1. Neuroactive steroids are steroid hormones that exert rapid, nongenomic effects at ligand-gated ion channels. There is increasing awareness of the possible role of these steroids in the pathology and manifestation of symptoms of psychiatric disorders. The aim of this paper is to review the current knowledge of neuroactive steroid functioning in the central nervous system, and to assess the role of neuroactive steroids in the pathophysiology and treatment of symptoms of schizophrenia, depression, and anxiety disorders. Particular emphasis will be placed on GABAA receptor modulation, given the extensive knowledge of the interactions between this receptor complex, neuroactive steroids, and psychiatric illness.
2. A brief description of neuroactive steroid metabolism is followed by a discussion of the interactions of neuroactive steroids with acute and chronic stress and the HPA axis. Preclinical and clinical studies related to psychiatric disorders that have been conducted on neuroactive steroids are also described.
3. Plasma concentrations of some neuroactive steroids are altered in individuals suffering from schizophrenia, depression, or anxiety disorders compared to values in healthy controls. Some drugs used to treat these disorders have been reported to alter plasma and brain concentrations in clinical and preclinical studies, respectively.
4. Further research is warranted into the role of neuroactive steroids in the pathophysiology of psychiatric illnesses and the possible role of these steroids in the successful treatment of these disorders.
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REFERENCES
Aguilera, G., and Rabadan-Diehl, C. (2000). Vasopressinergic regulation of the hypothalamic-pituitary-adrenal axis: Implications for stress adaptation. Regul. Pept. 96:23–29.
Akhondzadeh, S. (2001). The 5-HT hypothesis of schizophrenia. Drugs 4:295–300.
Albeck, D. S., McKittrick, C. R., Blanchard, D. C., Blanchard, R. J., Nikulina, J., McEwen, B. S., and Sakai, R. R. (1997). Chronic social stress alters levels of corticotropin-releasing factor and arginine vasopressin mRNA in rat brain. J. Neurosci. 17:4895–4903.
Assies, J., Visser, I., Nicolson, N. A., Eggelte, T. A., Wekking, E. M., Huyser, J., Lieverse, R., and Schene, A. H. (2004). Elevated salivary dehydroepiandrosterone-sulfate but normal cortisol levels in medicated depressed patients: Preliminary findings. Psychiatry Res. 128:117–122.
Aston-Jones, G., Zhu, Y., and Card, J. P. (2004). Numerous GABAergic afferents to locus ceruleus in the pericerulear dendritic zone: Possible interneuronal pool. J. Neurosci. 24:2313–2321.
Avital, A., Richter-Levin, G., Leschiner, S., Spanier, I., Veenman, L., Weizman, A., and Gavish, M. (2001). Acute and repeated swim stress effects on peripheral benzodiazepine receptors in the rat hippocampus, adrenal, and kidney. Neuropsychopharmacology 25:669–678.
Baghai, T. C., di Michele, F., Schule, C., Eser, D., Zwanzger, P., Pasini, A., Romeo, E., and Rupprecht, R. (2005). Plasma concentrations of neuroactive steroids before and after electroconvulsive therapy in major depression. Neuropsychopharmacology 30:1181–1186.
Barbaccia, M. L., Affricano, D., Purdy, R. H., Maciocco, E., Spiga, F., and Biggio, G. (2001a). Clozapine, but not haloperidol, increases brain concentrations of neuroactive steroids in the rat. Neuropsychopharmacol. 25:489–497.
Barbaccia, M. L., Concas, A., Serra, M., and Biggio, G. (1998). Stress and neurosteroids in adult and aged rats. Exp. Gerontol. 33:697–712.
Barbaccia, M. L., Roscetti, G., Bolacchi, F., Concas, A., Mostallino, M. C., Purdy, R. H., and Biggio, G. (1996a). Stress-induced increase in brain neuroactive steroids: antagonism by abecarnil. Pharmacol. Biochem. Behav. 54:205–210.
Barbaccia, M. L., Roscetti, G., Trabucchi, M., Cuccheddu, T., Concas, A., and Biggio, G. (1994). Neurosteroids in the brain of handling-habituated and naive rats: effect of CO2 inhalation. Eur. J. Pharmacol. 261:317–320.
Barbaccia, M. L., Roscetti, G., Trabucchi, M., Mostallino, M. C., Concas, A., Purdy, R. H., and Biggio, G. (1996b). Time-dependent changes in rat brain neuroactive steroid concentrations and GABAA receptor function after acute stress. Neuroendocrinology 63:166–172.
Barbaccia, M. L., Roscetti, G., Trabucchi, M., Purdy, R. H., Mostallino, M. C., Concas, A., and Biggio, G. (1997). The effects of inhibitors of GABAergic transmission and stress on brain and plasma allopregnanolone concentrations. Br. J. Pharmacol. 120:1582–1588.
Barbaccia, M. L., Roscetti, G., Trabucchi, M., Purdy, R. H., Mostallino, M. C., Perra, C., Concas, A., and Biggio, G. (1996c). Isoniazid-induced inhibition of GABAergic transmission enhances neurosteroid content in the rat brain. Neuropharmacology 35:1299–1305.
Barbaccia, M. L., Serra, M., Purdy, R. H., and Biggio, G. (2001b). Stress and neuroactive steroids. Int. Rev. Neurobiol. 46:243–272.
Barden, N. (2004). Implication of the hypothalamic-pituitary-adrenal axis in the physiopathology of depression. J. Psychiatry Neurosci. 29:185–193.
Bartanusz, V., Jezova, D., Bertini, L. T., Tilders, F. J., Aubry, J. M., and Kiss, J. Z. (1993). Stress-induced increase in vasopressin and corticotropin-releasing factor expression in hypophysiotrophic paraventricular neurons. Endocrinology 132:895–902.
Basile, A. S., Weissman, B. A., and Skolnick, P. (1987). Maximal electroshock increases the density of [3H]Ro 5-4864 binding to mouse cerebral cortex. Brain Res. Bull. 19:1–7.
Baulieu, E. E. (1997). Neurosteroids: of the nervous system, by the nervous system, for the nervous system. Recent Prog. Horm. Res. 52:1–32.
Belelli, D., Casula, A., Ling, A., and Lambert, J. J. (2002). The influence of subunit composition on the interaction of neurosteroids with GABA(A) receptors. Neuropharmacology 43:651–661.
Belelli, D., Lan, N. C., and Gee, K. W. (1990). Anticonvulsant steroids and the GABA/benzodiazepine receptor-chloride ionophore complex. Neurosci. Biobehav. Rev. 14:315–322.
Belelli, D., and Lambert, J. J. (2005). Neurosteroids: Endogenous regulators of the GABA(A) receptor. Nat. Rev. Neurosci. 6:565–575.
Berga, S. L., Parry, B. L., and Cyranouski, J. M. (2005). Special areas of interest: Psychiatry and reproductive medicine. In Sadock, B. J., and Sadock, V. A. (eds.), Kaplan and Sadock’s Comprehensive Textbook of Psychiatry, 8th edn. Lippincott Williams and Wilkins, Philadelphia, pp. 2293– 2315.
Bergeron, R., de Montigny, C., and Debonnel, G. (1996). Potentiation of neuronal NMDA response induced by dehydroepiandrosterone and its suppression by progesterone: effects mediated via sigma receptors. J. Neurosci. 16:1193–1202.
Bermack, J. E., and Debonnel, G. (2005). The role of sigma receptors in depression. J. Pharmacol. Sci. 97:317–336.
Berrettini, W. H., Nurnberger, J. I. Jr., Hare, T. A., Simmons-Alling, S., Gershon, E. S., and Post, R. M. (1983). Reduced plasma and CSF gamma-aminobutyric acid in affective illness: effect of lithium carbonate. Biol. Psychiatry 18:185–194.
Bicikova, M., Dibbelt, L., Hill, M., Hampl, R., and Starka, L. (1998). Allopregnanolone in women with premenstrual syndrome. Horm. Metab. Res. 30:227–230.
Bicikova, M., Tallova, J., Hill, M., Krausova, Z., and Hampl, R. (2000). Serum concentrations of some neuroactive steroids in women suffering from mixed anxiety-depressive disorder. Neurochem. Res. 25:1623–1627.
Biggio, G. (1983). The action of stress, beta-carbolines, diazepam and Ro 15-1788 on GABA receptors in the rat brain. In Biggio, G., and Costa, E. (eds.), Benzodiazepine Recognition Site Ligands: Biochemistry and Pharmacology. Raven Press, New York, pp. 105–117.
Biggio, G., Corda, M. G., Concas, A., Demontis, G., Rossetti, Z., and Gessa, G. L. (1981). Rapid changes in GABA binding induced by stress in different areas of the rat brain. Brain Res. 229:363–369.
Bitran, D., Purdy, R. H., and Kellogg, C. K. (1993). Anxiolytic effect of progesterone is associated with increases in cortical allopregnanolone and GABAA receptor function. Pharmacol. Biochem. Behav. 45:423–428.
Blum, B. P., and Mann, J. J. (2002). The GABAergic system in schizophrenia. Int. J. Neuropsychopharmacol. 5:159–179.
Brambilla, F., Biggio, G., Pisu, M. G., Bellodi, L., Perna, G., Bogdanovich-Djukic, V., Purdy, R. H., and Serra, M. (2003). Neurosteroid secretion in panic disorder. Psychiatry Res. 118:107–116.
Brambilla, F., Mellado, C., Alciati, A., Pisu, M. G., Purdy, R. H., Zanone, S., Perini, G., Serra, M., and Biggio, G. (2005). Plasma concentrations of anxiolytic neuroactive steroids in men with panic disorder. Psychiatry Res. 135:185–190.
Breier, A., and Buchanan, R. W. (1992). The effects of metabolic stress on plasma progesterone in healthy volunteers and schizophrenic patients. Life Sci. 51:1527–1534.
Bristow, L. J., Collinson, N., Cook, G. P., Curtis, N., Freedman, S. B., Kulagowski, J. J., Leeson, P. D., Patel, S., Ragan, C. I., Ridgill, M., Saywell, K. L., and Tricklebank, M. D. (1997). L-745,870, a subtype selective dopamine D4 receptor antagonist, does not exhibit a neuroleptic-like profile in rodent behavioural tests. J. Pharmacol. Exp. Ther. 283:1256–1263.
Brophy, M. H., Rush, A. J., and Crowley, G. (1983). Cortisol, estradiol, and androgens in acutely ill paranoid schizophrenics. Biol. Psychiatry 18:583–590.
Burgin, R., Weizman, R., and Gavish, M. (1996). Repeated swim stress and peripheral-type benzodiazepine receptors. Neuropsychobiology 33:28–31.
Clark, B. J., Wells, J., King, S. R., and Stocco, D. M. (1994). The purification, cloning, and expression of a novel luteinizing hormone-induced mitochondrial protein in MA-10 mouse Leydig tumor cells. Characterization of the steroidogenic acute regulatory protein (StAR). J. Biol. Chem. 269:28314–28322.
Concas, A., Mostallino, M. C., Perra, C., Lener, R., Roscetti, G., Barbaccia, M. L., Purdy, R. H., and Biggio, G. (1996). Functional correlation between allopregnanolone and [35S]TBPS binding in the brain of rats exposed to isonizad, pentylenetetrazol or stress. Br. J. Pharmacol. 118:839–846.
Concas, A., Pepitoni, S., Atsoggiu, T., Toffano, G., and Biggio, G. (1988). Aging reduces the GABA-dependent 36Cl-flux in rat brain membrane vesicles. Life Sci. 43:1761–1771.
Corpechot, C., Robel, P., Axelson, M., Sjovall, J., and Baulieu, E. E. (1981). Characterization and measurement of dehydroepiandrosterone sulfate in rat brain. Proc. Natl. Acad. Sci. U.S.A. 78:4704–4707.
Costa, E., Davis, J. M., Dong, E., Grayson, D. R., Guidotti, A., Tremolizzo, L., and Veldic, M. (2004). A GABAergic cortical deficit dominates schizophrenia pathophysiology. Crit. Rev. Neurobiol. 16:1–23.
Costall, B., Naylor, R. J., and Nohria, V. (1978). Climbing behaviour induced by apomorphine in mice: a potential model for the detection of neuroleptic activity. Eur. J. Pharmacol. 50:39–50.
Coyle, J. T., Tsai, G., and Goff, D. (2003). Converging evidence of NMDA receptor hypofunction in the pathophysiology of schizophrenia. Ann. N. Y. Acad. Sci. 1003:318–327.
Crawley, J. N., Glowa, J. R., Majewska, M. D., and Paul, S. M. (1986). Anxiolytic activity of an endogenous adrenal steroid. Brain Res. 398:382–385.
Crestani, F., Lorez, M., Baer, K., Essrich, C., Benke, D., Laurent, J. P., Belzung, C., Fritschy, J. M., Luscher, B., and Mohler, H. (1999). Decreased GABAA-receptor clustering results in enhanced anxiety and a bias for threat cues. Nature Neurosci. 2:833–839.
Czlonkowska, A. I., Zienowicz, M., Bidzinski, A., Maciejak, P., Lehner, M., Taracha, E., Wislowska, A., and Plaznik, A. (2003). The role of neurosteroids in the anxiolytic, antidepressive and anticonvulsive effects of selective serotonin reuptake inhibitors. Med. Sci. Monit. 9:RA270–RA275.
Davies, P. A., Hanna, M. C., Hales, T. G., and Kirkness, E. F. (1997). Insensitivity to anaesthetic agents conferred by a class of GABA(A) receptor subunit. Nature 385:820–823.
Dazzi, L., Serra, M., Vacca, G., Ladu, S., Latrofa, A., Trapani, G., and Biggio, G. (2002). Depletion of cortical allopregnanolone potentiates stress-induced increase in cortical dopamine output. Brain Res. 932:135–139.
de Goeij, D. C., Kvetnansky, R., Whitnall, M. H., Jezova, D., Berkenbosch, F., and Tilders, F. J. (1991). Repeated stress-induced activation of corticotropin-releasing factor neurons enhances vasopressin stores and colocalization with corticotropin-releasing factor in the median eminence of rats. Neuroendocrinology 53:150–159.
Demirgoren, S., Majewska, M. D., Spivak, C. E., and London, E. D. (1991). Receptor binding and electrophysiological effects of dehydroepiandrosterone sulfate, an antagonist of the GABAA receptor. Neuroscience 45:127–135.
Deuschle, M., Luppa, P., Gilles, M., Hamann, B., and Heuser, I. (2004). Antidepressant treatment and dehydroepiandrosterone sulfate: different effects of amitriptyline and paroxetine. Neuropsychobiology 50:252–256.
di Michele, F., Caltagirone, C., Bonaviri, G., Romeo, E., and Spalletta, G. (2005). Plasma dehydroepiandrosterone levels are strongly increased in schizophrenia. J. Psychiatr. Res. 39:267–273.
Dietschy, J. M., and Turley, S. D. (2001). Cholesterol metabolism in the brain. Curr. Opin. Lipidol. 12:105–112.
Dong, E., Matsumoto, K., Uzunova, V., Sugaya, I., Takahata, H., Nomura, H., Watanabe, H., Costa, E., and Guidotti, A. (2001). Brain 5 alpha-dihydroprogesterone and allopregnanolone synthesis in a mouse model of protracted social isolation. Proc. Natl. Acad. Sci. U.S.A. 98:2849– 2854.
Do-Rego, J. L., Mensah-Nyagan, G. A., Beaujean, D., Vaudry, D., Sieghart, W., Luu-The, V., Pelletier, G., and Vaudry, H. (2000). gamma-Aminobutyric acid, acting through gamma-aminobutyric acid type A receptors, inhibits the biosynthesis of neurosteroids in the frog hypothalamus. Proc. Natl. Acad. Sci. U.S.A. 97:13925–13930.
Droogleever Fortuyn, H. A., van Broekhoven, F., Span, P. N., Backstrom, T., Zitman, F. G., and Verkes, R. J. (2004). Effects of PhD examination stress on allopregnanolone and cortisol plasma levels and peripheral benzodiazepine receptor density. Psychoneuroendocrinology 29:1341–1344.
Drugan, R. C., Morrow, A. L., Weizman, R., Weizman, A., Deutsch, S. I., Crawley, J. N., and Paul, S. M. (1989). Stress-induced behavioural depression in the rat is associated with a decrease in GABA receptor-mediated chloride ion flux and brain benzodiazepine receptor occupancy. Brain Res. 487:45–51.
Dubrovsky, B. O. (2005). Steroids, neuroactive steroids and neurosteroids in psychopathology. Prog. Neuropsychopharmacol. Biol. Psychiatry 29:169–192.
Epperson, C. N., Haga, K., Mason, G. F., Sellers, E., Gueorguieva, R., Zhang, W., Weiss, E., Rothman, D. L., and Krystal, J. H. (2002). Cortical gamma-aminobutyric acid levels across the menstrual cycle in healthy women and those with premenstrual dysphoric disorder: a proton magnetic resonance spectroscopy study. Arch. Gen. Psychiatry 59:851–858.
Erb, J. L., Kadane, J. B., and Tourney, G. (1981). Discrimination between schizophrenic and control subjects by means of plasma dehydroepiandrosterone measurements. J. Clin. Endocrinol. Metab. 52:181–186.
Eser, D., di Michele, F., Zwanzger, P., Pasini, A., Baghai, T. C., Schule, C., Rupprecht, R., and Romeo, E. (2005). Panic induction with cholecystokinin-tetrapeptide (CCK-4) increases plasma concentrations of the neuroactive steroid 3 alpha, 5 alphatetrahydrodeoxycorticosterone (3 alpha, 5 alpha-THDOC) in healthy volunteers. Neuropsychopharmacology 30:192–195.
Farnbach-Pralong, D., Bradbury, R., Copolov, D., and Dean, B. (1998). Clozapine and olanzapine treatment decreases rat cortical and limbic GABA(A) receptors. Eur. J. Pharmacol. 349:R7–R8.
Fatemi, S. H., Stary, J. M., Earle, J. A., Araghi-Niknam, M., and Eagan, E. (2005). GABAergic dysfunction in schizophrenia and mood disorders as reflected by decreased levels of glutamic acid decarboxylase 65 and 67 kDa and Reelin proteins in cerebellum. Schizophr. Res. 72:109–122.
Ferguson, H. C., Bartram, A. C., Fowlie, H. C., Cathro, D. M., Birchall, K., and Mitchell, F. L. (1964). A preliminary investigation of steroid excretion in depressed patients before and after electroconvulsive therapy. Acta. Endocrinol. (Copenh.) 47:58–68.
Flood, J. F., Morley, J. E., and Roberts, E. (1992). Memory-enhancing effects in male mice of pregnenolone and steroids metabolically derived from it. Proc. Natl. Acad. Sci. U.S.A. 89:1567–1571.
Frieboes, R. M., Murck, H., Wiedemann, K., Holsboer, F., and Steiger, A. (1997). Open clinical trial on the sigma ligand panamesine in patients with schizophrenia. Psychopharmacology (Berl) 132:82–88.
Frye, C. A., and Walf, A. A. (2002). Changes in progesterone metabolites in the hippocampus can modulate open field and forced swim test behaviour of proestrous rats. Horm. Behav. 41:306–315.
Frye, C. A., and Walf, A. A. (2004). Hippocampal 3alpha,5alpha-THP may alter depressive behaviour of pregnant and lactating rats. Pharmacol. Biochem. Behav. 78:531–540.
Gao, X. M., Sakai, K., Roberts, R. C., Conley, R. R., Dean, B., and Tamminga, C. A. (2000). Ionotropic glutamate receptors and expression of N-methyl-d-aspartate receptor subunits in subregions of human hippocampus: effects of schizophrenia. Am. J. Psychiatry 157:1141–1149.
Gee, K. W., Bolger, M. B., Brinton, R. E., Coirini, H., and McEwen, B. S. (1988). Steroid modulation of the chloride ionophore in rat brain: structure-activity requirements, regional dependence and mechanism of action. J. Pharmacol. Exp. Ther. 246:803–812.
Gee, K. W., Chang, W. C., Brinton, R. E., and McEwen, B. S. (1987). GABA-dependent modulation of the Cl− ionophore by steroids in rat brain. Eur. J. Pharmacol. 136:419–423.
George, M. S., Guidotti, A., Rubinow, D., Pan, B., Mikalauskas, K., and Post, R. M. (1994). CSF neuroactive steroids in affective disorders: pregnenolone, progesterone, and DBI. Biol. Psychiatry 35:775–780.
Gerner, R. H., Fairbanks, L., Anderson, G. M., Young, J. G., Scheinin, M., Linnoila, M., Hare, T. A., Shaywitz, B. A., and Cohen, D. J. (1984). CSF neurochemistry in depressed, manic, and schizophrenic patients compared with that of normal controls. Am. J. Psychiatry 141:1533–1540.
Gerner, R. H., and Hare, T. A. (1981). CSF GABA in normal subjects and patients with depression, schizophrenia, mania, and anorexia nervosa. Am J Psychiatry 138:1098–1101.
Girdler, S. S., Straneva, P. A., Light, K. C., Pedersen, C. A., and Morrow, A. L. (2001). Allopregnanolone levels and reactivity to mental stress in premenstrual dysphoric disorder. Biol. Psychiatry 49:788–797.
Gispen-de Wied, C. C. (2000). Stress in schizophrenia: an integrative view. Eur. J. Pharmacol. 405:375–384.
Gold, B. I., Bowers, M. B. Jr., Roth, R. H., and Sweeney, D. W. (1980). GABA levels in CSF of patients with psychiatric disorders. Am. J. Psychiatry 137:362–364.
Goodyer, I. M., Herbert, J., and Altham, P. M. (1998). Adrenal steroid secretion and major depression in 8- to 16-year-olds, III. Influence of cortisol/DHEA ratio at presentation on subsequent rates of disappointing life events and persistent major depression. Psychol. Med. 28:265–273.
Griffin, L. D., and Mellon, S. H. (1999). Selective serotonin reuptake inhibitors directly alter activity of neurosteroidogenic enzymes. Proc. Natl. Acad. Sci. U.S.A. 96:13512–13517.
Grobin, A. C., Roth, R. H., and Deutch, A. Y. (1992). Regulation of the prefrontal cortical dopamine system by the neuroactive steroid 3 alpha,21-dihydroxy-5 alpha-pregnane-20-one. Brain Res. 578:351–356.
Guidotti, A., Auta, J., Davis, J. M., Di-Giorgi-Gerevini, V., Dwivedi, Y., Grayson, D. R., Impagnatiello, F., Pandey, G., Pesold, C., Sharma, R., Uzunov, D., and Costa, E. (2000). Decrease in reelin and glutamic acid decarboxylase67 (GAD67) expression in schizophrenia and bipolar disorder: A postmortem brain study. Arch. Gen. Psychiatry 57:1061–1069.
Guidotti, A., and Costa, E. (1998). Can the antidysphoric and anxiolytic profiles of selective serotonin reuptake inhibitors be related to their ability to increase brain 3 alpha, 5 alpha-tetrahydroprogesterone (allopregnanolone) availability? Biol. Psychiatry 44:865–873.
Guo, A. L., Petraglia, F., Criscuolo, M., Ficarra, G., Nappi, R. E., Palumbo, M. A., Trentini, G. P., Purdy, R. H., and Genazzani, A. R. (1995). Evidence for a role of neurosteroids in modulation of diurnal changes and acute stress-induced corticosterone secretion in rats. Gynecol. Endocrinol. 9:1–7.
Hafner, H., Riecher-Rossler, A., An Der Heiden, W., Maurer, K., Fatkenheuer, B., and Loffler, W. (1993). Generating and testing a causal explanation of the gender difference in age at first onset of schizophrenia. Psychol. Med. 23:925–940.
Halbreich, U., Petty, F., Yonkers, K., Kramer, G. L., Rush, A. J., and Bibi, K. W. (1996). Low plasma gamma-aminobutyric acid levels during the late luteal phase of women with premenstrual dysphoric disorder. Am. J. Psychiatry 153:718–720.
Hansen, S. L., Fjalland, B., and Jackson, M. B. (2003). Modulation of GABAA receptors and neuropeptide secretion by the neurosteroid allopregnanolone in posteriour and intermediate pituitary. Pharmacol. Toxicol. 93:91–97.
Hansen, C. R., Jr., Kroll, J., and Mackenzie, T. B. (1982). Dehydroepiandrosterone and affective disorders. Am. J. Psychiatry 139:386–387.
Harris, D. S., Wolkowitz, O. M., and Reus, V. I. (2001). Movement disorder, memory, psychiatric symptoms and serum DHEA levels in schizophrenic and schizoaffective patients. World J. Biol. Psychiatry 2:99–102.
Hauet, T., Yao, Z. X., Bose, H. S., Wall, C. T., Han, Z., Li, W., Hales, D. B., Miller, W. L., Culty, M., and Papadopoulos, V. (2005). Peripheral-type benzodiazepine receptor-mediated action of steroidogenic acute regulatory protein on cholesterol entry into leydig cell mitochondria. Mol. Endocrinol. 19:540–554.
Havoundjian, H., Paul, S. M., and Skolnick, P. (1986). Acute, stress-induced changes in the benzodiazepine/gamma-aminobutyric acid receptor complex are confined to the chloride ionophore. J. Pharmacol. Exp. Ther. 237:787–793.
Hayashi, T., and Su, T. P. (2004). Sigma-1 receptor ligands: potential in the treatment of neuropsychiatric disorders. CNS Drugs 18:269–284.
Hechter, O., Grossman, A., and Chatterton, R. T., Jr. (1997). Relationship of dehydroepiandrosterone and cortisol in disease. Med. Hypotheses 49:85–91.
Heresco-Levy, U., Ermilov, M., Lichtenberg, P., Bar, G., and Javitt, D. C. (2004). High-dose glycine added to olanzapine and risperidone for the treatment of schizophrenia. Biol. Psychiatry 55:165–171.
Herman, J. P., Adams, D., and Prewitt, C. (1995). Regulatory changes in neuroendocrine stress-integrative circuitry produced by a variable stress paradigm. Neuroendocrinology 61:180– 190.
Hermann, B., Wetzel, C. H., Pestel, E., Zieglgansberger, W., Holsboer, F., and Rupprecht, R. (1996). Functional antagonistic properties of clozapine at the 5-HT3 receptor. Biochem. Biophys. Res. Commun. 225:957–960.
Heuser, I., Deuschle, M., Luppa, P., Schweiger, U., Standhardt, H., and Weber, B. (1998). Increased diurnal plasma concentrations of dehydroepiandrosterone in depressed patients. J. Clin. Endocrinol. Metab. 83:3130–3133.
Heydari, B., and Le Melledo, J. M. (2002). Low pregnenolone sulphate plasma concentrations in patients with generalized social phobia. Psychol. Med. 32:929–933.
Higashi, T., Takido, N., and Shimada, K. (2005). Studies on neurosteroids XVII. Analysis of stress-induced changes in neurosteroid levels in rat brains using liquid chromatography-electron capture atmospheric pressure chemical ionization-mass spectrometry. Steroids 70:1–11.
Hoffman, A. R., Ceda, G., and Reisine, T. D. (1985). Corticotropin-releasing factor desensitization of adrenocorticotropic hormone release is augmented by arginine vasopressin. J. Neurosci. 5:234–242.
Howard, J. S. 3rd ,.(1992). Severe psychosis and the adrenal androgens. Integr. Physiol. Behav. Sci. 27:209–215.
Huber, M. T., Gotthardt, U., Schreiber, W., and Krieg, J. C. (1999). Efficacy and safety of the sigma receptor ligand EMD 57445 (panamesine) in patients with schizophrenia: an open clinical trial. Pharmacopsychiatry 32:68–72.
Huntsman, M. M., Tran, B. V., Potkin, S. G., Bunney, W. E. Jr. , and Jones, E. G. (1998). Altered ratios of alternatively spliced long and short gamma2 subunit mRNAs of the gamma-aminobutyrate type A receptor in prefrontal cortex of schizophrenics. Proc. Natl. Acad. Sci. U.S.A. 95:15066–15071.
Irwin, R. P., Maragakis, N. J., Rogawski, M. A., Purdy, R. H., Farb, D. H., and Paul, S. M. (1992). Pregnenolone sulfate augments NMDA receptor mediated increases in intracellular Ca2+ in cultured rat hippocampal neurons. Neurosci. Lett. 141:30–34.
Jaworska-Feil, L., Budziszewska, B., Leskiewicz, M., and Lason, W. (1998). Opposite effects of inhibitory and excitatory neurosteroids on [3H]dopamine release from rat nucleus accumbens. Pol. J. Pharmacol. 50:449–452.
Kasa, K., Otsuki, S., Yamamoto, M., Sato, M., Kuroda, H., and Ogawa, N. (1982). Cerebrospinal fluid gamma-aminobutyric acid and homovanillic acid in depressive disorders. Biol. Psychiatry 17:877–883.
Kash, S. F., Tecott, L. H., Hodge, C., and Baekkeshov, S. (1999). Increased anxiety and altered response to anxiolytics in mice deficient in the 65 kDa isoform of glutamic acid decarboxylase. Proc. Natl. Acad. Sci. U.S.A. 96:1698–1703.
Keller, E. A., Zamparini, A., Borodinsky, L. N., Gravielle, M. C., and Fiszman, M. L. (2004). Role of allopregnanolone on cerebellar granule cells neurogenesis. Brain Res. Dev. Brain Res. 153:13–17.
Khisti, R. T., and Chopde, C. T. (2000). Serotonergic agents modulate antidepressant-like effect of the neurosteroid 3alpha-hydroxy-5alpha-pregnan-20-one in mice. Brain Res. 865:291–300.
Khisti, R. T., Chopde, C. T., and Jain, S. P. (2000). Antidepressant-like effect of the neurosteroid 3alpha-hydroxy-5alpha-pregnan-20-one in mice forced swim test. Pharmacol. Biochem. Behav. 67:137– 143.
Khisti, R. T., Deshpande, L. S., and Chopde, C. T. (2002). The neurosteroid 3 alpha-hydroxy-5 alpha-pregnan-20-one affects dopamine-mediated behaviour in rodents. Psychopharmacology (Berl.) 161:120–128.
Kim, H. J., Ha, M., Park, C. H., Park, S. J., Youn, S. M., Kang, S. S., Cho, G. J., and Choi, W. S. (2003). StAR and steroidogenic enzyme transcriptional regulation in the rat brain: effects of acute alcohol administration. Brain Res. Mol. Brain Res. 115:39–49.
Kimonides, V. G., Khatibi, N. H., Svendsen, C. N., Sofroniew, M. V., and Herbert, J. (1998). Dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEAS) protect hippocampal neurons against excitatory amino acid-induced neurotoxicity. Proc. Natl. Acad. Sci. U.S.A. 95:1852–1857.
Koga, H., Ishibashi, H., Shimada, H., Jang, I. S., Nakamura, T. Y., and Nabekura, J. (2005). Activation of presynaptic GABAA receptors increases spontaneous glutamate release onto noradrenergic neurons of the rat locus coeruleus. Brain Res. 1046:24–31.
Konradi, C., and Heckers, S. (2003). Molecular aspects of glutamate dysregulation: implications for schizophrenia and its treatment. Pharmacol. Ther. 97:153–179.
Korneyev, A., and Costa, E. (1996). Allopregnanolone (THP) mediates anesthetic effects of progesterone in rat brain. Horm. Behav. 30:37–43.
Kurumaji, A., Wakai, T., and Toru, M. (1997). Decreases in peripheral-type benzodiazepine receptors in postmortem brains of chronic schizophrenics. J. Neural Transm. 104:1361– 1370.
Lambert, J. J., Belelli, D., Hill-Venning, C., and Peters, J. A. (1995). Neurosteroids and GABAA receptor function. Trends Pharmacol. Sci. 16:295–303.
Landgren, S., Aasly, J., Backstrom, T., Dubrovsky, B., and Danielsson, E. (1987). The effect of progesterone and its metabolites on the interictal epileptiform discharge in the cat’s cerebral cortex. Acta Physiol. Scand. 131:33–42.
Laufer, N., Maayan, R., Hermesh, H., Marom, S., Gilad, R., Strous, R., and Weizman, A. (2005). Involvement of GABAA receptor modulating neuroactive steroids in patients with social phobia. Psychiatry Res. 137:131–136.
Le Melledo, J. M., and Baker, G. B. (2002). Neuroactive steroids and anxiety disorders. J. Psychiatry Neurosci. 27:161–165.
Lee, D., Wang, L., Dong, P., Tran, T., Copolov, D., and Lim, A. T. (2001). Progesterone modulation of D5 receptor expression in hypothalamic ANP neurons, the role of estrogen. Mol. Psychiatry 6:112–117.
Lhullier, F. L., Nicolaidis, R., Riera, N. G., Cipriani, F., Junqueira, D., Dahm, K. C., Brusque, A. M., and Souza, D. O. (2004). Dehydroepiandrosterone increases synaptosomal glutamate release and improves the performance in inhibitory avoidance task. Pharmacol. Biochem. Behav. 77:601–606.
Lloyd, K. G., Morselli, P. L., Depoortere, H., Fournier, V., Zivkovic, B., Scatton, B., Broekkamp, C., Worms, P., and Bartholini, G. (1983). The potential use of GABA agonists in psychiatric disorders: evidence from studies with progabide in animal models and clinical trials. Pharmacol. Biochem. Behav. 18:957–966.
Lombardi, I., Luisi, S., Quirici, B., Monteleone, P., Bernardi, F., Liut, M., Casarosa, E., Palumbo, M., Petraglia, F., and Genazzani, A. R. (2004). Adrenal response to adrenocorticotropic hormone stimulation in patients with premenstrual syndrome. Gynecol. Endocrinol. 18:79–87.
Maayan, R., Morad, O., Dorfman, P., Overstreet, D. H., Weizman, A., and Yadid, G. (2005). The involvement of dehydroepiandrosterone (DHEA) and its sulfate ester (DHEAS) in blocking the therapeutic effect of electroconvulsive shocks in an animal model of depression. Eur. Neuropsychopharmacol. 15:253–262.
Maayan, R., Yagorowski, Y., Grupper, D., Weiss, M., Shtaif, B., Kaoud, M. A., and Weizman, A. (2000). Basal plasma dehydroepiandrosterone sulfate level: a possible predictor for response to electroconvulsive therapy in depressed psychotic inpatients. Biol. Psychiatry 48:693–701.
Maitra, R., and Reynolds, J. N. (1998). Modulation of GABA(A) receptor function by neuroactive steroids: evidence for heterogeneity of steroid sensitivity of recombinant GABA(A) receptor isoforms. Can. J. Physiol. Pharmacol. 76:909–920.
Maitra, R., and Reynolds, J. N. (1999). Subunit dependent modulation of GABAA receptor function by neuroactive steroids. Brain Res. 819:75–82.
Majewska, M. D. (1992). Neurosteroids: endogenous bimodal modulators of the GABAA receptor. Mechanism of action and physiological significance. Prog. Neurobiol. 38:379–395.
Makino, S., Smith, M. A., and Gold, P. W. (1995). Increased expression of corticotropin-releasing hormone and vasopressin messenger ribonucleic acid (mRNA) in the hypothalamic paraventricular nucleus during repeated stress: association with reduction in glucocorticoid receptor mRNA levels. Endocrinology 136:3299–3309.
Marco, E., Mao, C. C., Revuelta, A., Peralta, E., and Costa, E. (1978). Turnover rates of gamma-aminobutyric acid in substantia nigra, N. caudatus, globus pallidus and N. accumbens of rats injected with cataleptogenic and noncataleptogenic antipsychotics. Neuropharmacology 17:589–596.
Marx, C. E., Duncan, G. E., Gilmore, J. H., Lieberman, J. A., and Morrow, A. L. (2000). Olanzapine increases allopregnanolone in the rat cerebral cortex. Biol. Psychiatry 47:1000–1004.
Marx, C. E., VanDoren, M. J., Duncan, G. E., Lieberman, J. A., and Morrow, A. L. (2003). Olanzapine and clozapine increase the GABAergic neuroactive steroid allopregnanolone in rodents. Neuropsychopharmacology 28:1–13.
Marx, C. E., Stevens, R. D., Shampine, L. J., Uzunova, V., Trost, W. T., Butterfield, M. I., Massing, M. W., Hamer, R. M., Morrow, A. L., and Lieberman, J. A. (2006). Neuroactive Steroids are altered in schizophrenia and bipolar disorder: Relevance to pathophysiology and therapeutics. Neuropsychopharmacology 31:1249–1263.
Matsumoto, K., Uzunova, V., Pinna, G., Taki, K., Uzunov, D. P., Watanabe, H., Mienville, J. M., Guidotti, A., and Costa, E. (1999). Permissive role of brain allopregnanolone content in the regulation of pentobarbital-induced righting reflex loss. Neuropharmacology 38:955–963.
Matsumoto, K., Pinna, G., Puia, G., Guidotti, A., and Costa, E. (2005). Social isolation stress-induced aggression in mice: A model to study the pharmacology of neurosteroidogenesis. Stress 8:85–93.
Maurice, T., Junien, J. L., and Privat, A. (1997). Dehydroepiandrosterone sulfate attenuates dizocilpine-induced learning impairment in mice via sigma 1-receptors. Behav. Brain Res. 83:159–164.
Mayo, W., Dellu, F., Robel, P., Cherkaoui, J., Le Moal, M., Baulieu, E. E., and Simon, H. (1993). Infusion of neurosteroids into the nucleus basalis magnocellularis affects cognitive processes in the rat. Brain Res. 607:324–328.
Mayo, W., Le Moal, M., and Abrous, D. N. (2001). Pregnenolone sulfate and aging of cognitive functions: behavioural, neurochemical, and morphological investigations. Horm. Behav. 40:215–217.
Mayo, W., Vallee, M., Darnaudry, M., and Le Moal, M. (1999). Neurosteroids. Behavioural studies. In Baulieu, E. E., Robel, P., and Schumacher, M. (eds.), Contemporary Endocrinology: Neurosteroids. A new Regulatory Function in the Nervous System. Humana Press, Totowa, NJ, pp. 317–335.
Melchior, C. L., and Ritzmann, R. F. (1994a). Dehydroepiandrosterone is an anxiolytic in mice on the plus maze. Pharmacol. Biochem. Behav. 47:437–441.
Melchior, C. L., and Ritzmann, R. F. (1994b). Pregnenolone and pregnenolone sulfate, alone and with ethanol, in mice on the plus-maze. Pharmacol. Biochem. Behav. 48:893–897.
Mellon, S. H., and Griffin, L. D. (2002). Neurosteroids: biochemistry and clinical significance. Trends Endocrinol. Metab. 13:35–43.
Michael, A., Jenaway, A., Paykel, E. S., and Herbert, J. (2000). Altered salivary dehydroepiandrosterone levels in major depression in adults. Biol. Psychiatry 48:989–995.
Molina-Hernandez, M., Tellez-Alcantara, N. P., Garcia, J. P., Lopez, J. I., and Jaramillo, M. T. (2004). Synergistic interaction between ketoconazole and several antidepressant drugs with allopregnanolone treatments in ovariectomized Wistar rats forced to swim. Prog. Neuropsychopharmacol. Biol. Psychiatry 28:1337–1345.
Molina-Hernandez, M., Tellez-Alcantara, N. P., Garcia, J. P., Lopez, J. I., and Jaramillo, M. T. (2005). Antidepressant-like actions of intra-accumbens infusions of allopregnanolone in ovariectomized Wistar rats. Pharmacol. Biochem. Behav. 80:401–409.
Monnet, F. P., Mahe, V., Robel, P., and Baulieu, E. E. (1995). Neurosteroids, via sigma receptors, modulate the [3H]norepinephrine release evoked by N-methyl-D-aspartate in the rat hippocampus. Proc. Natl. Acad. Sci. U.S.A. 92:3774–3778.
Monteleone, P., Fabrazzo, M., Serra, M., Tortorella, A., Pisu, M. G., Biggio, G., and Maj, M. (2004). Long term treatment with clozapine does not affect morning circulating levels of allopregnanolone and THDOC in patients with schizophrenia. J. Clin. Psychopharmacol. 24:437–440.
Monteleone, P., Luisi, S., Tonetti, A., Bernardi, F., Genazzani, A. D., Luisi, M., Petraglia, F., and Genazzani, A. R. (2000). Allopregnanolone concentrations and premenstrual syndrome. Eur. J. Endocrinol. 142:269–273.
Morita, K., Arimochi, H., and Tsuruo, Y. (2004). Adrenergic activation of steroid 5 alpha-reductase gene expression in rat C6 glioma cells: involvement of cyclic AMP/protein kinase A-mediated signalling pathway. J. Mol. Neurosci. 22:205–212.
Morita, K., Arimochi, H., and Her, S. (2005). Serotonergic 5-HT2A receptor stimulation induces steroid 5alpha-reductase gene expression in rat C6 glioma cells via transcription factor Egr-1. Brain Res. Mol. Brain Res. 139:193–200.
Morrow, A. L., Pace, J. R., Purdy, R. H., and Paul, S. M. (1990). Characterization of steroid interactions with gamma-aminobutyric acid receptor-gated chloride ion channels: evidence for multiple steroid recognition sites. Mol. Pharmacol. 37:263–270.
Morrow, A. L., Suzdak, P. D., and Paul, S. M. (1987). Steroid hormone metabolites potentiate GABA receptor-mediated chloride ion flux with nanomolar potency. Eur. J. Pharmacol. 142:483–485.
Motzo, C., Porceddu, M. L., Maira, G., Flore, G., Concas, A., Dazzi, L., and Biggio, G. (1996). Inhibition of basal and stress-induced dopamine release in the cerebral cortex and nucleus accumbens of freely moving rats by the neurosteroid allopregnanolone. J. Psychopharmacol. 10:226–272.
Nadjafi-Triebsch, C., Huell, M., Burki, D., and Rohr, U. D. (2003). Progesterone increase under DHEA-substitution in males. Maturitas 45:231–235.
Nechmad, A., Maayan, R., Ramadan, E., Morad, O., Poyurovsky, M., and Weizman, A. (2003a). Clozapine decreases rat brain dehydroepiandrosterone and dehydroepiandrosterone sulfate levels. Eur. Neuropsychopharmacol. 13:29–31.
Nechmad, A., Maayan, R., Spivak, B., Ramadan, E., Poyurovsky, M., and Weizman, A. (2003b). Brain neurosteroid changes after paroxetine administration in mice. Eur. Neuropsychopharmacol. 13:327–332.
Nowak, G. (1996). Chronic electroconvulsive shock but not lithium reduces density of (+)[3H]pentazocine binding sites in rat hippocampus. Pol. J. Pharmacol. 48:287–289.
Oades, R. D., and Schepker, R. (1994). Serum gonadal steroid hormones in young schizophrenic patients. Psychoneuroendocrinology 19:373–385.
Oertel, G. W., Benes, P., Schirazi, M., Holzmann, H., and Hoffmann, G. (1974). Interaction between dehydroepiandrosterone, cyclic adenosine-3′,5′-monophosphate and glucose-6-phosphate-dehydrogenase in normal and diseased subjects. Experientia 30:872–873.
Ohnuma, T., Augood, S. J., Arai, H., McKenna, P. J., and Emson, P. C. (1999). Measurement of GABAergic parameters in the prefrontal cortex in schizophrenia: focus on GABA content, GABA(A) receptor alpha-1 subunit messenger RNA and human GABA transporter-1 (HGAT-1) messenger RNA expression. Neuroscience 93:441–448.
Ojima, K., Matsumoto, K., Tohda, M., and Watanabe, H. (1995). Hyperactivity of central noradrenergic and CRF systems is involved in social isolation-induced decrease in pentobarbital sleep. Brain Res. 684:87–94.
Olsen, R. W., and Betz, H. (2006). GABA and Glycine. In Siegel, G. J., Albers, R. W., Brady, S. K., and Price, D. L. (eds.), Basic Neurochemistry: Molecular, Cellular, and Medical Aspects, 7th edn. Elsevier Academic Press, Burlington, MA, p. 294.
Osran, H., Reist, C., Chen, C. C., Lifrak, E. T., Chicz-DeMet, A., and Parker, L. N. (1993). Adrenal androgens and cortisol in major depression. Am. J. Psychiatry 150:806–809.
Padberg, F., di Michele, F., Zwanzger, P., Romeo, E., Bernardi, G., Schule, C., Baghai, T. C., Ella, R., Pasini, A., and Rupprecht, R. (2002). Plasma concentrations of neuroactive steroids before and after repetitive transcranial magnetic stimulation (rTMS) in major depression. Neuropsychopharmacology 27:874–878.
Park-Chung, M., Malayev, A., Purdy, R. H., Gibbs, T. T., and Farb, D. H. (1999). Sulfated and unsulfated steroids modulate gamma-aminobutyric acidA receptor function through distinct sites. Brain Res. 830:72–87.
Patchev, V. K., Hassan, A. H., Holsboer, D. F., and Almeida, O. F. (1996). The neurosteroid tetrahydroprogesterone attenuates the endocrine response to stress and exerts glucocorticoid-like effects on vasopressin gene transcription in the rat hypothalamus. Neuropsychopharmacology 15:533– 540.
Patchev, V. K., Montkowski, A., Rouskova, D., Koranyi, L., Holsboer, F., and Almeida, O. F. (1997). Neonatal treatment of rats with the neuroactive steroid tetrahydrodeoxycorticosterone (THDOC) abolishes the behavioural and neuroendocrine consequences of adverse early life events. J. Clin. Invest 99:962–966.
Patchev, V. K., Shoaib, M., Holsboer, F., and Almeida, O. F. (1994). The neurosteroid tetrahydroprogesterone counteracts corticotropin-releasing hormone-induced anxiety and alters the release and gene expression of corticotropin-releasing hormone in the rat hypothalamus. Neuroscience 62:265–271.
Paul, S. M., and Purdy, R. H. (1992). Neuroactive steroids. FASEB J. 6:2311–2322.
Pearlstein, T. (2002). Selective serotonin reuptake inhibitors for premenstrual dysphoric disorder: the emerging gold standard? Drugs 62:1869–1885.
Petty, F., and Schlesser, M. A. (1981). Plasma GABA in affective illness. A preliminary investigation. J. Affect Disord. 3:339–343.
Petty, F., and Sherman, A. D. (1984). Plasma GABA levels in psychiatric illness. J. Affect Disord. 6:131–138.
Petty, F., Kramer, G. L., Dunnam, D., and Rush, A. J. (1990). Plasma GABA in mood disorders. Psychopharmacol. Bull. 26:157–161.
Petty, F., Kramer, G. L., Gullion, C. M., and Rush, A. J. (1992). Low plasma gamma-aminobutyric acid levels in male patients with depression. Biol. Psychiatry 32:354–363.
Pinna, G., Costa, E., and Guidotti, A. (2004). Fluoxetine and norfluoxetine stereospecifically facilitate pentobarbital sedation by increasing neurosteroids. Proc. Natl. Acad. Sci. U.S.A. 101:6222–6225.
Pinna, G., Costa, E., and Guidotti, A. (2006). Fluoxetine and norfluoxetine stereospecifically and selectively increase brain neurosteroid content at doses that are inactive on 5-HT reuptake. Psychopharmacology (Berl.) 186:362–372.
Pisu, M. G., and Serra, M. (2004). Neurosteroids and neuroactive drugs in mental disorders. Life Sci. 74:3181–3197.
Poor, V., Juricskay, S., Gati, A., Osvath, P., and Tenyi, T. (2004). Urinary steroid metabolites and 11beta-hydroxysteroid dehydrogenase activity in patients with unipolar recurrent major depression. J. Affect. Disord. 81:55–59.
Poor, V., Bufa, A., Biro, I., Telegdy, E., Tenyi, T., Gati, A., Osvath, P., Wilhelm, F., and Juricskay, S. (2005). Urinary steroid measurements in some endocrine and psychiatric diseases. Curr. Med. Chem. 12:1339–1342.
Prasad, A., Imamura, M., and Prasad, C. (1997). Dehydroepiandrosterone decreases behavioural despair in high- but not low-anxiety rats. Physiol. Behav. 62:1053–1057.
Prince, R. J., and Simmonds, M. A. (1992). 5 beta-pregnan-3 beta-ol-20-one, a specific antagonist at the neurosteroid site of the GABAA receptor-complex. Neurosci. Lett. 135:273–275.
Puia, G., Santi, M. R., Vicini, S., Prichett, 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.
Purdy, R. H., Morrow, A. L., Moore, P. H., Jr., and Paul, S. M. (1991). Stress-induced elevations of gamma-aminobutyric acid type A receptor-active steroids in the rat brain. Proc. Natl. Acad. Sci. U.S.A. 88:4553–4557.
Rago, L., Kiivet, R. A., Harro, J., and Pold, M. (1989). Central- and peripheral-type benzodiazepine receptors: similar regulation by stress and GABA receptor agonists. Pharmacol. Biochem. Behav. 32:879–883.
Rammes, G., Eisensamer, B., Ferrari, U., Shapa, M., Gimpl, G., Gilling, K., Parsons, C., Riering, K., Hapfelmeier, G., Bondy, B., Zieglgansberger, W., Holsboer, F., and Rupprecht, R. (2004). Antipsychotic drugs antagonize human serotonin type 3 receptor currents in a noncompetitive manner. Mol. Psychiatry 9:846–858, 818.
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.
Reddy, D. S., Kaur, G., and Kulkarni, S. K. (1998). Sigma (sigma1) receptor mediated anti-depressant-like effects of neurosteroids in the Porsolt forced swim test. Neuroreport 9:3069–3073.
Reddy, D. S. (2003). Is there a physiological role for the neurosteroid THDOC in stress-sensitive conditions? Trends Pharmacol. Sci. 24:103–106.
Ritsner, M., Maayan, R., Gibel, A., Strous, R. D., Modai, I., and Weizman, A. (2004). Elevation of the cortisol/dehydroepiandrosterone ratio in schizophrenia patients. Eur. Neuropsychopharmacol. 14:267–273.
Rivier, C., and Vale, W. (1987). Diminished responsiveness of the hypothalamic-pituitary-adrenal axis of the rat during exposure to prolonged stress: a pituitary-mediated mechanism. Endocrinology 121:1320–1328.
Robel, P., Schumacher, M., and Baulieu, E. E. (1999). Neurosteroids: From definition and biochemistry to physiopathologic function. In Baulieu, E. E., Robel, P., and Schumacher, M. (eds.), Neurosteroids: A New Regulatory Function in the Nervous System. Humana Press, Totowa, N.J., pp. 1–25.
Rode, A., Bidzinski, A., and Puzynski, S. (1991). [GABA levels in the plasma of patients with endogenous depression and during the treatment with thymoleptics]. Psychiatry Pol. 25:4–7.
Romeo, E., Strohle, A., Spalletta, G., di Michele, F., Hermann, B., Holsboer, F., Pasini, A., and Rupprecht, R. (1998). Effects of antidepressant treatment on neuroactive steroids in major depression. Am. J. Psychiatry 155:910–913.
Rupprecht, R. (2003). Neuroactive steroids: mechanisms of action and neuropsychopharmacological properties. Psychoneuroendocrinology 28:139–168.
Rupprecht, R., Koch, M., Montkowski, A., Lancel, M., Faulhaber, J., Harting, J., and Spanagel, R. (1999). Assessment of neuroleptic-like properties of progesterone. Psychopharmacology 143:29–38.
Sakamaki, K., Nomura, M., Yamato, K., and Tanaka, J. (2004). GABA-mediated attenuation of noradrenaline release in the rat median preoptic area caused by intravenous injection of metaraminol. Auton. Neurosci. 111:7–14.
Sanacora, G., Gueorguieva, R., Epperson, C. N., Wu, Y. T., Appel, M., Rothman, D. L., Krystal, J. H., and Mason, G. F. (2004). Subtype-specific alterations of gamma-aminobutyric acid and glutamate in patients with major depression. Arch. Gen. Psychiatry 61:705–713.
Sanacora, G., Mason, G. F., Rothman, D. L., Behar, K. L., Hyder, F., Petroff, O. A., Berman, R. M., Charney, D. S., and Krystal, J. H. (1999). Reduced cortical gamma-aminobutyric acid levels in depressed patients determined by proton magnetic resonance spectroscopy. Arch. Gen. Psychiatry 56:1043–1047.
Sanacora, G., Mason, G. F., Rothman, D. L., and Krystal, J. H. (2002). Increased occipital cortex GABA concentrations in depressed patients after therapy with selective serotonin reuptake inhibitors. Am. J. Psychiatry 159:663–665.
Sanacora, G., Mason, G. F., Rothman, D. L., Hyder, F., Ciarcia, J. J., Ostroff, R. B., Berman, R. M., and Krystal, J. H. (2003). Increased cortical GABA concentrations in depressed patients receiving ECT. Am. J. Psychiatry 160:577–579.
Sanfilipo, M., Wolkin, A., Angrist, B., van Kammen, D. P., Duncan, E., Wieland, S., Cooper, T. B., Peselow, E. D., and Rotrosen, J. (1996). Amphetamine and negative symptoms of schizophrenia. Psychopharmacology (Berl.) 123:211–214.
Schmidt, P. J., Daly, R. C., Bloch, M., Smith, M. J., Danaceau, M. A., St Clair, L. S., Murphy, J. H., Haq, N., and Rubinow, D. R. (2005). Dehydroepiandrosterone monotherapy in midlife-onset major and minor depression. Arch. Gen. Psychiatry 62:154–162.
Schmidt, P. J., Murphy, J. H., Haq, N., Danaceau, M. A., and St Clair, L. (2002). Basal plasma hormone levels in depressed perimenopausal women. Psychoneuroendocrinology 27:907–920.
Schmidt, P. J., Purdy, R. H., Moore, P. H., Jr., Paul, S. M., and Rubinow, D. R. (1994). Circulating levels of anxiolytic steroids in the luteal phase in women with premenstrual syndrome and in control subjects. J. Clin. Endocrinol. Metab. 79:1256–1260.
Scholtz, P., Ebert, V., and Seighart, W. (1996). Affinity of various ligands for GABAA receptors containing alpha4-beta3-gamma2, alpha4-gamma2, or alpha1-beta3-gamma2. Eur. J. Pharmacol. 304:155–162.
Schule, C., Di Michele, F., Baghai, T., Romeo, E., Bernardi, G., Zwanzger, P., Padberg, F., Pasini, A., and Rupprecht, R. (2004). Neuroactive steroids in responders and nonresponders to sleep deprivation. Ann. N. Y. Acad. Sci. 1032:216–223.
Schumacher, M., Robel, P., and Baulieu, E. E. (1996). Development and regeneration of the nervous system: a role for neurosteroids. Dev. Neurosci. 18:6–21.
Schumacher, M., Guennoun, R., Robert, F., Carelli, C., Gago, N., Ghoumari, A., Gonzalez Deniselle, M. C., Gonzalez, S. L., Ibanez, C., Labombarda, F., Coirini, H., Baulieu, E. E., and De Nicola, A. F. (2004). Local synthesis and dual actions of progesterone in the nervous system: neuroprotection and myelination. Growth Horm. IGF Res. 14(Suppl A):S18–S33.
Scott, L. V., Salahuddin, F., Cooney, J., Svec, F., and Dinan, T. G. (1999). Differences in adrenal steroid profile in chronic fatigue syndrome, in depression and in health. J. Affect Disord. 54:129–137.
Seeman, P., and Kapur, S. (2000). Schizophrenia: more dopamine, more D2 receptors. Proc. Natl. Acad. Sci. U.S.A. 97:7673–7675.
Semeniuk, T., Jhangri, G. S., and Le Melledo, J. M. (2001). Neuroactive steroid levels in patients with generalized anxiety disorder. J. Neuropsychiatry Clin. Neurosci. 13:396–398.
Serra, M., Pisu, M. G., Floris, I., Floris, S., Cannas, E., Mossa, A., Trapani, G., Latrofa, A., Purdy, R. H., and Biggio, G. (2004). Social isolation increases the response of peripheral benzodiazepine receptors in the rat. Neurochem. Int. 45:141–148.
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 decrease in both the abundance of neuroactive steroids and GABAA receptor function in rat brain. J. Neurochem. 75:732–740.
Serra, M., Pisu, M. G., Muggironi, M., Parodo, V., Papi, G., Sari, R., Dazzi, L., Spiga, F., Purdy, R. H., and Biggio, G. (2001). Opposite effects of short- versus long-term administration of fluoxetine on the concentrations of neuroactive steroids in rat plasma and brain. Psychopharmacology (Berl) 158:48–54.
Shirayama, Y., Hashimoto, K., Suzuki, Y., and Higuchi, T. (2002). Correlation of plasma neurosteroid levels to the severity of negative symptoms in male patients with schizophrenia. Schizophr. Res. 58:69–74.
Shulman, Y., and Tibbo, P. G. (2005). Neuroactive steroids in schizophrenia. Can. J. Psychiatry 50:695–702.
Smith, T. A. (2001). Type A gamma-aminobutyric acid (GABAA) receptor subunits and benzodiazepine binding: significance to clinical syndromes and their treatment. Br. J. Biomed. Sci. 58:111–121.
Smith, S. S. (2002). Withdrawal properties of a neuroactive steroid: implications for GABA(A) receptor gene regulation in the brain and anxiety behaviour. Steroids 67:519–528.
Sousa, A., and Ticku, M. K. (1997). Interactions of the neurosteroid dehydroepiandrosterone sulfate with the GABA(A) receptor complex reveals that it may act via the picrotoxin site. J. Pharmacol. Exp. Ther. 282:827–833.
Spalletta, G., Romeo, E., Bonaviri, G., Bernardi, G., Caltagirone, C., and di Michele, F. (2005). Preliminary evidence for an association between aggressive and hostile behaviour and 3alpha,5alpha-tetrahydroprogesterone plasma levels in schizophrenia. J. Psychiatry Neurosci. 30:49–52.
Spivak, B., Maayan, R., Kotler, M., Mester, R., Gil-Ad, I., Shtaif, B., and Weizman, A. (2000). Elevated circulatory level of GABA(A)–antagonistic neurosteroids in patients with combat-related post-traumatic stress disorder. Psychol. Med. 30:1227–1231.
Stocco, D. M., and Clark, B. J. (1996). Regulation of the acute production of steroids in steroidogenic cells. Endocr. Rev. 17:221–244.
Stoffel-Wagner, B. (2001). Neurosteroid metabolism in the human brain. Eur. J. Endocrinol. 145:669–679.
Stomati, M., Monteleone, P., Casarosa, E., Quirici, B., Puccetti, S., Bernardi, F., Genazzani, A. D., Rovati, L., Luisi, M., and Genazzani, A. R. (2000). Six-month oral dehydroepiandrosterone supplementation in early and late postmenopause. Gynecol. Endocrinol. 14:342–363.
Strauss, E. B., Sands, D. E., Robinson, A. M., and Tindall, W. J. (1952). Use of dehydroisoandrosterone in psychiatric treatment. Br. Med. J. 12:64–66.
Strohle, A., Pasini, A., Romeo, E., Hermann, B., Spalletta, G., di Michele, F., Holsboer, F., and Rupprecht, R. (2000). Fluoxetine decreases concentrations of 3 alpha, 5 alpha-tetrahydrodeoxycorticosterone (THDOC) in major depression. J. Psychiatr. Res. 34:183–186.
Strohle, A., Romeo, E., di Michele, F., Pasini, A., Yassouridis, A., Holsboer, F., and Rupprecht, R. (2002). GABA(A) receptor-modulating neuroactive steroid composition in patients with panic disorder before and during paroxetine treatment. Am. J. Psychiatry 159:145–147.
Strohle, A., Romeo, E., di Michele, F., Pasini, A., Hermann, B., Gajewsky, G., Holsboer, F., and Rupprecht, R. (2003). Induced panic attacks shift gamma-aminobutyric acid type A receptor modulatory neuroactive steroid composition in patients with panic disorder: preliminary results. Arch. Gen. Psychiatry 60:161–168.
Strohle, A., Romeo, E., Hermann, B., Pasini, A., Spalletta, G., di Michele, F., Holsboer, F., and Rupprecht, R. (1999). Concentrations of 3 alpha-reduced neuroactive steroids and their precursors in plasma of patients with major depression and after clinical recovery. Biol. Psychiatry 45:274– 277.
Strous, R. D., Maayan, R., Lapidus, R., Goredetsky, L., Zeldich, E., Kotler, M., and Weizman, A. (2004). Increased circulatory dehydroepiandrosterone and dehydroepiandrosterone-sulphate in first-episode schizophrenia: relationship to gender, aggression and symptomatology. Schizophr. Res. 71:427–434.
Strous, R. D., Maayan, R., Lapidus, R., Stryjer, R., Lustig, M., Kotler, M., and Weizman, A. (2003). Dehydroepiandrosterone augmentation in the management of negative, depressive, and anxiety symptoms in schizophrenia. Arch. Gen. Psychiatry 60:133–141.
Strous, R. D., Spivak, B., Yoran-Hegesh, R., Maayan, R., Averbuch, E., Kotler, M., Mester, R., and Weizman, A. (2001). Analysis of neurosteroid levels in attention deficit hyperactivity disorder. Int. J. Neuropsychopharmacol. 4:259–264.
Sundstrom, I., Andersson, A., Nyberg, S., Ashbrook, D., Purdy, R. H., and Backstrom, T. (1998). Patients with premenstrual syndrome have a different sensitivity to a neuroactive steroid during the menstrual cycle compared to control subjects. Neuroendocrinology 67:126–138.
Sundstrom, I., Nyberg, S., and Backstrom, T. (1997). Patients with premenstrual syndrome have reduced sensitivity to midazolam compared to control subjects. Neuropsychopharmacology 17:370–381.
Suzdak, P. D., and Gianutsos, G. (1985). Differential coupling of GABA-A and GABA-B receptors to the noradrenergic system. J. Neural Transm. 62:77–89.
Taherianfard, M., and Shariaty, M. (2004). Evaluation of serum steroid hormones in schizophrenic patients. Indian J. Med. Sci. 58:3–9.
Tait, G. R., McManus, K., Bellavance, F., Lara, N., Chrapko, W., and Le Melledo, J. M. (2002). Neuroactive steroid changes in response to challenge with the panicogenic agent pentagastrin. Psychoneuroendocrinology 27:417–429.
Takebayashi, M., Kagaya, A., Uchitomi, Y., Kugaya, A., Muraoka, M., Yokota, N., Horiguchi, J., and Yamawaki, S. (1998). Plasma dehydroepiandrosterone sulfate in unipolar major depression. Short communication. J. Neural Transm. 105:537–542.
Tollefson, G. D., Haus, E., Garvey, M. J., Evans, M., and Tuason, V. B. (1990). 24 hour urinary dehydroepiandrosterone sulfate in unipolar depression treated with cognitive and/or pharmacotherapy. Ann. Clin. Psychiatry 2:39–45.
Tourney, G., and Erb, J. L. (1979). Temporal variations in androgens and stress hormones in control and schizophrenic subjects. Biol. Psychiatry 14:395–404.
Tourney, G., and Hatfield, L. (1972). Plasma androgens in male schizophrenics. Arch. Gen. Psychiatry 27:753–755.
Trullas, R., Havoundjian, H., and Skolnick, P. (1987). Stress-induced changes in t-[35S]butylbicyclophosphorothionate binding to gamma-aminobutyric acid-gated chloride channels are mimicked by in vitro occupation of benzodiazepine receptors. J. Neurochem. 49:968–974.
Truss, M., and Beato, M. (1988). Steroid hormone receptors: interaction with deoxyribonucleic acid and transcription factors. Endocr. Rev. 14:459–479.
Ueno, S., Tsutsui, M., Toyohira, Y., Minami, K., and Yanagihara, N. (2004). Sites of positive allosteric modulation by neurosteroids on ionotropic gamma-aminobutyric acid receptor subunits. FEBS Lett. 566:213–217.
Ugale, R. R., Hirani, K., Morelli, M., and Chopde, C. T. (2004). Role of neuroactive steroid allopregnanolone in antipsychotic-like action of olanzapine in rodents. Neuropsychopharmacology 29:1597–1609.
Ulrich-Lai, Y. M., and Engeland, W. C. (2002). Adrenal splanchnic innervation modulates adrenal cortical responses to dehydration stress in rats. Neuroendocrinology 76:79–92.
Urani, A., Roman, F. J., Phan, V. L., Su, T. P., and Maurice, T. (2001). The antidepressant-like effect induced by sigma(1)-receptor agonists and neuroactive steroids in mice submitted to the forced swimming test. J. Pharmacol. Exp. Ther. 298:1269–1279.
Uzunov, D. P., Cooper, T. B., Costa, E., and Guidotti, A. (1996). Fluoxetine-elicited changes in brain neurosteroid content measured by negative ion mass fragmentography. Proc. Natl. Acad. Sci. U.S.A. 93:12599–12604.
Uzunova, V., Ceci, M., Kohler, C., Uzunov, D. P., and Wrynn, A. S. (2003). Region-specific dysregulation of allopregnanolone brain content in the olfactory bulbectomized rat model of depression. Brain Res. 976:1–8.
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 fluvoxamine. Proc. Natl. Acad. Sci. U.S.A. 95:3239– 3244.
Uzunova, V., Wrynn, A. S., Kinnunen, A., Ceci, M., Kohler, C., and Uzunov, D. P. (2004). Chronic antidepressants reverse cerebrocortical allopregnanolone decline in the olfactory-bulbectomized rat. Eur. J. Pharmacol. 486:31–34.
Vallee, M., Mayo, W., Darnaudery, M., Corpechot, C., Young, J., Koehl, M., Le Moal, M., Baulieu, E. E., Robel, P., and Simon, H. (1997). Neurosteroids: deficient cognitive performance in aged rats depends on low pregnenolone sulfate levels in the hippocampus. Proc. Natl. Acad. Sci. U.S.A. 94:14865–14870.
Vallee, M., Rivera, J. D., Koob, G. F., Purdy, R. H., and Fitzgerald, R. L. (2000). Quantification of neurosteroids in rat plasma and brain following swim stress and allopregnanolone administration using negative chemical ionization gas chromatography/mass spectrometry. Anal. Biochem. 287:153–166.
Verghese, C., DeLeon, J., Nair, C., and Simpson, G. M. (1996). Clozapine withdrawal effects and receptor profiles of typical and atypical neuroleptics. Biol. Psychiatry 39:135–138.
Verleye, M., Akwa, Y., Liere, P., Ladurelle, N., Pianos, A., Eychenne, B., Schumacher, M., and Gillardin, J. M. (2005). The anxiolytic etifoxine activates the peripheral benzodiazepine receptor and increases the neurosteroid levels in rat brain. Pharmacol. Biochem. Behav. 82:712–720.
Volz, H. P., and Stoll, K. D. (2004). Clinical trials with sigma ligands. Pharmacopsychiatry 37(Suppl 3):S214–S220.
Wadenberg, M. L., Soliman, A., VanderSpek, S. C., and Kapur, S. (2001). Dopamine D(2) receptor occupancy is a common mechanism underlying animal models of antipsychotics and their clinical effects. Neuropsychopharmacology 25:633–641.
Wang, M., Seippel, L., Purdy, R. H., and Backstrom, T. (1996). Relationship between symptom severity and steroid variation in women with premenstrual syndrome: study on serum pregnenolone, pregnenolone sulfate, 5 alpha-pregnane-3,20-dione and 3 alpha-hydroxy-5 alpha-pregnan-20-one. J Clin Endocrinol Metab 81:1076–1082.
Wassef, A., Baker, J., and Kochan, L. D. (2003). GABA and schizophrenia: a review of basic science and clinical studies. J. Clin. Psychopharmacol. 23:601–640.
Waters, S. L., Miller, G. W., Aleo, M. D., and Schnellmann, R. G. (1997). Neurosteroid inhibition of cell death. Am. J. Physiol. 273:F869–F876.
Weiss, E., Brunner, H., Clerc, G., Guibert, M., Orofiamma, B., Pagot, R., Robert, G., Thillez, D., and Musch, B. (1986). Multicenter double-blind study of progabide in depressed patients. In Lloyd, K. G. (ed.), GABA and Mood Disorders. Raven Press, New York, pp. 182–188.
Weizman, A., Bidder, M., Fares, F., and Gavish, M. (1990). Food deprivation modulates gamma-aminobutyric acid receptors and peripheral benzodiazepine binding sites in rats. Brain Res. 535:96–100.
Weizman, A., Burgin, R., Harel, Y., Karp, L., and Gavish, M. (1995). Platelet peripheral-type benzodiazepine receptor in major depression. J. Affect Disord. 33:257–261.
Wetzel, C. H., Hermann, B., Behl, C., Pestel, E., Rammes, G., Zieglgansberger, W., Holsboer, F., and Rupprecht, R. (1998). Functional antagonism of gonadal steroids at the 5-hydroxytryptamine type 3 receptor. Mol. Endocrinol. 12:1441–1451.
Wohlfarth, K. M., Bianchi, M. T., and Macdonald, R. L. (2002). Enhanced neurosteroid potentiation of ternary GABA(A) receptors containing the delta subunit. J. Neurosci. 22:1541–1549.
Wolkowitz, O. M., Reus, V. I., Keebler, A., Nelson, N., Friedland, M., Brizendine, L., and Roberts, E. (1999). Double-blind treatment of major depression with dehydroepiandrosterone. Am. J. Psychiatry 156:646–649.
Wolkowitz, O. M., Reus, V. I., Roberts, E., Manfredi, F., Chan, T., Raum, W. J., Ormiston, S., Johnson, R., Canick, J., Brizendine, L., and Weingartner, H. (1997). Dehydroepiandrosterone (DHEA) treatment of depression. Biol. Psychiatry 41:311–318.
Wu, F. S., Gibbs, T. T., and Farb, D. H. (1991). Pregnenolone sulfate: a positive allosteric modulator at the N-methyl-D-aspartate receptor. Mol. Pharmacol. 40:333–336.
Young, A. H., Gallagher, P., and Porter, R. J. (2002). Elevation of the cortisol-dehydroepiandrosterone ratio in drug-free depressed patients. Am. J. Psychiatry 159:1237–1239.
Zhu, W. J., Wang, J. F., Krueger, K. E., and Vicini, S. (1996). Delta subunit inhibits neurosteroid modulation of GABAA receptors. J. Neurosci. 16:6648–6656.
ACKNOWLEDGEMENTS
Funds for our research have been provided by the Canadian Institutes of Health Research, the Alberta Heritage Foundation for Medical Research (AHFMR), the Canada Research Chairs Program, the Canada Foundation for Innovation, the Bebensee Fund, the Davey Endowment and the Abraham and Freda Berger Memorial Endowment Fund. EM has received studentship funding from the Faculty of Medicine and Dentistry 75th Anniversary Fund, the Government of Alberta and the AHFMR.
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MacKenzie, E.M., Odontiadis, J., Le Mellédo, JM. et al. The Relevance of Neuroactive Steroids in Schizophrenia, Depression, and Anxiety Disorders. Cell Mol Neurobiol 27, 541–574 (2007). https://doi.org/10.1007/s10571-006-9086-0
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DOI: https://doi.org/10.1007/s10571-006-9086-0