Neurosteroidogenesis Today: Novel Targets for Neuroactive Steroid Synthesis and Action and Their Relevance for Translational Research

Journal of Neuroendocrinology

Volumn 28, Issue 2, 2016, Pages 1-19

  Porcu, P ^a   Barron, A M ^b   Frye, C A ^c,d   Walf, A A ^c,d,e   Yang, S Y ^f   He, X Y ^f   Morrow, A L ^g   Panzica, G C ^h   Melcangi, R C ⁱ  

^a CNR   (Italy)

^b NATIONAL INSTITUTE OF RADIOLOGICAL SCIENCES   (Japan)

^c UNIVERSITY OF ALASKA FAIRBANKS   (United States)

^d STATE UNIVERSITY OF NEW YORK   (United States)

^e RENSSELAER POLYTECHNIC INSTITUTE   (United States)

^f NEW YORK STATE INSTITUTE FOR BASIC RESEARCH IN DEVELOPMENTAL DISABILITIES   (United States)

^g UNIVERSITY OF NORTH CAROLINA SCHOOL OF MEDICINE   (United States)

^h UNIVERSITY OF TURIN   (Italy)

ⁱ UNIVERSITY OF MILAN   (Italy)

Author keywords

17 hydroxysteroid dehydrogenase type 10; 3 ,5 THP; Alcoholism; Alzheimer's disease; Neuroactive steroids; P450 side chain cleavage; Pregnane xenobiotic receptor; Translocator protein 18 kDa

Indexed keywords

17BETA HYDROXYSTEROID DEHYDROGENASE 10; ALCOHOL; ANDROSTANEDIOL; BENZODIAZEPINE DERIVATIVE; CARRIER PROTEIN; CYTOCHROME P450; DUTASTERIDE; ESTRADIOL; ESTRONE; ETHINYLESTRADIOL; FINASTERIDE; LEVONORGESTREL; LIPOPROTEIN; MORPHINE; NEUROACTIVE STEROID; NEUROSTEROID; PREGNANE X RECEPTOR; PREGNENOLONE; PROGESTERONE; TESTOSTERONE 17BETA DEHYDROGENASE; TRANSLOCATOR PROTEIN 18 KDA; UNCLASSIFIED DRUG; 3 (OR 17)-BETA-HYDROXYSTEROID DEHYDROGENASE; 4 AMINOBUTYRIC ACID RECEPTOR; AGENTS INTERACTING WITH TRANSMITTER, HORMONE OR DRUG RECEPTORS; HYDROXYSTEROID DEHYDROGENASE; STEROID RECEPTOR; TSPO PROTEIN, HUMAN;

ALCOHOL CONSUMPTION; ALCOHOL USE DISORDER; ALCOHOLISM; ALZHEIMER DISEASE; ANDROGEN SYNTHESIS; ANTICONVULSANT ACTIVITY; APOPTOSIS; CATAMENIAL EPILEPSY; CLINICAL TRIAL (TOPIC); DEGENERATIVE DISEASE; DEMENTIA; DRUG MECHANISM; HIPPOCAMPUS; HUMAN; IMMUNOREACTIVITY; MENTAL DISEASE; MULTIPLE SCLEROSIS; NERVOUS SYSTEM DEVELOPMENT; NEUROMODULATION; NEUROPROTECTION; NEUROSTEROIDOGENESIS; NONHUMAN; PRIORITY JOURNAL; PROTEIN CLEAVAGE; PROTEIN TARGETING; REINFORCEMENT; REVIEW; SCHIZOPHRENIA; STEROIDOGENESIS; TRANSLATIONAL RESEARCH; BIOSYNTHESIS; METABOLISM;

17-HYDROXYSTEROID DEHYDROGENASES; ALCOHOLISM; ALZHEIMER DISEASE; HUMANS; NEUROTRANSMITTER AGENTS; RECEPTORS, GABA; RECEPTORS, STEROID; TRANSLATIONAL MEDICAL RESEARCH;

EID: 85017083825     PISSN: 09538194     EISSN: 13652826     Source Type: Journal    
DOI: 10.1111/jne.12351     Document Type: Review

References (224)

1. Paul SM, Purdy RH. Neuroactive steroids. FASEB J 1992; 6: 2311-2322.
2. Baulieu EE. Neurosteroids: a novel function of the brain. Psychoneuroendocrinology 1998; 23: 963-987.
3. Charlier TD, Cornil CA, Patte-Mensah C, Meyer L, Mensah-Nyagan AG, Balthazart J. Local modulation of steroid action: rapid control of enzymatic activity. Front Neurosci 2015; 9: 83.
4. Agis-Balboa RC, Pinna G, Zhubi A, Maloku E, Veldic M, Costa E, Guidotti A. Characterization of brain neurons that express enzymes mediating neurosteroid biosynthesis. Proc Natl Acad Sci USA 2006; 103: 14602-14607.
5. A receptor. Nat Rev Neurosci 2005; 6: 565-575.
6. A receptors: regulation of subunit plasticity, phasic and tonic inhibition, and neuronal network excitability. Psychopharmacology 2013; 230: 151-188.
7. A receptors through two discrete transmembrane sites. Nature 2006; 444: 486-489.
8. Rupprecht R. Neuroactive steroids: mechanisms of action and neuropsychopharmacological properties. Psychoneuroendocrinology 2003; 28: 139-168.
9. Frye CA, Paris JJ, Walf AA, Rusconi JC. Effects and mechanisms of 3α, 5α, -THP on emotion, motivation, and reward functions involving pregnane xenobiotic receptor. Front Neurosci 2012; 5: 136.
10. Smith CC, Gibbs TT, Farb DH. Pregnenolone sulfate as a modulator of synaptic plasticity. Psychopharmacology 2014; 231: 3537-3556.
11. A receptors. Pharmacol Ther 2007; 116: 35-57.
12. A receptor. Brain Res 1991; 561: 157-161.
13. Khisti RT, Chopde CT, Jain SP. Antidepressant-like effect of the neurosteroid 3α-hydroxy-5α-pregnan-20-one in mice forced swim test. Pharmacol Biochem Behav 2000; 67: 137-143.
14. Belelli D, Bolger MB, Gee KW. Anticonvulsant profile of the progesterone metabolite 5α-pregnan-3α-ol-20-one. Eur J Pharmacol 1989; 166: 325-329.
15. Hogskilde S, Wagner J, Carl P, Sorensen MB. Anaesthetic properties of pregnanolone emulsion. A comparison with alphaxolone/alphadolone, propofol, thiopentone and midazolam in a rat model. Anaesthesia 1987; 42: 1045-1050.
16. Kavaliers M, Wiebe JP. Analgesic effects of the progesterone metabolite, 3α-hydroxy-5α-pregnan-20-one, and possible modes of action in mice. Brain Res 1987; 415: 393-398.
17. Ladurelle N, Eychenne B, Denton D, Blair-West J, Schumacher M, Robel P, Baulieu E. Prolonged intracerebroventricular infusion of neurosteroids affects cognitive performances in the mouse. Brain Res 2000; 858: 371-379.
18. Johansson IM, Birzniece V, Lindblad C, Olsson T, Backstrom T. Allopregnanolone inhibits learning in the Morris water maze. Brain Res 2002; 934: 125-131.
19. Frye CA, Bayon LE, Pursnani NK, Purdy RH. The neurosteroids, progesterone and 3α, 5α-THP, enhance sexual motivation, receptivity, and proceptivity in female rats. Brain Res 1998; 808: 72-83.
20. Finn DA, Phillips TJ, Okorn DM, Chester JA, Cunningham CL. Rewarding effect of the neuroactive steroid 3α-hydroxy-5α-pregnan-20-one in mice. Pharmacol Biochem Behav 1997; 56: 261-264.
21. Sinnott RS, Mark GP, Finn DA. Reinforcing effects of the neurosteroid allopregnanolone in rats. Pharmacol Biochem Behav 2002; 72: 923-929.
22. Purdy RH, Valenzuela CF, Janak PH, Finn DA, Biggio G, Backstrom T. Neuroactive steroids and ethanol. Alcohol Clin Exp Res 2005; 29: 1292-1298.
23. Porcu P, Morrow AL. Divergent neuroactive steroid responses to stress and ethanol in rat and mouse strains: relevance for human studies. Psychopharmacology 2014; 231: 3257-3272.
24. Anker JJ, Carroll ME. The role of progestins in the behavioral effects of cocaine and other drugs of abuse: human and animal research. Neurosci Biobehav Rev 2010; 35: 315-333.
25. VanDoren MJ, Matthews DB, Janis GC, Grobin AC, Devaud LL, Morrow AL. Neuroactive steroid 3α-hydroxy-5α-pregnan-20-one modulates electrophysiological and behavioral actions of ethanol. J Neurosci 2000; 20: 1982-1989.
26. Porcu P, Sogliano C, Cinus M, Purdy RH, Biggio G, Concas A. Nicotine-induced changes in cerebrocortical neuroactive steroids and plasma corticosterone concentrations in the rat. Pharmacol Biochem Behav 2003; 74: 683-690.
27. Porcu P, Sogliano C, Ibba C, Piredda M, Tocco S, Marra C, Purdy RH, Biggio G, Concas A. Failure of gamma-hydroxybutyric acid both to increase neuroactive steroid concentrations in adrenalectomized-orchiectomized rats and to induce tolerance to its steroidogenic effect in intact animals. Brain Res 2004; 1012: 160-168.
28. Grobin AC, VanDoren MJ, Porrino LJ, Morrow AL. Cortical 3α-hydroxy-5α-pregnan-20-one levels after acute administration of Δ9-tetrahydrocannabinol, cocaine and morphine. Psychopharmacology 2005; 179: 544-550.
29. Concas A, Sogliano C, Porcu P, Marra C, Brundu A, Biggio G. Neurosteroids in nicotine and morphine dependence. Psychopharmacology 2006; 186: 281-292.
30. Vallee M, Vitiello S, Bellocchio L, Hebert-Chatelain E, Monlezun S, Martin-Garcia E, Kasanetz F, Baillie GL, Panin F, Cathala A, Roullot-Lacarriere V, Fabre S, Hurst DP, Lynch DL, Shore DM, Deroche-Gamonet V, Spampinato U, Revest JM, Maldonado R, Reggio PH, Ross RA, Marsicano G, Piazza PV. Pregnenolone can protect the brain from cannabis intoxication. Science 2014; 343: 94-98.
31. Djebaili M, Guo Q, Pettus EH, Hoffman SW, Stein DG. The neurosteroids progesterone and allopregnanolone reduce cell death, gliosis, and functional deficits after traumatic brain injury in rats. J Neurotrauma 2005; 22: 106-118.
32. Labombarda F, Gonzalez S, Lima A, Roig P, Guennoun R, Schumacher M, De Nicola AF. Progesterone attenuates astro- and microgliosis and enhances oligodendrocyte differentiation following spinal cord injury. Exp Neurol 2011; 231: 135-146.
33. Panzica GC, Balthazart J, Frye CA, Garcia-Segura LM, Herbison AE, Mensah-Nyagan AG, McCarthy MM, Melcangi RC. Milestones on Steroids and the Nervous System: 10 years of basic and translational research. J Neuroendocrinol 2012; 24: 1-15.
34. Melcangi RC, Giatti S, Pesaresi M, Calabrese D, Mitro N, Caruso D, Garcia-Segura LM. Role of neuroactive steroids in the peripheral nervous system. Front Endocrinol (Lausanne) 2011; 2: 104.
35. Giatti S, Boraso M, Melcangi RC, Viviani B. Neuroactive steroids, their metabolites, and neuroinflammation. J Mol Endocrinol 2012; 49: R125-R134.
36. Sayeed I, Stein DG. Progesterone as a neuroprotective factor in traumatic and ischemic brain injury. Prog Brain Res 2009; 175: 219-237.
37. Guennoun R, Labombarda F, Gonzalez Deniselle MC, Liere P, De Nicola AF, Schumacher M. Progesterone and allopregnanolone in the central nervous system: response to injury and implication for neuroprotection. J Steroid Biochem Mol Biol 2015; 146: 48-61.
38. Ciriza I, Carrero P, Frye CA, Garcia-Segura LM. 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.
39. Noorbakhsh F, Ellestad KK, Maingat F, Warren KG, Han MH, Steinman L, Baker GB, Power C. Impaired neurosteroid synthesis in multiple sclerosis. Brain 2011; 134: 2703-2721.
40. Giatti S, Caruso D, Boraso M, Abbiati F, Ballarini E, Calabrese D, Pesaresi M, Rigolio R, Santos-Galindo M, Viviani B, Cavaletti G, Garcia-Segura LM, Melcangi RC. Neuroprotective effects of progesterone in chronic experimental autoimmune encephalomyelitis. J Neuroendocrinol 2012; 24: 851-861.
41. Giatti S, Rigolio R, Romano S, Mitro N, Viviani B, Cavaletti G, Caruso D, Garcia-Segura LM, Melcangi RC. Dihydrotestosterone as a protective agent in chronic experimental autoimmune encephalomyelitis. Neuroendocrinology 2015; 101: 296-308.
42. Brinton RD. Neurosteroids as regenerative agents in the brain: therapeutic implications. Nat Rev Endocrinol 2013; 9: 241-250.
43. Adeosun SO, Hou X, Jiao Y, Zheng B, Henry S, Hill R, He Z, Pani A, Kyle P, Ou X, Mosley T, Farley JM, Stockmeier C, Paul I, Bigler S, Brinton RD, Smeyne R, Wang JM. Allopregnanolone reinstates tyrosine hydroxylase immunoreactive neurons and motor performance in an MPTP-lesioned mouse model of Parkinson's disease. PLoS ONE 2012; 7: e50040.
44. Griffin LD, Gong W, Verot L, Mellon SH. Niemann-Pick type C disease involves disrupted neurosteroidogenesis and responds to allopregnanolone. Nat Med 2004; 10: 704-711.
45. Atif F, Yousuf S, Stein DG. Anti-tumor effects of progesterone in human glioblastoma multiforme: role of PI3K/Akt/mTOR signaling. J Steroid Biochem Mol Biol 2015; 146: 62-73.
46. Purdy RH, Morrow AL, Moore PH Jr, Paul SM. Stress-induced elevations of gamma-aminobutyric acid type A receptor-active steroids in the rat brain. Proc Natl Acad Sci USA 1991; 88: 4553-4557.
47. Girdler SS, Straneva PA, Light KC, Pedersen CA, Morrow AL. Allopregnanolone levels and reactivity to mental stress in premenstrual dysphoric disorder. Biol Psychiatry 2001; 49: 788-797.
48. A receptor-acting neurosteroids: a role in the development and regulation of the stress response. Front Neuroendocrinol 2015; 36: 28-48.
49. - flux across development in rat cerebral cortex. Brain Res Dev Brain Res 2001; 131: 31-39.
50. A receptors triggers anxiety at puberty. Nat Neurosci 2007; 10: 469-477.
51. Corpechot C, Collins BE, Carey MP, Tsouros A, Robel P, Fry JP. Brain neurosteroids during the mouse oestrous cycle. Brain Res 1997; 766: 276-280.
52. Wang M, Seippel L, Purdy RH, Backstrom T. Relationship between symptom severity and steroid variation in women with premenstrual syndrome: study on serum pregnenolone, pregnenolone sulfate, 5α-pregnane-3, 20-dione and 3α-hydroxy-5α-pregnan-20-one. J Clin Endocrinol Metab 1996; 81: 1076-1082.
53. A receptors mediating tonic inhibition alter seizure susceptibility and anxiety. Nat Neurosci 2005; 8: 797-804.
54. Concas A, Mostallino MC, Porcu P, Follesa P, Barbaccia ML, Trabucchi M, Purdy RH, Grisenti P, Biggio G. Role of brain allopregnanolone in the plasticity of γ-aminobutyric acid type A receptor in rat brain during pregnancy and after delivery. Proc Natl Acad Sci USA 1998; 95: 13284-13289.
55. Gilbert Evans SE, Ross LE, Sellers EM, Purdy RH, Romach MK. 3α-reduced neuroactive steroids and their precursors during pregnancy and the postpartum period. Gynecol Endocrinol 2005; 21: 268-279.
56. AR plasticity during pregnancy: relevance to postpartum depression. Neuron 2008; 59: 207-213.
57. A receptors in the rat hippocampus during pregnancy and after delivery. J Neurosci 2009; 29: 1755-1765.
58. A receptors: focus on the α4 and δ subunits. Pharmacol Ther 2007; 116: 58-76.
59. A receptor γ2 subunit gene expression induced by long-term administration of oral contraceptives in rats. Neuropharmacology 2002; 42: 325-336.
60. Sassoè-Pognetto M, Follesa P, Panzanelli P, Perazzini AZ, Porcu P, Sogliano C, Cherchi C, Concas A. Fluctuations in brain concentrations of neurosteroids are not associated to changes in gephyrin levels. Brain Res 2007; 1169: 1-8.
61. A receptor subunit expression and anxiety-like behavior. Pharmacol Biochem Behav 2012; 102: 366-372.
62. McCarthy MM. Estradiol and the developing brain. Physiol Rev 2008; 88: 91-124.
63. A receptor expression, and behavioral sensitivity to anxiolytic drugs. J Neurochem 2010; 113: 1285-1295.
64. Berretti R, Santoru F, Locci A, Sogliano C, Calza A, Choleris E, Porcu P, Concas A. Neonatal exposure to estradiol decreases hypothalamic allopregnanolone concentrations and alters agonistic and sexual but not affective behavior in adult female rats. Horm Behav 2014; 65: 142-153.
65. AR subunits expression and behavioural responses to progesterone in adult rats. Int J Neuropsychopharmacol 2014; 17: 259-273.
66. A receptors. Proc Natl Acad Sci USA 2014; 111: 7132-7137.
67. Melcangi RC, Panzica GC. Allopregnanolone: state of the art. Prog Neurobiol 2014; 113: 1-5.
68. Schule C, Nothdurfter C, Rupprecht R. The role of allopregnanolone in depression and anxiety. Prog Neurobiol 2014; 113: 79-87.
69. Girdler SS, Lindgren M, Porcu P, Rubinow DR, Johnson JL, Morrow AL. A history of depression in women is associated with an altered GABAergic neuroactive steroid profile. Psychoneuroendocrinology 2012; 37: 543-553.
70. Backstrom T, Bixo M, Johansson M, Nyberg S, Ossewaarde L, Ragagnin G, Savic I, Stromberg J, Timby E, van Broekhoven F, van Wingen G. Allopregnanolone and mood disorders. Prog Neurobiol 2014; 113: 88-94.
71. Pinna G. Targeting neurosteroidogenesis as therapy for PTSD. Front Pharmacol 2014; 4: 166.
72. Marx CE, Stevens RD, Shampine LJ, Uzunova V, Trost WT, Butterfield MI, Massing MW, Hamer RM, Morrow AL, Lieberman JA. Neuroactive steroids are altered in schizophrenia and bipolar disorder: relevance to pathophysiology and therapeutics. Neuropsychopharmacology 2006; 31: 1249-1263.
73. Romeo E, Brancati A, De Lorenzo A, Fucci P, Furnari C, Pompili E, Sasso GF, Spalletta G, Troisi A, Pasini A. Marked decrease of plasma neuroactive steroids during alcohol withdrawal. Clin Neuropharmacol 1996; 19: 366-369.
74. Porcu P, O'Buckley TK, Morrow AL, Adinoff B. Differential hypothalamic-pituitary-adrenal activation of the neuroactive steroids pregnenolone sulfate and deoxycorticosterone in healthy controls and alcohol-dependent subjects. Psychoneuroendocrinology 2008; 33: 214-226.
75. A receptor function in rat brain. J Neurochem 2000; 75: 732-740.
76. Serra M, Sanna E, Mostallino MC, Biggio G. Social isolation stress and neuroactive steroids. Eur Neuropsychopharmacol 2007; 17: 1-11.
77. Uzunova V, Ceci M, Kohler C, Uzunov DP, Wrynn AS. Region-specific dysregulation of allopregnanolone brain content in the olfactory bulbectomized rat model of depression. Brain Res 2003; 976: 1-8.
78. Pibiri F, Nelson M, Guidotti A, Costa E, Pinna G. 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.
79. Caruso D, Abbiati F, Giatti S, Romano S, Fusco L, Cavaletti G, Melcangi RC. Patients treated for male pattern hair with finasteride show, after discontinuation of the drug, altered levels of neuroactive steroids in cerebrospinal fluid and plasma. J Steroid Biochem Mol Biol 2015; 146: 74-79.
80. Marx CE, VanDoren MJ, Duncan GE, Lieberman JA, Morrow AL. Olanzapine and clozapine increase the GABAergic neuroactive steroid allopregnanolone in rodents. Neuropsychopharmacology 2003; 28: 1-13.
81. Marx CE, Keefe RS, Buchanan RW, Hamer RM, Kilts JD, Bradford DW, Strauss JL, Naylor JC, Payne VM, Lieberman JA, Savitz AJ, Leimone LA, Dunn L, Porcu P, Morrow AL, Shampine LJ. Proof-of-concept trial with the neurosteroid pregnenolone targeting cognitive and negative symptoms in schizophrenia. Neuropsychopharmacology 2009; 34: 1885-1903.
82. Pieribone VA, Tsai J, Soufflet C, Rey E, Shaw K, Giller E, Dulac O. Clinical evaluation of ganaxolone in pediatric and adolescent patients with refractory epilepsy. Epilepsia 2007; 48: 1870-1874.
83. Herzog AG, Frye CA. Allopregnanolone levels and seizure frequency in progesterone-treated women with epilepsy. Neurology 2014; 83: 345-348.
84. Rogawski MA, Loya CM, Reddy K, Zolkowska D, Lossin C. Neuroactive steroids for the treatment of status epilepticus. Epilepsia 2013; 54(Suppl 6): 93-98.
85. Caruso D, D'Intino G, Giatti S, Maschi O, Pesaresi M, Calabrese D, Garcia-Segura LM, Calza L, Melcangi RC. Sex-dimorphic changes in neuroactive steroid levels after chronic experimental autoimmune encephalomyelitis. J Neurochem 2010; 114: 921-932.
86. Caruso D, Melis M, Fenu G, Giatti S, Romano S, Grimoldi M, Crippa D, Marrosu MG, Cavaletti G, Melcangi RC. Neuroactive steroid levels in plasma and cerebrospinal fluid of male multiple sclerosis patients. J Neurochem 2014; 130: 591-597.
87. Schumacher M, Weill-Engerer S, Liere P, Robert F, Franklin RJ, Garcia-Segura LM, Lambert JJ, Mayo W, Melcangi RC, Parducz A, Suter U, Carelli C, Baulieu EE, Akwa Y. Steroid hormones and neurosteroids in normal and pathological aging of the nervous system. Prog Neurobiol 2003; 71: 3-29.
88. Caruso D, Barron AM, Brown MA, Abbiati F, Carrero P, Pike CJ, Garcia-Segura LM, Melcangi RC. Age-related changes in neuroactive steroid levels in 3×Tg-AD mice. Neurobiol Aging 2013; 34: 1080-1089.
89. Marx CE, Trost WT, Shampine LJ, Stevens RD, Hulette CM, Steffens DC, Ervin JF, Butterfield MI, Blazer DG, Massing MW, Lieberman JA. The neurosteroid allopregnanolone is reduced in prefrontal cortex in Alzheimer's disease. Biol Psychiatry 2006; 60: 1287-1294.
90. di Michele F, Longone P, Romeo E, Lucchetti S, Brusa L, Pierantozzi M, Bassi A, Bernardi G, Stanzione P. Decreased plasma and cerebrospinal fluid content of neuroactive steroids in Parkinson's disease. Neurol Sci 2003; 24: 172-173.
91. Lopez-Rodriguez AB, Acaz-Fonseca E, Giatti S, Caruso D, Viveros MP, Melcangi RC, Garcia-Segura LM. Correlation of brain levels of progesterone and dehydroepiandrosterone with neurological recovery after traumatic brain injury in female mice. Psychoneuroendocrinology 2015; 56: 1-11.
92. Pesaresi M, Maschi O, Giatti S, Garcia-Segura LM, Caruso D, Melcangi RC. Sex differences in neuroactive steroid levels in the nervous system of diabetic and non-diabetic rats. Horm Behav 2010; 57: 46-55.
93. Melcangi RC, Giatti S, Calabrese D, Pesaresi M, Cermenati G, Mitro N, Viviani B, Garcia-Segura LM, Caruso D. Levels and actions of progesterone and its metabolites in the nervous system during physiological and pathological conditions. Prog Neurobiol 2014; 113: 56-69.
94. Wang JM, Singh C, Liu L, Irwin RW, Chen S, Chung EJ, Thompson RF, Brinton RD. Allopregnanolone reverses neurogenic and cognitive deficits in mouse model of Alzheimer's disease. Proc Natl Acad Sci USA 2010; 107: 6498-6503.
95. Irwin RW, Brinton RD. Allopregnanolone as regenerative therapeutic for Alzheimer's disease: translational development and clinical promise. Prog Neurobiol 2014; 113: 40-55.
96. Leonelli E, Bianchi R, Cavaletti G, Caruso D, Crippa D, Garcia-Segura LM, Lauria G, Magnaghi V, Roglio I, Melcangi RC. Progesterone and its derivatives are neuroprotective agents in experimental diabetic neuropathy: a multimodal analysis. Neuroscience 2007; 144: 1293-1304.
97. Liu A, Margaill I, Zhang S, Labombarda F, Coqueran B, Delespierre B, Liere P, Marchand-Leroux C, O'Malley BW, Lydon JP, De Nicola AF, Sitruk-Ware R, Mattern C, Plotkine M, Schumacher M, Guennoun R. Progesterone receptors: a key for neuroprotection in experimental stroke. Endocrinology 2012; 153: 3747-3757.
98. Timby E, Balgard M, Nyberg S, Spigset O, Andersson A, Porankiewicz-Asplund J, Purdy RH, Zhu D, Backstrom T, Poromaa IS. Pharmacokinetic and behavioral effects of allopregnanolone in healthy women. Psychopharmacology 2006; 186: 414-424.
99. Irwin RW, Solinsky CM, Brinton RD. Frontiers in therapeutic development of allopregnanolone for Alzheimer's disease and other neurological disorders. Front Cell Neurosci 2014; 8: 203.
100. Zhu D, Birzniece V, Backstrom T, Wahlstrom G. Dynamic aspects of acute tolerance to allopregnanolone evaluated using anaesthesia threshold in male rats. Br J Anaesth 2004; 93: 560-567.
101. Kask K, Backstrom T, Nilsson LG, Sundstrom-Poromaa I. Allopregnanolone impairs episodic memory in healthy women. Psychopharmacology 2008; 199: 161-168.
102. Grant KA, Helms CM, Rogers LS, Purdy RH. Neuroactive steroid stereospecificity of ethanol-like discriminative stimulus effects in monkeys. J Pharmacol Exp Ther 2008; 326: 354-361.
103. Wang HJ, Fan J, Papadopoulos V. Translocator protein (Tspo) gene promoter-driven green fluorescent protein synthesis in transgenic mice: an in vivo model to study Tspo transcription. Cell Tissue Res 2012; 350: 261-275.
104. Rupprecht R, Papadopoulos V, Rammes G, Baghai TC, Fan J, Akula N, Groyer G, Adams D, Schumacher M. Translocator protein (18 kDa) (TSPO) as a therapeutic target for neurological and psychiatric disorders. Nat Rev Drug Discov 2010; 9: 971-988.
105. Costa E, Guidotti A. Diazepam binding inhibitor (DBI): a peptide with multiple biological actions. Life Sci 1991; 49: 325-344.
106. Do-Rego JL, Mensah-Nyagan AG, Feuilloley M, Ferrara P, Pelletier G, Vaudry H. The endozepine triakontatetraneuropeptide diazepam-binding inhibitor [17-50] stimulates neurosteroid biosynthesis in the frog hypothalamus. Neuroscience 1998; 83: 555-570.
107. Tu LN, Morohaku K, Manna PR, Pelton SH, Butler WR, Stocco DM, Selvaraj V. Peripheral benzodiazepine receptor/translocator protein global knock-out mice are viable with no effects on steroid hormone biosynthesis. J Biol Chem 2014; 289: 27444-27454.
108. Morohaku K, Pelton SH, Daugherty DJ, Butler WR, Deng W, Selvaraj V. Translocator protein/peripheral benzodiazepine receptor is not required for steroid hormone biosynthesis. Endocrinology 2014; 155: 89-97.
109. Banati RB, Middleton RJ, Chan R, Hatty CR, Kam WW, Quin C, Graeber MB, Parmar A, Zahra D, Callaghan P, Fok S, Howell NR, Gregoire M, Szabo A, Pham T, Davis E, Liu GJ. Positron emission tomography and functional characterization of a complete PBR/TSPO knockout. Nat Commun 2014; 5: 5452.
110. Fan J, Campioli E, Midzak A, Culty M, Papadopoulos V. Conditional steroidogenic cell-targeted deletion of TSPO unveils a crucial role in viability and hormone-dependent steroid formation. Proc Natl Acad Sci USA 2015; 112: 7261-7266.
111. Gut P, Zweckstetter M, Banati RB. Lost in translocation: the functions of the 18-kD translocator protein. Trends Endocrinol Metab 2015; 26: 349-356.
112. Bitran D, Foley M, Audette D, Leslie N, Frye CA. Activation of peripheral mitochondrial benzodiazepine receptors in the hippocampus stimulates allopregnanolone synthesis and produces anxiolytic-like effects in the rat. Psychopharmacology 2000; 151: 64-71.
113. Romeo E, Cavallaro S, Korneyev A, Kozikowski AP, Ma D, Polo A, Costa E, Guidotti A. Stimulation of brain steroidogenesis by 2-aryl-indole-3-acetamide derivatives acting at the mitochondrial diazepam-binding inhibitor receptor complex. J Pharmacol Exp Ther 1993; 267: 462-471.
114. Serra M, Madau P, Chessa MF, Caddeo M, Sanna E, Trapani G, Franco M, Liso G, Purdy RH, Barbaccia ML, Biggio G. 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 1999; 127: 177-187.
115. Verleye M, Akwa Y, Liere P, Ladurelle N, Pianos A, Eychenne B, Schumacher M, Gillardin JM. The anxiolytic etifoxine activates the peripheral benzodiazepine receptor and increases the neurosteroid levels in rat brain. Pharmacol Biochem Behav 2005; 82: 712-720.
116. Barron AM, Garcia-Segura LM, Caruso D, Jayaraman A, Lee JW, Melcangi RC, Pike CJ. Ligand for translocator protein reverses pathology in a mouse model of Alzheimer's disease. J Neurosci 2013; 33: 8891-8897.
117. Rupprecht R, Rammes G, Eser D, Baghai TC, Schule C, Nothdurfter C, Troxler T, Gentsch C, Kalkman HO, Chaperon F, Uzunov V, McAllister KH, Bertaina-Anglade V, La Rochelle CD, Tuerck D, Floesser A, Kiese B, Schumacher M, Landgraf R, Holsboer F, Kucher K. Translocator protein (18 kD) as target for anxiolytics without benzodiazepine-like side effects. Science 2009; 325: 490-493.
118. Korneyev A, Pan BS, Polo A, Romeo E, Guidotti A, Costa E. Stimulation of brain pregnenolone synthesis by mitochondrial diazepam binding inhibitor receptor ligands in vivo. J Neurochem 1993; 61: 1515-1524.
119. Barron AM, Pike CJ. Sex hormones, aging, and Alzheimer's disease. Front Biosci (Elite Ed) 2012; 4: 976-997.
120. Papadopoulos V, Lecanu L. Translocator protein (18 kDa) TSPO: an emerging therapeutic target in neurotrauma. Exp Neurol 2009; 219: 53-57.
121. Zimmer ER, Leuzy A, Benedet AL, Breitner J, Gauthier S, Rosa-Neto P. Tracking neuroinflammation in Alzheimer's disease: the role of positron emission tomography imaging. J Neuroinflammation 2014; 11: 120.
122. Li F, Liu J, Valls L, Hiser C, Ferguson-Miller S. Identification of a key cholesterol binding enhancement motif in translocator protein 18 kDa. Biochemistry 2015; 54: 1441-1443.
123. Jaremko L, Jaremko M, Giller K, Becker S, Zweckstetter M. Structure of the mitochondrial translocator protein in complex with a diagnostic ligand. Science 2014; 343: 1363-1366.
124. Li F, Liu J, Zheng Y, Garavito RM, Ferguson-Miller S. Protein structure. Crystal structures of translocator protein (TSPO) and mutant mimic of a human polymorphism. Science 2015; 347: 555-558.
125. Costa B, Pini S, Gabelloni P, Da Pozzo E, Abelli M, Lari L, Preve M, Lucacchini A, Cassano GB, Martini C. The spontaneous Ala147Thr amino acid substitution within the translocator protein influences pregnenolone production in lymphomonocytes of healthy individuals. Endocrinology 2009; 150: 5438-5445.
126. Banati RB, Gehrmann J, Czech C, Monning U, Jones LL, Konig G, Beyreuther K, Kreutzberg GW. Early and rapid de novo synthesis of Alzheimer beta A4-amyloid precursor protein (APP) in activated microglia. Glia 1993; 9: 199-210.
127. Veiga S, Azcoitia I, Garcia-Segura LM. Ro5-4864, a peripheral benzodiazepine receptor ligand, reduces reactive gliosis and protects hippocampal hilar neurons from kainic acid excitotoxicity. J Neurosci Res 2005; 80: 129-137.
128. Veiga S, Carrero P, Pernia O, Azcoitia I, Garcia-Segura LM. Translocator protein 18 kDa is involved in the regulation of reactive gliosis. Glia 2007; 55: 1426-1436.
129. 2+]i responses in human microglia by the peripheral benzodiazepine receptor ligand PK11195. J Neurochem 2002; 83: 546-555.
130. Szekely CA, Thorne JE, Zandi PP, Ek M, Messias E, Breitner JC, Goodman SN. Nonsteroidal anti-inflammatory drugs for the prevention of Alzheimer's disease: a systematic review. Neuroepidemiology 2004; 23: 159-169.
131. Nothdurfter C, Rammes G, Baghai TC, Schule C, Schumacher M, Papadopoulos V, Rupprecht R. Translocator protein (18 kDa) as a target for novel anxiolytics with a favourable side-effect profile. J Neuroendocrinol 2012; 24: 82-92.
132. Kita A, Kinoshita T, Kohayakawa H, Furukawa K, Akaike A. Lack of tolerance to anxiolysis and withdrawal symptoms in mice repeatedly treated with AC-5216, a selective TSPO ligand. Prog Neuropsychopharmacol Biol Psychiatry 2009; 33: 1040-1045.
133. Sink KM, Holden KF, Yaffe K. Pharmacological treatment of neuropsychiatric symptoms of dementia: a review of the evidence. JAMA 2005; 293: 596-608.
134. Do Rego JL, Seong JY, Burel D, Leprince J, Vaudry D, Luu-The V, Tonon MC, Tsutsui K, Pelletier G, Vaudry H. Regulation of neurosteroid biosynthesis by neurotransmitters and neuropeptides. Front Endocrinol (Lausanne) 2012; 3: 4.
135. King SR, Manna PR, Ishii T, Syapin PJ, Ginsberg SD, Wilson K, Walsh LP, Parker KL, Stocco DM, Smith RG, Lamb DJ. An essential component in steroid synthesis, the steroidogenic acute regulatory protein, is expressed in discrete regions of the brain. J Neurosci 2002; 22: 10613-10620.
136. Mellon SH, Deschepper CF. Neurosteroid biosynthesis: genes for adrenal steroidogenic enzymes are expressed in the brain. Brain Res 1993; 629: 283-292.
137. Papadopoulos V, Baraldi M, Guilarte TR, Knudsen TB, Lacapere JJ, Lindemann P, Norenberg MD, Nutt D, Weizman A, Zhang MR, Gavish M. Translocator protein (18 kDa): new nomenclature for the peripheral-type benzodiazepine receptor based on its structure and molecular function. Trends Pharmacol Sci 2006; 27: 402-409.
138. Frye CA. Novel substrates for, and sources of, progestogens for reproduction. J Neuroendocrinol 2011; 23: 961-973.
139. Bertilsson G, Heidrich J, Svensson K, Asman M, Jendeberg L, Sydow-Backman M, Ohlsson R, Postlind H, Blomquist P, Berkenstam A. Identification of a human nuclear receptor defines a new signaling pathway for CYP3A induction. Proc Natl Acad Sci USA 1998; 95: 12208-12213.
140. Kliewer SA, Moore JT, Wade L, Staudinger JL, Watson MA, Jones SA, McKee DD, Oliver BB, Willson TM, Zetterstrom RH, Perlmann T, Lehmann JM. An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway. Cell 1998; 92: 73-82.
141. Lamba V, Yasuda K, Lamba JK, Assem M, Davila J, Strom S, Schuetz EG. PXR (NR1I2): splice variants in human tissues, including brain, and identification of neurosteroids and nicotine as PXR activators. Toxicol Appl Pharmacol 2004; 199: 251-265.
142. Dutheil F, Dauchy S, Diry M, Sazdovitch V, Cloarec O, Mellottee L, Bieche I, Ingelman-Sundberg M, Flinois JP, de Waziers I, Beaune P, Decleves X, Duyckaerts C, Loriot MA. Xenobiotic-metabolizing enzymes and transporters in the normal human brain: regional and cellular mapping as a basis for putative roles in cerebral function. Drug Metab Dispos 2009; 37: 1528-1538.
143. Frye CA, Koonce CJ, Walf AA. Pregnane xenobiotic receptors and membrane progestin receptors: role in neurosteroid-mediated motivated behaviours. J Neuroendocrinol 2013; 25: 1002-1011.
144. Frye CA, Koonce CJ, Walf AA. Involvement of pregnane xenobiotic receptor in mating-induced allopregnanolone formation in the midbrain and hippocampus and brain-derived neurotrophic factor in the hippocampus among female rats. Psychopharmacology 2014; 231: 3375-3390.
145. Marini S, Nannelli A, Sodini D, Dragoni S, Valoti M, Longo V, Gervasi PG. Expression, microsomal and mitochondrial activities of cytochrome P450 enzymes in brain regions from control and phenobarbital-treated rabbits. Life Sci 2007; 80: 910-917.
146. Frye CA, Koonce CJ, Walf AA, Rusconi JC. Motivated behaviors and levels of 3α, 5α-THP in the midbrain are attenuated by knocking down expression of pregnane xenobiotic receptor in the midbrain ventral tegmental area of proestrous rats. J Sex Med 2013; 10: 1692-1706.
147. Frye CA, Koonce CJ, Walf AA. Novel receptor targets for production and action of allopregnanolone in the central nervous system: a focus on pregnane xenobiotic receptor. Front Cell Neurosci 2014; 8: 106.
148. Frye CA, Koonce CJ, Walf AA. Role of pregnane xenobiotic receptor in the midbrain ventral tegmental area for estradiol- and 3α, 5α-THP-facilitated lordosis of female rats. Psychopharmacology 2014; 231: 3365-3374.
149. Frye CA, Koonce CJ, Walf AA. The pregnane xenobiotic receptor, a prominent liver factor, has actions in the midbrain for neurosteroid synthesis and behavioral/neural plasticity of female rats. Front Syst Neurosci 2014; 8: 60.
150. Walf AA, Rhodes ME, Frye CA. Ovarian steroids enhance object recognition in naturally cycling and ovariectomized, hormone-primed rats. Neurobiol Learn Mem 2006; 86: 35-46.
151. Frye CA, Walf AA. Progesterone enhances learning and memory of aged wildtype and progestin receptor knockout mice. Neurosci Lett 2010; 472: 38-42.
152. Frye CA, Koonce CJ, Walf AA. Progesterone, compared to medroxyprogesterone acetate, to C57BL/6, but not 5α-reductase mutant, mice enhances object recognition and placement memory and is associated with higher BDNF levels in the hippocampus and cortex. Neurosci Lett 2013; 551: 53-57.
153. Paris JJ, Walf AA, Frye CA. II. Cognitive performance of middle-aged female rats is influenced by capacity to metabolize progesterone in the prefrontal cortex and hippocampus. Brain Res 2011; 1379: 149-163.
154. Smith CD, Wekstein DR, Markesbery WR, Frye CA. 3α, 5α-THP: a potential plasma neurosteroid biomarker in Alzheimer's disease and perhaps non-Alzheimer's dementia. Psychopharmacology 2006; 186: 481-485.
155. Borchelt DR, Ratovitski T, van Lare J, Lee MK, Gonzales V, Jenkins NA, Copeland NG, Price DL, Sisodia SS. Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins. Neuron 1997; 19: 939-945.
156. Frye CA, Walf AA. Effects of progesterone administration and APPswe+PSEN1Deltae9 mutation for cognitive performance of mid-aged mice. Neurobiol Learn Mem 2008; 89: 17-26.
157. Frye CA, Walf AA. Progesterone reduces depression-like behavior in a murine model of Alzheimer's Disease. Age (Dordr) 2009; 31: 143-153.
158. Mandrekar-Colucci S, Karlo JC, Landreth GE. Mechanisms underlying the rapid peroxisome proliferator-activated receptor-γ-mediated amyloid clearance and reversal of cognitive deficits in a murine model of Alzheimer's disease. J Neurosci 2012; 32: 10117-10128.
159. Wang K, Wan YJ. Nuclear receptors and inflammatory diseases. Exp Biol Med (Maywood) 2008; 233: 496-506.
160. Miller WL. Steroid hormone synthesis in mitochondria. Mol Cell Endocrinol 2013; 379: 62-73.
161. Cook JB, Werner DF, Maldonado-Devincci AM, Leonard MN, Fisher KR, O'Buckley TK, Porcu P, McCown TJ, Besheer J, Hodge CW, Morrow AL. Overexpression of the steroidogenic enzyme cytochrome P450 side chain cleavage in the ventral tegmental area increases 3α, 5α-THP and reduces long-term operant ethanol self-administration. J Neurosci 2014; 34: 5824-5834.
162. Pradhan DS, Lau LY, Schmidt KL, Soma KK. 3β-HSD in songbird brain: subcellular localization and rapid regulation by estradiol. J Neurochem 2010; 115: 667-675.
163. He XY, Wegiel J, Yang YZ, Pullarkat R, Schulz H, Yang SY. Type 10 17beta-hydroxysteroid dehydrogenase catalyzing the oxidation of steroid modulators of gamma-aminobutyric acid type A receptors. Mol Cell Endocrinol 2005; 229: 111-117.
164. He XY, Wegiel J, Yang SY. Intracellular oxidation of allopregnanolone by human brain type 10 17β-hydroxysteroid dehydrogenase. Brain Res 2005; 1040: 29-35.
165. Yang SY, He XY, Schulz H. Multiple functions of type 10 17β-hydroxysteroid dehydrogenase. Trends Endocrinol Metab 2005; 16: 167-175.
166. Yang SY, He XY, Miller D. HSD17B10: a gene involved in cognitive function through metabolism of isoleucine and neuroactive steroids. Mol Genet Metab 2007; 92: 36-42.
167. Yang SY, He XY, Miller D. Hydroxysteroid (17β) dehydrogenase X in human health and disease. Mol Cell Endocrinol 2011; 343: 1-6.
168. Yang SY, He XY, Isaacs C, Dobkin C, Miller D, Philipp M. Roles of 17β-hydroxysteroid dehydrogenase type 10 in neurodegenerative disorders. J Steroid Biochem Mol Biol 2014; 143: 460-472.
169. He XY, Yang YZ, Schulz H, Yang SY. Intrinsic alcohol dehydrogenase and hydroxysteroid dehydrogenase activities of human mitochondrial short-chain L-3-hydroxyacyl-CoA dehydrogenase. Biochem J 2000; 345: 139-143.
170. He XY, Merz G, Mehta P, Schulz H, Yang SY. Human brain short chain L-3-hydroxyacyl coenzyme A dehydrogenase is a single-domain multifunctional enzyme. Characterization of a novel 17β-hydroxysteroid dehydrogenase. J Biol Chem 1999; 274: 15014-15019.
171. He XY, Merz G, Yang YZ, Mehta P, Schulz H, Yang SY. Characterization and localization of human type10 17β-hydroxysteroid dehydrogenase. Eur J Biochem 2001; 268: 4899-4907.
172. He XY, Yang YZ, Peehl DM, Lauderdale A, Schulz H, Yang SY. Oxidative 3α-hydroxysteroid dehydrogenase activity of human type 10 17β-hydroxysteroid dehydrogenase. J Steroid Biochem Mol Biol 2003; 87: 191-198.
173. He XY, Merz G, Yang YZ, Pullakart R, Mehta P, Schulz H, Yang SY. Function of human brain short chain L-3-hydroxyacyl coenzyme A dehydrogenase in androgen metabolism. Biochim Biophys Acta 2000; 1484: 267-277.
174. Yang SY, He XY, Olpin SE, Sutton VR, McMenamin J, Philipp M, Denman RB, Malik M. Mental retardation linked to mutations in the HSD17B10 gene interfering with neurosteroid and isoleucine metabolism. Proc Natl Acad Sci USA 2009; 106: 14820-14824.
175. Seaver LH, He XY, Abe K, Cowan T, Enns GM, Sweetman L, Philipp M, Lee S, Malik M, Yang SY. A novel mutation in the HSD17B10 gene of a 10-year-old boy with refractory epilepsy, choreoathetosis and learning disability. PLoS ONE 2011; 6: e27348.
176. Yang SY, Dobkin C, He XY, Philipp M, Brown WT. A 5-methylcytosine hotspot responsible for the prevalent HSD17B10 mutation. Gene 2013; 515: 380-384.
177. Yang SY, He XY. Role of type 10 17β-hydroxysteroid dehydrogenase in the pathogenesis of Alzheimer's disease. Adv Exp Med Biol 2001; 487: 101-110.
178. Jazbutyte V, Kehl F, Neyses L, Pelzer T. Estrogen receptor alpha interacts with 17β-hydroxysteroid dehydrogenase type 10 in mitochondria. Biochem Biophys Res Commun 2009; 384: 450-454.
179. He XY, Wen GY, Merz G, Lin D, Yang YZ, Mehta P, Schulz H, Yang SY. Abundant type 10 17β-hydroxysteroid dehydrogenase in the hippocampus of mouse Alzheimer's disease model. Brain Res Mol Brain Res 2002; 99: 46-53.
180. Grimm A, Schmitt K, Lang UE, Mensah-Nyagan AG, Eckert A. Improvement of neuronal bioenergetics by neurosteroids: implications for age-related neurodegenerative disorders. Biochim Biophys Acta 2014; 1842: 2427-2438.
181. Yang SY, He XY, Dobkin C, Isaacs C, Brown WT. Mental retardation and isoleucine metabolism. In: Rajendram R, Preedy VR, Patel VB, eds. Branched Chain Amino Acids in Clinical Nutrition: Volume I, Nutrition and Health. New York: Springer, 2015: 157-170.
182. Porcu P, O'Buckley TK, Alward SE, Song SC, Grant KA, de Wit H, Morrow AL. Differential effects of ethanol on serum GABAergic 3α, 5α/3α, 5β neuroactive steroids in mice, rats, cynomolgus monkeys, and humans. Alcohol Clin Exp Res 2010; 34: 432-442.
183. Barbaccia ML, Affricano D, Trabucchi M, Purdy RH, Colombo G, Agabio R, Gessa GL. Ethanol markedly increases "GABAergic" neurosteroids in alcohol-preferring rats. Eur J Pharmacol 1999; 384: R1-R2.
184. Cook JB, Dumitru AM, O'Buckley TK, Morrow AL. Ethanol administration produces divergent changes in GABAergic neuroactive steroid immunohistochemistry in the rat brain. Alcohol Clin Exp Res 2014; 38: 90-99.
185. Khisti RT, VanDoren MJ, O'Buckley T, Morrow AL. Neuroactive steroid 3α-hydroxy-5α-pregnan-20-one modulates ethanol-induced loss of righting reflex in rats. Brain Res 2003; 980: 255-265.
186. O'Dell LE, Alomary AA, Vallee M, Koob GF, Fitzgerald RL, Purdy RH. Ethanol-induced increases in neuroactive steroids in the rat brain and plasma are absent in adrenalectomized and gonadectomized rats. Eur J Pharmacol 2004; 484: 241-247.
187. Boyd KN, Kumar S, O'Buckley TK, Porcu P, Morrow AL. Ethanol induction of steroidogenesis in rat adrenal and brain is dependent upon pituitary ACTH release and de novo adrenal StAR synthesis. J Neurochem 2010; 112: 784-796.
188. A receptor activity in rat hippocampus. J Neurosci 2004; 24: 6521-6530.
189. Tokuda K, Izumi Y, Zorumski CF. Ethanol enhances neurosteroidogenesis in hippocampal pyramidal neurons by paradoxical NMDA receptor activation. J Neurosci 2011; 31: 9905-9909.
190. Cook JB, Nelli SM, Neighbors MR, Morrow DH, O'Buckley TK, Maldonado-Devincci AM, Morrow AL. Ethanol alters local cellular levels of (3α, 5α)-3-hydroxypregnan-20-one (3α, 5α-THP) independent of the adrenals in subcortical brain regions. Neuropsychopharmacology 2014; 39: 1978-1987.
191. Morrow AL, Porcu P, Boyd KN, Grant KA. Hypothalamic-pituitary-adrenal axis modulation of GABAergic neuroactive steroids influences ethanol sensitivity and drinking behavior. Dialogues Clin Neurosci 2006; 8: 463-477.
192. Porcu P, Locci A, Santoru F, Berretti R, Morrow AL, Concas A. Failure of acute ethanol administration to alter cerebrocortical and hippocampal allopregnanolone levels in C57BL/6J and DBA/2J mice. Alcohol Clin Exp Res 2014; 38: 948-958.
193. Gabriel KI, Cunningham CL, Finn DA. Allopregnanolone does not influence ethanol-induced conditioned place preference in DBA/2J mice. Psychopharmacology 2004; 176: 50-56.
194. Finn DA, Sinnott RS, Ford MM, Long SL, Tanchuck MA, Phillips TJ. Sex differences in the effect of ethanol injection and consumption on brain allopregnanolone levels in C57BL/6 mice. Neuroscience 2004; 123: 813-819.
195. Torres JM, Ortega E. Alcohol intoxication increases allopregnanolone levels in female adolescent humans. Neuropsychopharmacology 2003; 28: 1207-1209.
196. Torres JM, Ortega E. Alcohol intoxication increases allopregnanolone levels in male adolescent humans. Psychopharmacology 2004; 172: 352-355.
197. Holdstock L, Penland SN, Morrow AL, de Wit H. Moderate doses of ethanol fail to increase plasma levels of neurosteroid 3α-hydroxy-5α-pregnan-20-one-like immunoreactivity in healthy men and women. Psychopharmacology 2006; 186: 442-450.
198. Pierucci-Lagha A, Covault J, Feinn R, Khisti RT, Morrow AL, Marx CE, Shampine LJ, Kranzler HR. Subjective effects and changes in steroid hormone concentrations in humans following acute consumption of alcohol. Psychopharmacology 2006; 186: 451-461.
199. Pierucci-Lagha A, Covault J, Feinn R, Nellissery M, Hernandez-Avila C, Oncken C, Morrow AL, Kranzler HR. GABRA2 alleles moderate the subjective effects of alcohol, which are attenuated by finasteride. Neuropsychopharmacology 2005; 30: 1193-1203.
200. Covault J, Pond T, Feinn R, Arias AJ, Oncken C, Kranzler HR. Dutasteride reduces alcohol's sedative effects in men in a human laboratory setting and reduces drinking in the natural environment. Psychopharmacology 2014; 231: 3609-3618.
201. Irwig MS. Decreased alcohol consumption among former male users of finasteride with persistent sexual side effects: a preliminary report. Alcohol Clin Exp Res 2013; 37: 1823-1826.
202. Maldonado-Devincci AM, Cook JB, O'Buckley TK, Morrow DH, McKinley RE, Lopez MF, Becker HC, Morrow AL. Chronic intermittent ethanol exposure and withdrawal alters (3α, 5α)-3-hydroxy-pregnan-20-one immunostaining in cortical and limbic brain regions of C57BL/6J mice. Alcohol Clin Exp Res 2014; 38: 2561-2571.
203. Milivojevic V, Kranzler HR, Gelernter J, Burian L, Covault J. Variation in genes encoding the neuroactive steroid synthetic enzymes 5α-reductase type 1 and 3α-reductase type 2 is associated with alcohol dependence. Alcohol Clin Exp Res 2011; 35: 946-952.
204. O'Dell LE, Purdy RH, Covey DF, Richardson HN, Roberto M, Koob GF. Epipregnanolone and a novel synthetic neuroactive steroid reduce alcohol self-administration in rats. Pharmacol Biochem Behav 2005; 81: 543-550.
205. Besheer J, Lindsay TG, O'Buckley TK, Hodge CW, Morrow AL. Pregnenolone and ganaxolone reduce operant ethanol self-administration in alcohol-preferring P rats. Alcohol Clin Exp Res 2010; 34: 2044-2052.
206. Papadopoulos V. On the role of the translocator protein (18-kDa) TSPO in steroid hormone biosynthesis. Endocrinology 2014; 155: 15-20.
207. Giatti S, Garcia-Segura LM, Melcangi RC. New steps forward in the neuroactive steroid field. J Steroid Biochem Mol Biol 2015; 153: 127-134.
208. Giatti S, Romano S, Pesaresi M, Cermenati G, Mitro N, Caruso D, Tetel MJ, Garcia-Segura LM, Melcangi RC. Neuroactive steroids and the peripheral nervous system: an update. Steroids 2015; 103: 23-30.
209. Cummins CL, Mangelsdorf DJ. Liver X receptors and cholesterol homoeostasis: spotlight on the adrenal gland. Biochem Soc Trans 2006; 34: 1110-1113.
210. Mitro N, Cermenati G, Giatti S, Abbiati F, Pesaresi M, Calabrese D, Garcia-Segura LM, Caruso D, Melcangi RC. LXR and TSPO as new therapeutic targets to increase the levels of neuroactive steroids in the central nervous system of diabetic animals. Neurochem Int 2012; 60: 616-621.
211. Cermenati G, Giatti S, Cavaletti G, Bianchi R, Maschi O, Pesaresi M, Abbiati F, Volonterio A, Saez E, Caruso D, Melcangi RC, Mitro N. Activation of the liver X receptor increases neuroactive steroid levels and protects from diabetes-induced peripheral neuropathy. J Neurosci 2010; 30: 11896-11901.
212. Sironi L, Mitro N, Cimino M, Gelosa P, Guerrini U, Tremoli E, Saez E. Treatment with LXR agonists after focal cerebral ischemia prevents brain damage. FEBS Lett 2008; 582: 3396-3400.
213. Xu P, Li D, Tang X, Bao X, Huang J, Tang Y, Yang Y, Xu H, Fan X. LXR agonists: new potential therapeutic drug for neurodegenerative diseases. Mol Neurobiol 2013; 48: 715-728.
214. Uzunova V, Sheline Y, Davis JM, Rasmusson A, Uzunov DP, Costa E, Guidotti A. 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.
215. Romeo E, Strohle A, Spalletta G, di Michele F, Hermann B, Holsboer F, Pasini A, Rupprecht R. Effects of antidepressant treatment on neuroactive steroids in major depression. Am J Psychiatry 1998; 155: 910-913.
216. Pinna G, Rasmusson AM. Ganaxolone improves behavioral deficits in a mouse model of post-traumatic stress disorder. Front Cell Neurosci 2014; 8: 256.
217. Rasmusson AM, Pinna G, Paliwal P, Weisman D, Gottschalk C, Charney D, Krystal J, Guidotti A. Decreased cerebrospinal fluid allopregnanolone levels in women with posttraumatic stress disorder. Biol Psychiatry 2006; 60: 704-713.
218. Hardoy MC, Serra M, Carta MG, Contu P, Pisu MG, Biggio G. Increased neuroactive steroid concentrations in women with bipolar disorder or major depressive disorder. J Clin Psychopharmacol 2006; 26: 379-384.
219. Fish EW, Whitman BJ, DiBerto JF, Robinson JE, Morrow AL, Malanga CJ. Effects of the neuroactive steroid allopregnanolone on intracranial self-stimulation in C57BL/6J mice. Psychopharmacology 2014; 231: 3415-3423.
220. Anker JJ, Zlebnik NE, Carroll ME. Differential effects of allopregnanolone on the escalation of cocaine self-administration and sucrose intake in female rats. Psychopharmacology 2010; 212: 419-429.
221. Ford MM, Mark GP, Nickel JD, Phillips TJ, Finn DA. Allopregnanolone influences the consummatory processes that govern ethanol drinking in C57BL/6J mice. Behav Brain Res 2007; 179: 265-272.
222. Finn DA, Mark GP, Fretwell AM, Gililland-Kaufman KR, Strong MN, Ford MM. Reinstatement of ethanol and sucrose seeking by the neurosteroid allopregnanolone in C57BL/6 mice. Psychopharmacology 2008; 201: 423-433.
223. Broomall E, Natale JE, Grimason M, Goldstein J, Smith CM, Chang C, Kanes S, Rogawski MA, Wainwright MS. Pediatric super-refractory status epilepticus treated with allopregnanolone. Ann Neurol 2014; 76: 911-915.
224. Howard RB, Sayeed I, Stein D. Suboptimal dosing parameters as possible factors in the negative Phase III clinical trials of progesterone in TBI. J Neurotrauma 2015; Sep 15. [Epub ahead of print].