title: Anxiety disorders and GABA neurotransmission: a disturbance of modulation.
abstract: Lines of evidence coming from many branches of neuroscience indicate that anxiety disorders arise from a dysfunction in the modulation of brain circuits which regulate emotional responses to potentially threatening stimuli. The concept of anxiety disorders as a disturbance of emotional response regulation is a useful one as it allows anxiety to be explained in terms of a more general model of aberrant salience and also because it identifies avenues for developing psychological, behavioral, and pharmacological strategies for the treatment of anxiety disorder. These circuits involve bottom-up activity from the amygdala, indicating the presence of potentially threatening stimuli, and top-down control mechanisms originating in the prefrontal cortex, signaling the emotional salience of stimuli. Understanding the factors that control cortical mechanisms may open the way to identification of more effective cognitive behavioral strategies for managing anxiety disorders. The brain circuits in the amygdala are thought to comprise inhibitory networks of γ-aminobutyric acid-ergic (GABAergic) interneurons and this neurotransmitter thus plays a key role in the modulation of anxiety responses both in the normal and pathological state. The presence of allosteric sites on the GABAA receptor allows the level of inhibition of neurons in the amygdala to be regulated with exquisite precision, and these sites are the molecular targets of the principal classes of anxiolytic drugs. Changes in the levels of endogenous modulators of these allosteric sites as well as changes in the subunit composition of the GABAA receptor may represent mechanisms whereby the level of neuronal inhibition is downregulated in pathological anxiety states. Neurosteroids are synthesized in the brain and act as allosteric modulators of the GABAA receptor. Since their synthesis is itself regulated by stress and by anxiogenic stimuli, targeting the neurosteroid-GABAA receptor axis represents an attractive target for the modulation of anxiety.
authors: Department of Psychiatry, Hôpital St Antoine, AP-HP, Paris, France ; UMR 7203, INSERM ERL 1057 - Bioactive Molecules Laboratory, Pierre and Marie Curie University, Paris, France.
authors: Philippe
authors: P
authors: Nuss
keywords: allosteric modulation; amygdala; neurosteroids; salience; γ-aminobutyric acid
references: Neuroimage. 2006 Jan 1;29(1):125-35
references: 16087353
references: J Neurosci. 2000 Dec 15;20(24):9034-9
references: 11124979
references: Curr Pharm Des. 2008;14(33):3525-33
references: 19075729
references: Psychopharmacology (Berl). 1999 Jul;145(2):205-12
references: 10463322
references: Expert Opin Ther Targets. 2011 Nov;15(11):1317-31
references: 21995655
references: Neurosci Res. 2002 Oct;44(2):167-72
references: 12354631
references: J Neurosci. 1999 Dec 1;19(23):10575-83
references: 10575053
references: Neuropharmacology. 2000 Jul 10;39(9):1523-35
references: 10854897
references: Pharmacol Biochem Behav. 2005 Dec;82(4):712-20
references: 16388839
references: Nat Rev Drug Discov. 2010 Dec;9(12):971-88
references: 21119734
references: Psychoneuroendocrinology. 2004 May;29(4):486-500
references: 14749094
references: J Affect Disord. 2002 Aug;70(3):241-9
references: 12128236
references: J Psychopharmacol. 2012 Apr;26(4):443-51
references: 21106607
references: Trends Neurosci. 2012 Nov;35(11):649-59
references: 22974560
references: Curr Top Behav Neurosci. 2010;2:303-30
references: 21309115
references: Prog Neurobiol. 2003 Sep;71(1):67-80
references: 14611869
references: J Neurochem. 1994 Feb;62(2):815-8
references: 7507518
references: CNS Neurol Disord Drug Targets. 2009 Dec;8(6):451-8
references: 19839936
references: J Neurosci. 2004 Nov 10;24(45):10280-7
references: 15537900
references: Cereb Cortex. 2007 Jun;17(6):1307-13
references: 16880223
references: Brain Res Brain Res Rev. 2001 Nov;37(1-3):98-109
references: 11744078
references: Dialogues Clin Neurosci. 2002 Sep;4(3):261-9
references: 22034214
references: Neuromolecular Med. 2004;5(1):27-40
references: 15001810
references: Psychoneuroendocrinology. 2004 Apr;29(3):339-54
references: 14644065
references: Trends Endocrinol Metab. 2002 Jan-Feb;13(1):35-43
references: 11750861
references: J Psychopharmacol. 2014 May;28(5):403-39
references: 24713617
references: J Psychopharmacol. 2012 Jan;26(1):23-39
references: 21768162
references: Trends Cogn Sci. 2005 May;9(5):242-9
references: 15866151
references: Eur J Neurosci. 1998 Sep;10(9):2924-33
references: 9758162
references: J Neuropsychiatry Clin Neurosci. 2001 Summer;13(3):396-8
references: 11514647
references: Proc Natl Acad Sci U S A. 1991 May 15;88(10):4553-7
references: 1852011
references: Subst Abus. 2012;33(4):336-49
references: 22989277
references: Trends Neurosci. 1997 Nov;20(11):517-23
references: 9364666
references: Curr Top Med Chem. 2002 Aug;2(8):795-816
references: 12171572
references: Neuroscience. 1996 Mar;71(1):55-75
references: 8834392
references: Neuroscience. 2011 Sep 15;191:55-77
references: 21439354
references: Neuroimage. 2008 Aug 15;42(2):998-1031
references: 18579414
references: Science. 2000 Oct 6;290(5489):131-4
references: 11021797
references: Mol Psychiatry. 2008 Mar;13(3):325-33
references: 17579609
references: Psychopharmacology (Berl). 2013 Oct;229(3):435-52
references: 23836029
references: Adv Pharmacol. 2010;58:1-18
references: 20655476
references: Biol Psychiatry. 2006 Aug 15;60(4):376-82
references: 16919525
references: Psychoneuroendocrinology. 2003 Feb;28(2):139-68
references: 12510009
references: Hum Psychopharmacol. 2006 Apr;21(3):139-49
references: 16625522
references: Pharmacol Biochem Behav. 1995 Dec;52(4):701-6
references: 8587908
references: J Cogn Neurosci. 2005 Jun;17(6):874-83
references: 15969906
references: Behav Res Ther. 1993 Jan;31(1):57-62
references: 8417729
references: Curr Top Behav Neurosci. 2010;2:251-77
references: 21309113
references: Int J Psychiatry Clin Pract. 2012 Jun;16(2):77-84
references: 22540422
references: Brain Res. 2012 Oct 2;1476:211-34
references: 22516107
references: Brain Res. 1997 Aug 22;766(1-2):276-80
references: 9359616
references: Psychiatry Res. 2005 Jun 30;135(3):185-90
references: 15996752
references: Exp Biol Med (Maywood). 2010 Oct;235(10):1163-7
references: 20881320
references: Curr Opin Pharmacol. 2009 Feb;9(1):24-30
references: 19157982
references: Neuropsychopharmacology. 2009 Feb;34(3):539-47
references: 18235425
references: Nature. 1971 Feb 26;229(5287):628-30
references: 4925465
references: Compr Psychiatry. 2012 Jul;53(5):427-33
references: 21917245
references: Psychoneuroendocrinology. 2000 May;25(4):407-20
references: 10725616
references: Int Rev Neurobiol. 2001;46:243-72
references: 11599302
references: Prog Brain Res. 2010;186:113-37
references: 21094889
references: FASEB J. 1992 Mar;6(6):2311-22
references: 1347506
references: Psychol Med. 2002 Jul;32(5):929-33
references: 12171387
references: Neuron. 1994 Apr;12(4):775-82
references: 8161449
references: Eur Neuropsychopharmacol. 2006 Jul;16(5):329-39
references: 16309898
references: Nat Neurosci. 2001 May;4(5):477-85
references: 11319555
references: Science. 2008 Jul 4;321(5885):53-7
references: 18599766
references: Curr Top Med Chem. 2011;11(2):241-6
references: 21189125
references: Arch Gen Psychiatry. 2005 Mar;62(3):282-8
references: 15753241
references: Encephale. 1998 Nov-Dec;24(6):569-74
references: 9949940
references: Can J Psychiatry. 2006 Jul;51(8 Suppl 2):9S-91S
references: 16933543
references: Trends Neurosci. 2004 Sep;27(9):569-75
references: 15331240
references: Pain. 2005 Oct;117(3):326-339
references: 16150542
references: Dialogues Clin Neurosci. 2002 Sep;4(3):305-19
references: 22034140
references: Neuron. 2005 Jun 16;46(6):957-69
references: 15953423
references: J Physiol. 2011 Apr 15;589(Pt 8):1911-25
references: 21224220
references: Nature. 2006 Nov 23;444(7118):486-9
references: 17108970
references: Pain. 2009 Dec 15;147(1-3):54-9
references: 19786322
references: Neuroimage. 2011 Jan 1;54(1):689-96
references: 20673804
references: Neuropharmacology. 2004 Mar;46(4):570-9
references: 14975681
references: Neuropsychologia. 1999 Sep;37(10):1111-7
references: 10509833
references: Mol Med Rep. 2013 Jul;8(1):75-80
references: 23670018
references: Transl Psychiatry. 2012 Nov 13;2:e181
references: 23149445
references: Fundam Clin Pharmacol. 2001 Jun;15(3):209-16
references: 11468032
references: Psychol Sci. 2009 Nov;20(11):1322-31
references: 19883494
references: Am J Psychiatry. 2007 Oct;164(10):1476-88
references: 17898336
references: J Neuroendocrinol. 2012 Jan;24(1):82-92
references: 21609361
references: Neuropharmacology. 2003 Sep;45(3):293-303
references: 12871647
references: Behav Brain Res. 2011 Oct 1;223(2):403-10
references: 21536077
references: Brain Res. 2007 Dec 12;1184:193-201
references: 17950705
references: J Clin Psychiatry. 2003;64 Suppl 3:21-7
references: 12662130
references: J Neurosci. 2011 Mar 30;31(13):5131-44
references: 21451049
references: Brain Res. 2009 Apr 24;1267:65-76
references: 19268657
references: Adv Pharmacol. 2006;54:231-63
references: 17175817
references: J Affect Disord. 1986 Nov-Dec;11(3):219-25
references: 2951409
references: Neuroimage. 2003 Jul;19(3):513-31
references: 12880784
references: Brain Struct Funct. 2008 Sep;213(1-2):159-75
references: 18340460
references: Eur J Pharmacol. 1997 Apr 23;325(1):1-7
references: 9151931
references: Addiction. 2011 Dec;106(12):2086-109
references: 21714826
references: Neuroimage. 2002 Jun;16(2):331-48
references: 12030820
references: Eur Arch Psychiatry Clin Neurosci. 2012 Nov;262 Suppl 2:S107-12
references: 22923187
references: Psychopharmacology (Berl). 2008 May;197(4):523-34
references: 18236028
references: J Clin Invest. 1997 Mar 1;99(5):962-6
references: 9062354
references: Clin Psychol Rev. 2006 Jan;26(1):17-31
references: 16199119
references: J Neurosci. 2003 Dec 3;23(35):11158-66
references: 14657175
references: Biol Psychol. 2006 Jan;71(1):2-11
references: 15951099
references: Ann Med. 1997 Aug;29(4):275-82
references: 9375983
references: Neuroscience. 1994 Sep;62(1):265-71
references: 7816204
references: Nat Rev Neurosci. 2005 Mar;6(3):215-29
references: 15738957
references: Gynecol Endocrinol. 2005 Nov;21(5):268-79
references: 16373246
references: Biol Psychiatry. 1998 Nov 15;44(10):1027-36
references: 9821567
references: Neuropsychopharmacology. 2005 Jan;30(1):192-5
references: 15467707
references: Soc Cogn Affect Neurosci. 2011 Jan;6(1):74-81
references: 20207692
references: Front Endocrinol (Lausanne). 2011 Oct 04;2:44
references: 22654809
references: Int Rev Neurobiol. 2001;46:33-78
references: 11599305
references: Neuron. 2005 Dec 22;48(6):1025-37
references: 16364905