Neurosteroids: Endogenous bimodal modulators of the GABAA receptor mechanism of action and physiological significance

The abundant CNS cholesterol and its sulfate derivative serve as precursors of different neurosteroids, which bidirectionally modulate neuronal excitability, by potentiating or inhibiting function of the GABAA receptors. The regulation of GABAA receptors in the CNS by the steroids of central or peripheral origin may constitute a vital means of brain-body communication, essential for integrated whole organism responses to external stimuli or internal signals. Modulation of the brain GABA receptors by neurosteroids may form the basis of a myriad of psychophysiological phenomena, such as memory, stress, anxiety, sleep, depression, seizures and others. Therefore, the aberrant synthesis of centrally-active steroids may contribute to defects in neurotransmission, resulting in a variety of neural and affective disorders. The biosynthesis of neurosteroids may also be altered by diet and certain psychotropic drugs, thereby affecting excitation of neurons. Hereditary differences in the level of synthesis and catabolism of different neurosteroids may underlie individual variations in CNS excitability, contributing to differences in personality traits, including the inherited susceptibility to drug addition.

[1]  H. Roffwarg,et al.  Dehydroisoandrosterone is secreted episodically and synchronously with cortisol by normal man. , 1971, The Journal of clinical endocrinology and metabolism.

[2]  T. Roth,et al.  Effects of hypnotics on memory. , 1983, Journal of clinical psychopharmacology.

[3]  P. Mandel,et al.  Effects of the potentiation of the GABAergic neurotransmission in the olfactory bulbs on mouse-killing behavior , 1986, Pharmacology Biochemistry and Behavior.

[4]  H. Moser,et al.  Cholesterol sulfate in rat tissues. Tissue distribution, developmental change and brain subcellular localization. , 1976, Biochimica et biophysica acta.

[5]  P. Seeburg,et al.  Sequence and functional expression of the GABAA receptor shows a ligand-gated receptor super-family , 1987, Nature.

[6]  Alice R. Johnson,et al.  Steroid 5α-reductase activity in endothelial cells from human umbilical cord vessels , 1987 .

[7]  R. Olsen,et al.  Molecular biology of GABAA receptors , 1990, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[8]  M. Santi,et al.  Neurosteroids act on recombinant human GABAA receptors , 1990, Neuron.

[9]  A. Lanthier,et al.  Sex steroids and 5-en-3 beta-hydroxysteroids in specific regions of the human brain and cranial nerves. , 1986, Journal of steroid biochemistry.

[10]  G. Biggio,et al.  Changes in GABAergic transmission induced by stress, anxiogenic and anxiolytic β-carbolines , 1987, Brain Research Bulletin.

[11]  R. Douglas,et al.  Inhibitory modulation of long-term potentiation: Evidence for a postsynaptic locus of control , 1982, Brain Research.

[12]  M. Schambelan,et al.  Deoxycorticosterone production and regulation in man. , 1972, The Journal of clinical endocrinology and metabolism.

[13]  F. Rommerts,et al.  Occurrence and localization of 5α-steroid reductase, 3α- and 17β-hydroxysteroid dehydrogenases in hypothalamus and other brain tissues of the male rat☆ , 1971 .

[14]  E. Baulieu,et al.  Neurosteroids: A new brain function? , 1990, The Journal of Steroid Biochemistry and Molecular Biology.

[15]  J. Mcgaugh,et al.  Facilitation of maze learning with posttrial injections of picrotoxin. , 1961, Journal of comparative and physiological psychology.

[16]  B. Dubrovsky,et al.  Distribution, metabolism and biological activity of deoxycorticosterone in the central nervous system , 1975, Brain Research.

[17]  B. McEwen,et al.  Steroid modulation of the chloride ionophore in rat brain: structure-activity requirements, regional dependence and mechanism of action. , 1988, The Journal of pharmacology and experimental therapeutics.

[18]  J. Barker,et al.  Structure-activity relationships for steroid interaction with the gamma-aminobutyric acidA receptor complex. , 1987, The Journal of pharmacology and experimental therapeutics.

[19]  B. Bloom,et al.  Central activity and structure in a series of water-soluble steroids. , 1957, The Journal of pharmacology and experimental therapeutics.

[20]  C. Kubli-Garfias.  Physiological role of 5α-and 5β-progesterone metabolites on the CNS , 1984 .

[21]  A. F. Nicola,et al.  In vivo secretion of 3α-hydroxy-5α-pregnan-20-one, a potent anaesthetic steroid, by the adrenal gland of the rat , 1985 .

[22]  J. A. Peters,et al.  Actions of synthetic and endogenous steroids on the GABAA receptor , 1987 .

[23]  B. Scatton,et al.  The potential use of GABA agonists in psychiatric disorders: Evidence from studies with progabide in animal models and clinical trials , 1983, Pharmacology Biochemistry and Behavior.

[24]  E. Baulieu,et al.  Pregnenolone and its sulfate ester in the rat brain , 1983, Brain Research.

[25]  M. Lader.  Anxiety and Depression , 1983 .

[26]  M. Majewska,et al.  Steroid regulation of the GABAA receptor: ligand binding, chloride transport and behaviour. , 2007, Ciba Foundation symposium.

[27]  J. A. Peters,et al.  Steroid modulation of the GABAA receptor complex: electrophysiological studies. , 1990, Ciba Foundation symposium.

[28]  R. Olsen,et al.  Steroid anesthetics and naturally occurring analogs modulate the gamma-aminobutyric acid receptor complex at a site distinct from barbiturates. , 1989, The Journal of pharmacology and experimental therapeutics.

[29]  S. Vicini,et al.  Pregnenolone sulfate antagonizes GABAA receptor-mediated currents via a reduction of channel opening frequency , 1989, Brain Research.

[30]  M. D. Majewska.  Steroids and brain activity. Essential dialogue between body and mind. , 1987, Biochemical pharmacology.

[31]  J. Flood,et al.  Dehydroepiandrosterone sulfate improves memory in aging mice , 1988, Brain Research.

[32]  E. Baulieu,et al.  Neurosteroids: biosynthesis of pregnenolone and progesterone in primary cultures of rat glial cells. , 1989, Endocrinology.

[33]  W. Kostowski,et al.  Effects of some steroids on aggressive behaviour in mice and rats. , 1970, Neuroendocrinology.

[34]  J. Canick,et al.  Localization of aromatase and 5α-reductase to neuronal and non-neuronal cells in the fetal rat hypothalamus , 1986, Brain Research.

[35]  S. Vicini,et al.  Neurosteroid pregnenolone sulfate antagonizes electrophysiological responses to GABA in neurons , 1988, Neuroscience Letters.

[36]  R. D. Schwartz,et al.  Pregnenolone-sulfate: an endogenous antagonist of the γ-aminobutyric acid receptor complex in brain? , 1987, Brain Research.

[37]  M. Majewska,et al.  Pregnancy-induced alterations of GABAA receptor sensitivity in maternal brain: an antecedent of post-partum ‘blues’? , 1989, Brain Research.

[38]  E. Kirkness,et al.  Modulation of the GABAA receptor by depressant barbiturates and pregnane steroids , 1988, British journal of pharmacology.

[39]  D. Pfaff,et al.  Progesterone Receptors in CNS Correlated with Reproductive Behavior , 1985 .

[40]  D. Kerr,et al.  Cortisol: A potent biphasic modulator at GABAA-receptor complexes in the guinea pig isolated ileum , 1987, Neuroscience Letters.

[41]  E. Baulieu,et al.  Neurosteroids: oligodendrocyte mitochondria convert cholesterol to pregnenolone. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[42]  N. Greenfield,et al.  A heuristic proposal for understanding steroidogenic processes. , 1984, Endocrine reviews.

[43]  S. Paul,et al.  Steroid hormone metabolites are barbiturate-like modulators of the GABA receptor. , 1986, Science.

[44]  H. Selye.  CORRELATIONS BETWEEN THE CHEMICAL STRUCTURE AND THE PHARMACOLOGICAL ACTIONS OF THE STEROIDS1 , 1942 .

[45]  P. H. Moore,et al.  Radioimmunoassay of 3α-hydroxy-5α-pregnan-20-one in rat and human plasma , 1990, Steroids.

[46]  R. Siegel,et al.  In vitro conversion of pregnenolone to progesterone by discrete brain areas of the male rat. , 1980, Journal of steroid biochemistry.

[47]  D. Pfaff,et al.  The brain as a target for steroid hormone action. , 1979, Annual review of neuroscience.

[48]  P. Bertics,et al.  Partial characterization of the microsomal and solubilized hypothalamic progesterone 5 alpha-reductase. , 1984, Journal of steroid biochemistry.

[49]  S. Irwin,et al.  Pentylenetetrazol Enhances Memory Function , 1966, Science.

[50]  T. Shohmori,et al.  Sex Hormone Metabolism in the Brain: Influence of Central Acting Drugs on 5α-Reduction in Rat Diencephalon , 1979 .

[51]  S. Paul,et al.  Anxiolytic activity of an endogenous adrenal steroid , 1986, Brain Research.

[52]  N. Harrison,et al.  Interactions of steroids with the GABA-A receptor complex , 1984, Neuropharmacology.

[53]  M. Haug,et al.  Studies on the effects of dehydroepiandrosterone and its metabolites on attack by castrated mice on lactating intruders , 1985, Physiology & Behavior.

[54]  J. Krause,et al.  Subcellular location of hypothalamic progesterone metabolizing enzymes and evidence for distinct NADH- and NADPH-linked 3 alpha-hydroxysteroid oxidoreductase activities. , 1980, Journal of steroid biochemistry.

[55]  S. Amir,et al.  Systemic hypoglycemia following central injection of endotoxin in mice , 1985, Brain Research.

[56]  C. Roselli,et al.  Progesterone 5α-reductase in mouse brain , 1984, Brain Research.

[57]  M. Majewska,et al.  Interaction of ethanol with the GABAA receptor in the rat brain: possible involvement of endogenous steroids. , 1988, Alcohol.

[58]  Donald J. Woodward,et al.  Progesterone alters GABA and glutamate responsiveness: a possible mechanism for its anxiolytic action , 1987, Brain Research.

[59]  B. Dubrovsky,et al.  Effects of 5α-dihydrocorticosterone on evoked responses and long-term potentiation , 1987, Brain Research Bulletin.

[60]  H. Eysenck.  Psychophysiology and Personality: Extraversion, Neuroticism and Psychoticism , 1983 .

[61]  P. Seeburg,et al.  Importance of a novel GABAA receptor subunit for benzodiazepine pharmacology , 1989, Nature.

[62]  E. Baulieu,et al.  Characterization and measurement of dehydroepiandrosterone sulfate in rat brain. , 1981, Proceedings of the National Academy of Sciences of the United States of America.

[63]  J. Flood,et al.  Dehydroepiandrosterone and its sulfate enhance memory retention in mice , 1988, Brain Research.

[64]  E. London,et al.  Receptor binding and electrophysiological effects of Dehydroepiandrosterone sulfate, an antagonist of the GABAA receptor , 1991, Neuroscience.

[65]  M. Waterman,et al.  Neurosteroids: cytochrome P-450scc in rat brain. , 1987, Science.

[66]  S. Paul,et al.  Acute stress enhances the activity of the GABA receptor-gated chloride ion channel in brain , 1987, Brain Research.

[67]  Paul I. Robinson,et al.  STUDIES ON THE INFLUENCE OF MORPHINE, PAPAVERINE AND QUINIDINE UPON THE HEART , 1929 .

[68]  H SELYE,et al.  Stress and the General Adaptation Syndrome* , 1950, British medical journal.

[69]  E. London,et al.  The neurosteroid dehydroepiandrosterone sulfate is an allosteric antagonist of the GABAA receptor , 1990, Brain Research.

[70]  S. Vicini.  Pharmacologic significance of the structural heterogeneity of the GABAA receptor-chloride ion channel complex. , 1991, Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology.

[71]  Martin F. Cashin,et al.  THE PHYSIOLOGICAL ACTION OF CHOLESTEROL , 1927 .

[72]  J. Reinisch,et al.  Behavioral Effects on Humans of Progesterone-Related Compounds During Development and in the Adult , 1985 .

[73]  E. Baulieu,et al.  Steroid synthesis in rat brain cell cultures. , 1989, Journal of steroid biochemistry.

[74]  J. O. Davis,et al.  Control of deoxycorticosterone secretion in the dog. , 1972, The American journal of physiology.

[75]  P. Poulain,et al.  Excitatory effect of dehydroepiandrosterone, its sulphate ester and pregnenolone sulphate, applied by iontophoresis and pressure, on single neurones in the septo-preoptic area of the guinea pig , 1984, Neuroscience Letters.

[76]  M. Holzbauer.  Physiological aspects of steroids with anaesthetic properties. , 1976, Medical biology.

[77]  A. Sastre,et al.  Electrophysiologic and Clinical Aspects of Glucocorticoids on Certain Neural Systems , 1982 .

[78]  E. Baulieu,et al.  Pregnenolone sulfate antagonizes barbiturate-induced hypnosis , 1989, Pharmacology Biochemistry and Behavior.

[79]  H. Moser,et al.  STEROID SULFATASE IN BRAIN: COMPARISON OF SULFOHYDROLASE ACTIVITIES FOR VARIOUS STEROID SULFATES IN NORMAL AND PATHOLOGICAL BRAINS, INCLUDING THE VARIOUS FORMS OF METACHROMATIC LEUKODYSTROPHY , 1976, Journal of neurochemistry.

[80]  J. Fiet,et al.  Simultaneous radioimmunoassay of progesterone, androst-4-enedione, pregnenolone, dehydroepiandrosterone and 17-hydroxyprogesterone in specific regions of human brain. , 1987, Journal of steroid biochemistry.

[81]  M. Majewska,et al.  Antagonist-type interaction of glucocorticoids with the GABA receptor-coupled chloride channel , 1987, Brain Research.

[82]  E. London,et al.  Binding of pregnenolone sulfate to rat brain membranes suggests multiple sites of steroid action at the GABAA receptor. , 1990, European journal of pharmacology.

[83]  H. Kamaya,et al.  Anesthesia cutoff phenomenon: interfacial hydrogen bonding. , 1990, Science.

[84]  B. Buntner,et al.  Ovarian hormones, anticonvulsant drugs, and seizures during the menstrual cycle in women with epilepsy. , 1986, Journal of neurology, neurosurgery, and psychiatry.

[85]  E. Eidelberg,et al.  Steroid-induced convulsions in experimental animals. , 1961, Endocrinology.

[86]  R. Eskay,et al.  Glucocorticoids are modulators of GABAA receptors in brain , 1985, Brain Research.

[87]  J. Dall,et al.  Disturbances of Pigmentation with Chloroquine , 1959, British medical journal.

[88]  N. Harrison,et al.  Modulation of the GABA receptor complex by a steroid anaesthetic , 1984, Brain Research.

[89]  R. Melcangi,et al.  Differential distribution of the 5-alpha-reductase in the central nervous system of the rat and the mouse: are the white matter structures of the brain target tissue for testosterone action? , 1987, Journal of steroid biochemistry.

[90]  Y. Nakamura,et al.  Ovarian secretion of pregnane compounds during the estrous cycle and pregnancy in rats. , 1974, Endocrinology.

[91]  N. Krieger,et al.  Nonneuronal Localization for Steroid Converting Enzyme: 3α‐Hydroxysteroid Oxidoreductase in Olfactory Tubercle of Rat Brain , 1989, Journal of neurochemistry.

[92]  B. Schwarz,et al.  5α-Reductase activity in human placenta , 1979 .

[93]  S. Fesik,et al.  Geometric requirements for membrane perturbation and anesthetic activity. Conformational analysis of alphaxalone and delta 16-alphaxalone and 2H NMR studies on their interactions with model membranes. , 1985, Molecular pharmacology.

[94]  H. Wigström,et al.  Facilitation of hippocampal long-lasting potentiation by GABA antagonists. , 1985, Acta physiologica Scandinavica.

[95]  R. Matsumoto.  GABA receptors: are cellular differences reflected in function? , 1989, Brain Research Reviews.