kohler, C., and Uzunov, D. P. (2004). Chronic antidepressants reverse cerebrocor-tical allopregnanolone decline in the olfactory-bulbectomized rat. Eur. J. Pharmacol. 486, 31-34.
143. van Praag, H., Christie, B. R., Sejnowski, T. J., and Gage, E H. (1999). Running enhances neurogenesis, learning, and long-term potentiation in mice. Proc. Natl. Acad. Sci. U.S.A. 96, 13427-13431.
144. Velasco, I. (2011). Stem cells with neu-rogenic potential and steroid hormones. Curr. Top. Med. Chem. 11, 1684-1693.
145. Vermetten, E., Vythilingam, M., South-wick, S. M., Charney, D. S., and Bremner, J. D. (2003). Long-term treatment with paroxetine increases verbal declarative memory and hip-pocampal volume in posttraumatic stress disorder. Biol Psychiatry 54, 693-702.
146. Viola, J., Ditzler, T., Batzer, W., Harazin, J., Adams, D., Lettich, L., and Berigan, T. (1997). Pharmacological management of post-traumatic stress disorder: clinical summary of a five-year retrospective study, 1990-1995. Mil Med. 162, 616-619.
147. Wang, J. M., Johnston, P. B., Ball, B. G., and Brinton, R. D. (2005). The neurosteroid allopregnanolone promotes proliferation of rodent and human neural progenitor cells and regulates cell-cycle gene and protein expression. J. Neurosci. 25, 4706-4718.
148. Wang, J. M., Liu, L., Irwin, R. W., Chen, S., and Brinton, R. D. (2008). Regenerative potential of allopregnanolone. Brain Res. Rev. 57, 398-409.
149. Wang, J. M., Singh, C., Liu, L., Irwin, R. W., Chen, S., Chung, E. J., Thompson, R. F., and Brinton, R. D. (2010). Allopregnanolone reverses neurogenic and cognitive deficits in mouse model of Alzheimer's disease. Proc. Natl. Acad. Sci. U.S.A. 107, 6498-6503.
150. Waterhouse, E. G., and Xu, B. (2009). New insights into the role of brain-derived neurotrophic factor in synaptic plasticity. Mol. Cell. Neu-rosci. 42,81-89.
151. Wetmore, C., Olson, L., and Bean, A. J. (1994). Regulation of brain-derived neurotrophic factor (BDNF) expression and release from hippocampal neurons is mediated by non-NMDA type glutamate receptors. J. Neurosci. 14, 1688-1700.
152. Wieland, S., Lan, N. C., Mirasedeghi, S., and Gee, K. W (1991). Anx-iolytic activity of the progesterone metabolite 5 alpha-pregnan-3 alpha-o1-20-one. Brain Res. 565, 263-268.
153. Wong, E. Y., and Herbert, J. (2004). The corticoid environment: a determining factor for neural progenitors' survival in the adult hippocampus. Eur. J. Neurosci. 20, 2491-2498.
154. Zhang, Z., Yang, R., Zhou, R., Li, L., Sok-abe, M., and Chen, L. (2010). Progesterone promotes the survival of newborn neurons in the dentate gyrus of adult male mice. Hippocampus 20, 402-412