Certain steroid metabolites of progesterone and deoxycorticosterone potently and specifically bind to the GABAA (γ-aminobutyric acid type A) receptor — the main inhibitory receptor in the mammalian CNS — to enhance receptor function. Consequently, these steroids have anxiolytic, analgesic, anticonvulsant, sedative, hypnotic and anaesthetic effects.
Such steroids are synthesized both in the periphery and in the CNS (neurosteroids), and, therefore, can act as both endocrine and paracrine messengers to facilitate inhibitory neurotransmission. The enzymes that synthesize and metabolize neurosteroids present new therapeutic targets.
Perturbations of neurosteroid levels are associated with various physiological (for example, stress, pregnancy and ageing), psychological (including depression, post-partum depression and premenstrual tension) and neurological (such as catamenial epilepsy) conditions.
Neurosteroid levels are altered by psychoactive drugs, such as ethanol, γ-hydroxybutyrate (GHB) and certain antidepressants, including fluoxetine; these effects might contribute to the behavioural actions of these drugs.
GABA is an inhibitory neurotransmitter, but it is also an important neurotrophic factor. Consequently, an unappreciated role for neurosteroids in brain development and plasticity is emerging. Furthermore, certain neurodegenerative diseases are associated with abnormal neurosteroid levels.
Given the ubiquitous expression of GABAA receptors throughout the CNS, physiological, pathophysiological or pharmacological changes in neurosteroid levels should nonselectively influence neuronal inhibition. However, the interactions between GABAA receptors and neurosteroids are highly selective, and discriminate not only between different neurons but also among different receptor pools in a neuron. This heterogeneity depends on receptor subunit composition, phosphorylation and local steroid metabolism.
GABAA (γ-aminobutyric acid type A) receptors mediate most of the 'fast' synaptic inhibition in the mammalian brain and are targeted by many clinically important drugs. Certain naturally occurring pregnane steroids can potently and specifically enhance GABAA receptor function in a nongenomic (direct) manner, and consequently have anxiolytic, analgesic, anticonvulsant, sedative, hypnotic and anaesthetic properties. These steroids not only act as remote endocrine messengers, but also can be synthesized in the brain, where they modify neuronal activity locally by modulating GABAA receptor function. Such 'neurosteroids' can influence mood and behaviour in various physiological and pathophysiological situations, and might contribute to the behavioural effects of psychoactive drugs.
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McEwen, B. S., Coirini, H. & Schumacher, M. Steroid effects on neuronal activity: when is the genome involved? Ciba Found. Symp. 153, 3–12 (1990).
McEwen, B. S. Non-genomic and genomic effects of steroids on neural activity. Trends Pharmacol. Sci. 12, 141–147 (1991).
Cashin, M. F. & Moravek, V. The physiological action of cholesterol. Am. J. Physiol. 82, 294–298 (1927).
Selye, H. Anesthetics of steroid hormones. Proc. Soc. Exp. Biol. Med. 46, 116–121 (1941).
Selye, H. The antagonism between anesthetic steroid hormones and pentamethylentetrazol (metrazol). J. Lab. Clin. Med. 27, 1051–1053 (1942).
Schofield, C. N. Potentiation of inhibition by general anesthetics in neurons of the olfactory cortex in vitro. Pflugers Arch. 38, 249–255 (1980).
Harrison, N. L. & Simmonds, M. A. Modulation of the GABA receptor complex by a steroid anaesthetic. Brain Res. 323, 287–292 (1984). This paper presents the first evidence that the synthetic anaesthetic steroid alphaxalone potently enhances GABA A receptor-mediated responses. The authors speculate that this property might be shared by endogenous pregnane steroids.
Belelli, D., Lan, N. C. & Gee, K. W. Anticonvulsant steroids and the GABA/benzodiazepine receptor–chloride ionophore complex. Neurosci. Biobehav. Rev. 14, 315–322 (1990).
Lambert, J. J., Belelli, D., Hill-Venning, C. & Peters, J. A. Neurosteroids and GABAA receptor function. Trends Pharmacol. Sci. 16, 295–303 (1995).
Callachan, H. et al. Modulation of the GABAA receptor by progesterone metabolites. Proc. R. Soc. Lond. B Biol. Sci. 231, 359–369 (1987). In this study, single-channel recordings show that low concentrations of certain progesterone metabolites prolong the open state of the GABA-gated ion channel and, at slightly greater concentrations, directly activate the receptor.
Lambert, J. J., Peters, J. A. & Cottrell, G. A. Actions of synthetic and endogenous steroids on the GABAA receptor. Trends Pharmacol. Sci. 8, 224–227 (1987).
Shu, H. -J. et al. Slow actions of neurosteroids at GABAA receptors. J. Neurosci. 24, 6667–6675 (2004).
Gasior, M., Carter, R. B. & Witkin, J. M. Neuroactive steroids: potential therapeutic use in neurological and psychiatric disorders. Trends Pharmacol. Sci. 20, 107–112 (1999).
Rupprecht, R. Neuroactive steroids: mechanisms of action and neuropsychopharmacological properties. Psychoneuroendocrinology 28, 139–168 (2003).
Goodchild, C. S., Robinson, A. & Nadeson, R. Antinociceptive properties of neurosteroids IV: pilot study demonstrating the analgesic effects of alphadolone administered orally to humans. Br. J. Anaesth. 86, 528–534 (2001).
Purdy, R. H., Morrow, A. L., Moore, P. H. Jr. & Paul, S. M. Stress-induced elevations of γ-aminobutyric acid type A receptor-active steroids in the rat brain. Proc. Natl Acad. Sci. USA 88, 4553–4557 (1991).
Paul, S. M. & Purdy, R. H. Neuroactive steroids. FASEB J. 6, 2311–2322 (1992).
Robel, P., Scumacher, M. & Baulieu, E. E. in Neurosteroids: a New Regulatory Function in the Nervous System (eds Baulieu, E. E., Robel, P. & Schumacher, M.) 1–26 (Humana, Totowa, 1999).
Melcangi, R. C., Magnaghi, V., Galbiati, M. & Martini, L. in Neurosteroid and Brain Function (eds Biggio, G. & Purdy, R. H.) 146–176 (Academic, San Diego, 2001).
Mellon, S. H., Griffin, L. D. & Compagnone, N. A. Biosynthesis and action of neurosteroids. Brain Res. Brain Res. Rev. 37, 3–12 (2001).
Mellon, S. H. & Griffin, L. D. Neurosteroids: biochemistry and clinical significance. Trends Endocrinol. Metab. 13, 35–43 (2002).
Schumacher, M. et al. Steroid hormones and neurosteroids in normal and pathological aging of the nervous system. Prog. Neurobiol. 71, 3–29 (2003).
Kumar, S., Fleming, R. L. & Morrow, A. L. Ethanol regulation of γ-aminobutyric acidA receptors: genomic and nongenomic mechanisms. Pharmacol. Ther. 101, 211–226 (2004).
Sanna, E. et al. Brain steroidogenesis mediates ethanol modulation of GABAA receptor activity in rat hippocampus. J. Neurosci. 24, 6521–6530 (2004). This paper presents electrophysiological evidence that the influence of ethanol and GHB on inhibitory transmission might be mediated, in part, by an ability of these agents to release neurosteroids locally.
Barbaccia, M. L. Neurosteroidogenesis: relevance to neurosteroid actions in brain and modulation by psychotropic drugs. Crit. Rev. Neurobiol. 16, 67–74 (2004).
Uzunova, V. et al. Increase in the cerebrospinal fluid content of neurosteroids in patients with unipolar major depression who are receiving fluoxetine or fluvoxamine. Proc. Natl Acad. Sci. USA 95, 3239–3244 (1998).
Smith, S. S. in Neurosteroid Effects in the Central Nervous System: the Role of the GABAA Receptor (ed. Smith, S. S.) 143–172 (CRC, New York, 2004).
Sundstrom-Poromaa, I. in Neurosteroid Effects in the Central Nervous System: the Role of the GABAA Receptor (ed. Smith, S. S.) 291–304 (CRC, New York, 2004).
Mtchedlishvili, Z. & Kapur, J. in Neurosteroid Effects in the Central Nervous System: the Role of the GABAA Receptor (ed. Smith, S. S.) 305–316 (CRC, New York, 2004).
Lambert, J. J. et al. Neurosteroid modulation of GABAA receptors. Prog. Neurobiol. 71, 67–80 (2003).
Harney, S. C., Frenguelli, B. G. & Lambert, J. J. Phosphorylation influences neurosteroid modulation of synaptic GABAA receptors in rat CA1 and dentate gyrus neurones. Neuropharmacology 45, 873–883 (2003).
Vicini, S., Losi, G. & Homanics, G. E. GABAA receptor δ subunit deletion prevents neurosteroid modulation of inhibitory synaptic currents in cerebellar neurons. Neuropharmacology 43, 646–650 (2002).
Cooper, E. J., Johnston, G. A. & Edwards, F. A. Effects of a naturally occurring neurosteroid on GABAA IPSCs during development in rat hippocampal or cerebellar slices. J. Physiol. (Lond.) 521, 437–449 (1999).
Brussaard, A. B. et al. Plasticity in fast synaptic inhibition of adult oxytocin neurons caused by switch in GABAA receptor subunit expression. Neuron 19, 1103–1114 (1997).
Koksma, J. J. et al. Oxytocin regulates neurosteroid modulation of GABAA receptors in supraoptic nucleus around parturition. J. Neurosci. 23, 788–797 (2003). This study provides clear evidence that neurosteroid modulation of synaptic GABA A receptors can be dynamically regulated by the activity of resident kinases and phosphatases. This mechanism is implicated in the control of the timed release of oxytocin during parturition.
Leroy, C., Poisbeau, P., Keller, A. F. & Nehlig, A. Pharmacological plasticity of GABAA receptors at dentate gyrus synapses in a rat model of temporal lobe epilepsy. J. Physiol. (Lond.) 557, 473–487 (2004).
Grosso, S. et al. Inter-ictal and post-ictal circulating levels of allopregnanolone, an anticonvulsant metabolite of progesterone, in epileptic children. Epilepsy Res. 54, 29–34 (2003).
Farrant, M. & Nusser, Z. Variations on an inhibitory theme: phasic and tonic activation of GABAA receptors. Nature Rev. Neurosci. 6, 215–229 (2005).
Stell, B. M. et al. Neuroactive steroids reduce neuronal excitability by selectively enhancing tonic inhibition mediated by δ subunit-containing GABAA receptors. Proc. Natl Acad. Sci. USA 100, 14439–14444 (2003). This study describes the selective neurosteroid enhancement in DGCs and CGCs of the 'tonic current' mediated by δ-subunit-containing extrasynaptic GABA A receptors. These extrasynaptic receptors can greatly influence neuronal excitability and might, therefore, be an important locus of neurosteroid action.
Mody, I. Aspects of the homeostatic plasticity of GABAA receptor-mediated inhibition. J. Physiol. (Lond.) 562, 37–46 (2005).
Fritschy, J. M. & Brunig, I. Formation and plasticity of GABAergic synapses: physiological mechanisms and pathophysiological implications. Pharmacol. Ther. 98, 299–323 (2003).
Mihalek, R. M. et al. Attenuated sensitivity to neuroactive steroids in γ-aminobutyrate type A receptor δ subunit knockout mice. Proc. Natl Acad. Sci. USA 96, 12905–12910 (1999).
Hamann, M., Rossi, D. J. & Attwell, D. Tonic and spillover inhibition of granule cells control information flow through cerebellar cortex. Neuron 33, 625–633 (2002).
Porcello, D. M. et al. Intact synaptic GABAergic inhibition and altered neurosteroid modulation of thalamic relay neurons in mice lacking δ subunit. J. Neurophysiol. 89, 1378–1386 (2003).
Caraiscos, V. B. et al. Tonic inhibition in mouse hippocampal CA1 pyramidal neurons is mediated by α5 subunit-containing γ-aminobutyric acid type A receptors. Proc. Natl Acad. Sci. USA 101, 3662–3667 (2004).
Belelli, D., Casula, A., Ling, A. & Lambert, J. J. The influence of subunit composition on the interaction of neurosteroids with GABAA receptors. Neuropharmacology 43, 651–661 (2002).
Davies, P. A., Hanna, M. C., Hales, T. G. & Kirkness, E. F. Insensitivity to anaesthetic agents conferred by a class of GABAA receptor subunit. Nature 385, 820–823 (1997).
Whiting, P. J. et al. Neuronally restricted RNA splicing regulates the expression of a novel GABAA receptor subunit conferring atypical functional properties. J. Neurosci. 17, 5027–5037 (1997).
Thompson, S. A. et al. Overexpression of the GABAA receptor δ subunit results in insensitivity to anaesthetics. Neuropharmacology 43, 662–668 (2002).
Brown, N. et al. Pharmacological characterization of a novel cell line expressing human α4β3δGABAA receptors. Br. J. Pharmacol. 136, 965–974 (2002).
Wohlfarth, K. M., Bianchi, M. T. & Macdonald, R. L. Enhanced neurosteroid potentiation of ternary GABAA receptors containing the δ subunit. J. Neurosci. 22, 1541–1549 (2002).
Bianchi, M. T. & Macdonald, R. L. Neurosteroids shift partial agonist activation of GABAA receptor channels from low- to high-efficacy gating patterns. J. Neurosci. 23, 10934–10943 (2003).
Smart, T. G., Thomas, P., Brandon, N. J. & Moss, S. J. in Pharmacology of GABA and Glycine Transmission Vol. 150 (ed. Mohler, H.) 195–226 (Springer, Berlin, 2001).
Moss, S. J. & Smart, T. G. Constructing inhibitory synapses. Nature Rev. Neurosci. 2, 240–250 (2001).
Song, M. & Messing, R. O. Protein kinase C regulation of GABAA receptors. Cell. Mol. Life Sci. 62, 119–127 (2005).
Luscher, B. & Keller, C. A. Regulation of GABAA receptor trafficking, channel activity, and functional plasticity of inhibitory synapses. Pharmacol. Ther. 102, 195–221 (2004).
Collingridge, G. L., Isaac, J. T. & Wang, Y. T. Receptor trafficking and synaptic plasticity. Nature Rev. Neurosci. 5, 952–962 (2004).
Hodge, C. W. et al. Supersensitivity to allosteric GABAA receptor modulators and alcohol in mice lacking PKCε. Nature Neurosci. 2, 997–1002 (1999).
Hodge, C. W. et al. Decreased anxiety-like behavior, reduced stress hormones, and neurosteroid supersensitivity in mice lacking protein kinase Cε. J. Clin. Invest. 110, 1003–1010 (2002).
Carter, R. B. et al. Characterization of the anticonvulsant properties of ganaxolone (CCD 1042; 3α-hydroxy-3β-methyl-5α-pregnan-20-one), a selective, high-affinity, steroid modulator of the γ-aminobutyric acidA receptor. J. Pharmacol. Exp. Ther. 280, 1284–1295 (1997).
Belelli, D. & Herd, M. B. The contraceptive agent Provera enhances GABAA receptor-mediated inhibitory neurotransmission in the rat hippocampus: evidence for endogenous neurosteroids? J. Neurosci. 23, 10013–10020 (2003). This paper reports that inhibitors of 3α-HSD, including the widely prescribed contraceptive methoxyprogesterone acetate (Provera), enhance synaptic and extrasynaptic GABA A -receptor-mediated responses, which indicate the presence of a background 'neurosteroid tone'.
Li, X., Bertics, P. J. & Karavolas, H. J. Regional distribution of cytosolic and particulate 5α-dihydroprogesterone 3α-hydroxysteroid oxidoreductases in female rat brain. J. Steroid Biochem. Mol. Biol. 60, 311–318 (1997).
Mensah-Nyagan, A. G. et al. Neurosteroids: expression of steroidogenic enzymes and regulation of steroid biosynthesis in the central nervous system. Pharmacol. Rev. 51, 63–81 (1999).
Normington, K. & Russell, D. W. Tissue distribution and kinetic characteristics of rat steroid 5α-reductase isozymes. Evidence for distinct physiological functions. J. Biol. Chem. 267, 19548–19554 (1992).
Pinna, G. et al. Brain allopregnanolone regulates the potency of the GABAA receptor agonist muscimol. Neuropharmacology 39, 440–448 (2000). In this study, the treatment of mice with a 5α-reductase inhibitor rapidly decreased the brain content of 3α,5α-THPROG, and both the behavioural and electrophysiological responses to the GABA A receptor agonist muscimol. These data support the concept of an endogenous neurosteroid tone.
Puia, G. et al. On the putative physiological role of allopregnanolone on GABAA receptor function. Neuropharmacology 44, 49–55 (2003).
Gibbs, T. T. & Farb, D. H. in Neurosteroid Effects in the Central Nervous System: the Role of the GABAA Receptor (ed. Smith S. S.) 339–358 (CRC, New York, 2004).
Keller, A. F., Breton, J. D., Schlichter, R. & Poisbeau, P. Production of 5α-reduced neurosteroids is developmentally regulated and shapes GABAA miniature IPSCs in lamina II of the spinal cord. J. Neurosci. 24, 907–915 (2004).
Schlichter, R. et al. Modulation of GABAergic synaptic transmission by the non-benzodiazepine anxiolytic etifoxine. Neuropharmacology 39, 1523–1535 (2000).
Mennerick, S. et al. Selective antagonism of 5α-reduced neurosteroid effects at GABAA receptors. Mol. Pharmacol. 65, 1191–1197 (2004). This study presents the first evidence of a neurosteroid 'antagonist', which antagonizes both the GABA-enhancing and anaesthetic actions of the 5α-pregnanes. This compound had no effect on GABA-evoked responses per se , or on the GABA-modulatory actions of barbiturates, benzodiazepines or 5β-pregnane steroids. These results further strengthen the concept of a neurosteroid binding site on the receptor protein.
Wittmer, L. L. et al. Enantioselectivity of steroid-induced γ-aminobutyric acidA receptor modulation and anesthesia. Mol. Pharmacol. 50, 1581–1586 (1996). In this report, both the GABA-modulatory and the anaesthetic effects of a neurosteroid are shown to be enantioselective, which indicates that the anaesthetic effects are mediated by the GABA A receptor. Furthermore, the enantioselectivity indicates a specific protein binding site for this neurosteroid.
Covey, D. F. et al. Enantioselectivity of pregnanolone-induced γ-aminobutyric acidA receptor modulation and anesthesia. J. Pharmacol. Exp. Ther. 293, 1009–1016 (2000).
Mohler, H., Battersby, M. K. & Richards, J. G. Benzodiazepine receptor protein identified and visualized in brain tissue by a photoaffinity label. Proc. Natl Acad. Sci. USA 77, 1666–1670 (1980).
Duncalfe, L. L. et al. The major site of photoaffinity labeling of the γ-aminobutyric acid type A receptor by [3H]flunitrazepam is histidine 102 of the δ subunit. J. Biol. Chem. 271, 9209–9214 (1996).
Smith, G. B. & Olsen, R. W. Identification of a [3H] muscimol photoaffinity substrate in the bovine γ-aminobutyric acidA receptor α subunit. J. Biol. Chem. 269, 20380–20387 (1994).
Darbandi-Tonkabon, R. et al. Photoaffinity labeling with a neuroactive steroid analogue. 6-azi-pregnanolone labels voltage-dependent anion channel-1 in rat brain. J. Biol. Chem. 278, 13196–13206 (2003).
Darbandi-Tonkabon, R. et al. Neuroactive steroid interactions with voltage-dependent anion channels: lack of relationship to GABAA receptor modulation and anesthesia. J. Pharmacol. Exp. Ther. 308, 502–511 (2004).
Rick, C. E., Ye, Q., Finn, S. E. & Harrison, N. L. Neurosteroids act on the GABAA receptor at sites on the N-terminal side of the middle of TM2. Neuroreport 9, 379–383 (1998).
Chang, C. S., Olcese, R. & Olsen, R. W. A single M1 residue in the β2 subunit alters channel gating of GABAA receptor in anesthetic modulation and direct activation. J. Biol. Chem. 278, 42821–42828 (2003).
Morris, K. D., Moorefield, C. N. & Amin, J. Differential modulation of the γ-aminobutyric acid type C receptor by neuroactive steroids. Mol. Pharmacol. 56, 752–759 (1999).
Morris, K. D. W. & Amin, J. Insight into the mechanism of action of neuroactive steroids. Mol. Pharmacol. 66, 56–69 (2004).
Belelli, D. et al. A single amino acid confers barbiturate sensitivity upon the GABA ρ1 receptor. Br. J. Pharmacol. 127, 601–604 (1999).
Walters, R. J., Hadley, S. H., Morris, K. D. & Amin, J. Benzodiazepines act on GABAA receptors via two distinct and separable mechanisms. Nature Neurosci. 3, 1274–1281 (2000).
Belelli, D., Pistis, I., Peters, J. A. & Lambert, J. J. General anaesthetic action at transmitter-gated inhibitory amino acid receptors. Trends Pharmacol. Sci. 20, 496–502 (1999).
Belelli, D. et al. The interaction of the general anesthetic etomidate with the γ-aminobutyric acid type A receptor is influenced by a single amino acid. Proc. Natl Acad. Sci. USA 94, 11031–11036 (1997).
Ueno, S. et al. Sites of positive allosteric modulation by neurosteroids on ionotropic γ-aminobutyric acid receptor subunits. FEBS Lett. 566, 213–217 (2004).
Akk, G. et al. Neuroactive steroids have multiple actions to potentiate GABAA receptors. J. Physiol. (Lond.) 558, 59–74 (2004).
Paradiso, K., Zhang, J. & Steinbach, J. H. The C terminus of the human nicotinic α4β2 receptor forms a binding site required for potentiation by an estrogenic steroid. J. Neurosci. 21, 6561–6568 (2001).
Wallner, M., Hanchar, H. J. & Olsen, R. W. Ethanol enhances α4β3δ and α6β3δγ-aminobutyric acid type A receptors at low concentrations known to affect humans. Proc. Natl Acad. Sci. USA 100, 15218–15223 (2003).
Wei, W., Faria, L. C. & Mody, I. Low ethanol concentrations selectively augment the tonic inhibition mediated by δ subunit-containing GABAA receptors in hippocampal neurons. J. Neurosci. 24, 8379–8382 (2004).
Tokunaga, S., McDaniel, J. R., Morrow, A. L. & Matthews, D. B. Effect of acute ethanol administration and acute allopregnanolone administration on spontaneous hippocampal pyramidal cell neural activity. Brain Res. 967, 273–280 (2003).
Perrais, D. & Ropert, N. Effect of zolpidem on miniature IPSCs and occupancy of postsynaptic GABAA receptors in central synapses. J. Neurosci. 19, 578–588 (1999).
Akk, G. & Steinbach, J. H. Low doses of ethanol and a neuroactive steroid positively interact to modulate rat GABAA receptor function. J. Physiol. (Lond.) 546, 641–646 (2003).
Colombo, G. et al. Characterization of the discriminative stimulus effects of γ-hydroxybutyric acid as a means for unraveling the neurochemical basis of γ-hydroxybutyric acid actions and its similarities to those of ethanol. Alcohol 20, 237–245 (2000).
Galloway, G. P. et al. γ-hydroxybutyrate: an emerging drug of abuse that causes physical dependence. Addiction 92, 89–96 (1997).
Sigel, E. & Buhr, A. The benzodiazepine binding site of GABAA receptors. Trends Pharmacol. Sci. 18, 425–429 (1997).
Dong, E. et al. Brain 5α-dihydroprogesterone and allopregnanolone synthesis in a mouse model of protracted social isolation. Proc. Natl Acad. Sci. USA 98, 2849–2854 (2001).
Guidotti, A. et al. The socially-isolated mouse: a model to study the putative role of allopregnanolone and 5α-dihydroprogesterone in psychiatric disorders. Brain Res. Brain Res. Rev. 37, 110–115 (2001).
Pinna, G., Costa, E. & Guidotti, A. Fluoxetine and norfluoxetine stereospecifically facilitate pentobarbital sedation by increasing neurosteroids. Proc. Natl Acad. Sci. USA 101, 6222–6225 (2004).
Peters, J. A. et al. Modulation of the GABAA receptor by depressant barbiturates and pregnane steroids. Br. J. Pharmacol. 94, 1257–1269 (1988).
Griffin, L. D. & Mellon, S. H. Selective serotonin reuptake inhibitors directly alter activity of neurosteroidogenic enzymes. Proc. Natl Acad. Sci. USA 96, 13512–13517 (1999).
Trauger, J. W., Jiang, A., Stearns, B. A. & LoGrasso, P. V. Kinetics of allopregnanolone formation catalyzed by human 3α-hydroxysteroid dehydrogenase type III (AKR1C2). Biochemistry 41, 13451–13459 (2002).
Rosciszevska, D., Buntner, B., Guz, I. & Zawisza, L. Ovarian hormones, anticonvulsant drugs, and seizures during the menstrual cycle in women with epilepsy. J. Neurol. Neurosurg. Psychiatry 49, 47–51 (1986).
Herzog, A. G. & Frye, C. A. Seizure exacerbation associated with inhibition of progesterone metabolism. Ann. Neurol. 53, 390–391 (2003).
Reddy, D. S. Role of neurosteroids in catamenial epilepsy. Epilepsy Res. 62, 99–118 (2004).
Newmark, M. E. & Penry, J. K. Catamenial epilepsy: a review. Epilepsia 21, 281–300 (1980).
Owens, D. F. & Kriegstein, A. R. Is there more to GABA than synaptic inhibition? Nature Rev. Neurosci. 3, 715–727 (2002).
Ben Ari, Y. Excitatory actions of GABA during development: the nature of the nurture. Nature Rev. Neurosci. 3, 728–739 (2002).
Brinton, R. D. The neurosteroid 3α-hydroxy-5α-pregnan-20-one induces cytoarchitectural regression in cultured fetal hippocampal neurons. J. Neurosci. 14, 2763–2774 (1994).
Grobin, A. C., Heenan, E. J., Lieberman, J. A. & Morrow, A. L. Perinatal neurosteroid levels influence GABAergic interneuron localization in adult rat prefrontal cortex. J. Neurosci. 23, 1832–1839 (2003).
Xu, W. et al. Slow death of postnatal hippocampal neurons by GABAA receptor overactivation. J. Neurosci. 20, 3147–3156 (2000).
Griffin, L. D., Gong, W., Verot, L. & Mellon, S. H. Niemann-Pick type C disease involves disrupted neurosteroidogenesis and responds to allopregnanolone. Nature Med. 10, 704–711 (2004). This report describes a mouse model of NP-C disease, in which the neurosteroid 3α,5α-THPROG is undetectable. Remarkably, neonatal administration of this steroid delayed the appearance of neuropathology in these mice and prolonged their lifespan, which points to a possible therapy.
Weill-Engerer, S. et al. Neurosteroid quantification in human brain regions: comparison between Alzheimer's and nondemented patients. J. Clin. Endocrinol. Metab. 87, 5138–5143 (2002).
di Michele, F. et al. Decreased plasma and cerebrospinal fluid content of neuroactive steroids in Parkinson's disease. Neurol. Sci. 24, 172–173 (2003).
Rudolph, U. & Mohler, H. Analysis of GABAA receptor function and dissection of the pharmacology of benzodiazepines and general anesthetics through mouse genetics. Annu. Rev. Pharmacol. Toxicol. 44, 475–498 (2004). A review of how transgenic 'knock-in' mice are being used to determine which GABA A receptor isoforms mediate the behavioural actions of benzodiazepines and certain general anaesthetics.
Rudolph, U. & Antkowiak, B. Molecular and neuronal substrates for general anaesthetics. Nature Rev. Neurosci. 5, 709–720 (2004).
Reynolds, D. S. et al. Sedation and anesthesia mediated by distinct GABAA receptor isoforms. J. Neurosci. 23, 8608–8617 (2003).
Barnard, E. A. et al. International Union of Pharmacology. XV. Subtypes of γ-aminobutyric acidA receptors: classification on the basis of subunit structure and receptor function. Pharmacol. Rev. 50, 291–313 (1998).
Sieghart, W. & Sperk, G. Subunit composition, distribution and function of GABAA receptor subtypes. Curr. Top. Med. Chem. 2, 795–816 (2002).
Simon, J. et al. Analysis of the set of GABAA receptor genes in the human genome. J. Biol. Chem. 279, 41422–41435 (2004).
Minier, F. & Sigel, E. Techniques: use of concatenated subunits for the study of ligand-gated ion channels. Trends Pharmacol. Sci. 25, 499–503 (2004).
Mohler, H. et al. Specific GABAA circuits in brain development and therapy. Biochem. Pharmacol. 68, 1685–1690 (2004).
Some of the work reported here was supported by the Medical Research Council (MRC) and by the Commission of the European Communities Research and Technical Development (RTD) programme entitled 'Quality of Life and Management of Living Resources'. The authors would like to thank J. Peters for helpful discussions.
The authors declare no competing financial interests.
- PREGNANE STEROID
A saturated steroid nucleus that contains methyl groups at C18 and C19, and an ethyl side chain at C17.
A naturally occurring metabolite of progesterone that is synthesized in both the periphery and the CNS. This steroid potently and selectively enhances the function of the GABAA receptor.
A term that is used to describe the actions of a drug that has little effect alone but, at relatively low concentrations, enhances the response that is mediated by GABA. Examples include diazepam, certain neuroactive steroids and many intravenous general anaesthetics, including etomidate, propofol and thiopental.
A term that is used to describe the direct activation of the GABAA receptor by a drug. Examples include certain neuroactive steroids, etomidate, propofol and thiopental. The GABA-mimetic effect of these agents usually occurs at concentrations that are greater than those required for their GABA-modulatory effects.
A steroid that is synthesized in the nervous system.
- CATAMENIAL EPILEPSY
In women with this type of epilepsy, seizures do not occur randomly but cluster in association with the menstrual cycle.
- WHOLE-CELL-CLAMP TECHNIQUE
A high-resolution electrophysiological recording method that allows the electrical currents that flow across the cell membrane to be recorded under voltage-clamp conditions.
- MINIATURE INHIBITORY POSTSYNAPTIC CURRENT
(mIPSC). The postsynaptic current that results from the activation of synaptic receptors by neurotransmitters (GABA or glycine) that are usually released from a single vesicle.
- PHASIC INHIBITORY RESPONSE
The transient inhibitory response that results from the activation of postsynaptic GABAA receptors by the relatively high concentration of GABA that occurs in the synapse subsequent to vesicular release.
- TONIC INHIBITION
An inhibitory response that is mediated by the activation of extra- or perisynaptic GABAA receptors through ambient concentrations of GABA. In some neurons, these receptors have a distinct subunit composition and, as a consequence, have a relatively high affinity for GABA and show little or no desensitization.
A chemical class of compounds that bind between the interfaces of the α- and γ-GABAA receptor subunits. Benzodiazepine 'agonists', such as diazepam, enhance GABA-evoked responses and, consequently, are sedative, anxiolytic and anticonvulsant. Benzodiazepine 'inverse agonists' decrease GABA-evoked responses, and are proconvulsant and anxiogenic. Benzodiazepine antagonists, such as flumazenil, prevent the actions of both benzodiazepine agonists and inverse agonists.
- CORTICAL MICROSACS
A preparation of synaptosomes ('pinched off' nerve terminals) from cortical neurons.
A pair of stereoisomers that are nonsuperimposable mirror images of one another.
- NEUROACTIVE STEROIDS
This term describes both synthetic and naturally occurring steroids that have an effect on neural function.
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Belelli, D., Lambert, J. Neurosteroids: endogenous regulators of the GABAA receptor. Nat Rev Neurosci 6, 565–575 (2005). https://doi.org/10.1038/nrn1703
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