GABA-based therapeutic approaches: GABAA receptor subtype functions.

It is increasingly being appreciated that GABAA receptor subtypes, through their specific regional, cellular and subcellular localization, are linked to distinct neuronal circuits and consequently serve distinct functions. GABAA receptor subtype-selective drugs are therefore expected to provide novel pharmacological profiles. Receptors containing the alpha1 subunit mediate sedation and serve as targets for sedative hypnotics. Agonists selective for alpha2- and/or alpha3-containing GABAA receptors have been shown to provide anxiolysis without sedation in preclinical models, whereas inverse agonists selective for alpha5-containing GABAA receptors provide memory enhancement. Agonists selective for alpha3-containing GABAA receptors might be suitable for the treatment of deficits in sensorimotor processing in psychiatric disorders. Thus, a new pharmacology based on GABAA receptor subtype-specific actions is emerging.

[1]  M. Wilson,et al.  Formation of Temporal Memory Requires NMDA Receptors within CA1 Pyramidal Neurons , 2000, Neuron.

[2]  E. Burón,et al.  Anxiogenic-like activity of L-655,708, a selective ligand for the benzodiazepine site of GABAA receptors which contain the alpha-5 subunit, in the elevated plus-maze test , 2002, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[3]  G. Dawson,et al.  Evidence for a Significant Role of α3-Containing GABAA Receptors in Mediating the Anxiolytic Effects of Benzodiazepines , 2005, The Journal of Neuroscience.

[4]  P. Whiting,et al.  The GABAA receptor gene family: new opportunities for drug development. , 2003, Current opinion in drug discovery & development.

[5]  G. Perrault,et al.  SL651498, a GABAA receptor agonist with subtype-selective efficacy, as a potential treatment for generalized anxiety disorder and muscle spasms. , 2003, CNS drug reviews.

[6]  P. Somogyi,et al.  Input‐dependent synaptic targeting of α2‐subunit‐containing GABAA receptors in synapses of hippocampal pyramidal cells of the rat , 2001, The European journal of neuroscience.

[7]  Dabney K. Johnson,et al.  Independent assembly and subcellular targeting of GABAA-receptor subtypes demonstrated in mouse hippocampal and olfactory neurons in vivo , 1998, Neuroscience Letters.

[8]  J. Benson,et al.  Benzodiazepine actions mediated by specific γ-aminobutyric acidA receptor subtypes , 1999, Nature.

[9]  R. Harris,et al.  Sites of alcohol and volatile anaesthetic action on GABAA and glycine receptors , 1997, Nature.

[10]  Irene Tobler,et al.  Diazepam-induced changes in sleep: Role of the α1 GABAA receptor subtype , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[11]  P. Whiting,et al.  Overexpression of the GABAA receptor ε subunit results in insensitivity to anaesthetics , 2002, Neuropharmacology.

[12]  F. Kuenzi,et al.  Enhanced Learning and Memory and Altered GABAergic Synaptic Transmission in Mice Lacking the α5 Subunit of the GABAAReceptor , 2002, The Journal of Neuroscience.

[13]  G. Dawson,et al.  TPA023 [7-(1,1-Dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine], an Agonist Selective for α2- and α3-Containing GABAA Receptors, Is a Nonsedating Anxiolytic in Rodents and Primates , 2006, Journal of Pharmacology and Experimental Therapeutics.

[14]  J. Fritschy,et al.  Intact sorting, targeting, and clustering of γ‐aminobutyric acid A receptor subtypes in hippocampal neurons in vitro , 2002, The Journal of comparative neurology.

[15]  G. Dawson,et al.  3-Heteroaryl-2-pyridones: Benzodiazepine Site Ligands with Functional Selectivity for α2/α3-Subtypes of Human GABAA Receptor-Ion Channels , 2002 .

[16]  G. Dawson,et al.  An orally bioavailable, functionally selective inverse agonist at the benzodiazepine site of GABAA alpha5 receptors with cognition enhancing properties. , 2004, Journal of medicinal chemistry.

[17]  N L Harrison,et al.  Propofol and other intravenous anesthetics have sites of action on the gamma-aminobutyric acid type A receptor distinct from that for isoflurane. , 1998, Molecular pharmacology.

[18]  J. Fritschy,et al.  GABAA‐receptor heterogeneity in the adult rat brain: Differential regional and cellular distribution of seven major subunits , 1995, The Journal of comparative neurology.

[19]  U. Egerland,et al.  Characterization in Rats of the Anxiolytic Potential of ELB139 [1-(4-Chlorophenyl)-4-piperidin-1-yl-1,5-dihydro-imidazol-2-on], a New Agonist at the Benzodiazepine Binding Site of the GABAA Receptor , 2005, Journal of Pharmacology and Experimental Therapeutics.

[20]  T. Rülicke,et al.  Molecular and neuronal substrate for the selective attenuation of anxiety. , 2000, Science.

[21]  A. Delini-Stula,et al.  Antipsychotic effects of bretazenil, a partial benzodiazepine agonist in acute schizophrenia--a study group report. , 1996, Journal of psychiatric research.

[22]  K. Miller,et al.  Mechanisms of actions of inhaled anesthetics. , 2003, The New England journal of medicine.

[23]  I. Tobler,et al.  Sleep EEG changes after zolpidem in mice , 2004, Neuroreport.

[24]  Kerstin Dmgen,et al.  Zaleplon displays a selectivity to recombinant GABAA receptors different from zolipdem, zopiclone and benzodiazepines , 1999 .

[25]  R. Olsen,et al.  Ethanol enhances α4β3δ and α6β3δ γ-aminobutyric acid type A receptors at low concentrations known to affect humans , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[26]  I. Tobler,et al.  Modulation of rhythmic brain activity by diazepam: GABA(A) receptor subtype and state specificity. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[27]  K. Vogt,et al.  Trace fear conditioning involves hippocampal α5 GABAA receptors , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[28]  R. Malenka,et al.  A schizophrenia-related sensorimotor deficit links alpha 3-containing GABAA receptors to a dopamine hyperfunction. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[29]  S. Tonegawa,et al.  The Essential Role of Hippocampal CA1 NMDA Receptor–Dependent Synaptic Plasticity in Spatial Memory , 1996, Cell.

[30]  E. Eger,et al.  &bgr;3-Containing Gamma-Aminobutyric AcidA Receptors Are Not Major Targets for the Amnesic and Immobilizing Actions of Isoflurane , 2005, Anesthesia and analgesia.

[31]  R. Mckernan,et al.  Which GABAA-receptor subtypes really occur in the brain? , 1996, Trends in Neurosciences.

[32]  Desmond O'Connor,et al.  Selective, Orally Active γ-Aminobutyric AcidA α5 Receptor Inverse Agonists as Cognition Enhancers , 2004 .

[33]  B. Antkowiak,et al.  General anesthetic actions in vivo strongly attenuated by a point mutation in the GABAA receptor β3 subunit , 2003, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[34]  U. Rudolph,et al.  Analysis of GABAA receptor function and dissection of the pharmacology of benzodiazepines and general anesthetics through mouse genetics. , 2004, Annual review of pharmacology and toxicology.

[35]  Signe í Stórustovu,et al.  Gaboxadol: in vitro interaction studies with benzodiazepines and ethanol suggest functional selectivity. , 2003, European journal of pharmacology.

[36]  R. Mckernan,et al.  Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABAA receptor α1 subtype , 2000, Nature Neuroscience.

[37]  K. Gee,et al.  Modifying quinolone antibiotics yields new anxiolytics , 2004, Nature Medicine.

[38]  T. Rosahl,et al.  γ-Aminobutyric Acid Type A Receptor β2 Subunit Mediates the Hypothermic Effect of Etomidate in Mice , 2004 .

[39]  G. Sperk,et al.  GABAA receptors: immunocytochemical distribution of 13 subunits in the adult rat brain , 2000, Neuroscience.

[40]  M. Lancel,et al.  gamma-aminobutyric Acid(A) (GABA(A)) agonist 4,5,6, 7-tetrahydroisoxazolo[4,5-c]pyridin-3-ol persistently increases sleep maintenance and intensity during chronic administration to rats. , 2000, The Journal of pharmacology and experimental therapeutics.

[41]  G. Dawson,et al.  Anxiogenic properties of an inverse agonist selective for α3 subunit‐containing GABAA receptors , 2005 .

[42]  B. Antkowiak,et al.  Molecular and neuronal substrates for general anaesthetics , 2004, Nature Reviews Neuroscience.

[43]  V. V. Dolgov,et al.  GABAA receptors containing the α5 subunit mediate the trace effect in aversive and appetitive conditioning and extinction of conditioned fear , 2004, The European journal of neuroscience.

[44]  G. Dawson,et al.  Sedation and Anesthesia Mediated by Distinct GABAA Receptor Isoforms , 2003, The Journal of Neuroscience.

[45]  B. Orser,et al.  Tonic inhibition in mouse hippocampal CA1 pyramidal neurons is mediated by α5 subunit-containing γ-aminobutyric acid type A receptors , 2004 .

[46]  I. Tobler,et al.  Diazepam‐induced changes on sleep and the EEG spectrum in mice: role of the α3‐GABAA receptor subtype , 2003, The European journal of neuroscience.

[47]  E. Burón,et al.  Behavioral profile of L-655,708, a selective ligand for the benzodiazepine site of GABA-A receptors which contain the α5 subunit, in social encounters between male mice , 2004 .

[48]  M. Bianchi,et al.  Neurosteroids Shift Partial Agonist Activation of GABAA Receptor Channels from Low- to High-Efficacy Gating Patterns , 2003, The Journal of Neuroscience.

[49]  M. Arras,et al.  Distinct molecular targets for the central respiratory and cardiac actions of the general anesthetics etomidate and propofol , 2005, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[50]  M. Joppa,et al.  In Vivo Pharmacological Characterization of Indiplon, a Novel Pyrazolopyrimidine Sedative-Hypnotic , 2004, Journal of Pharmacology and Experimental Therapeutics.

[51]  U. Rudolph,et al.  Mechanism of action of the hypnotic zolpidem in vivo , 2000, British journal of pharmacology.

[52]  J. Feldon,et al.  Hippocampal α5 subunit-containing GABAA receptors modulate the expression of prepulse inhibition , 2005, Molecular Psychiatry.

[53]  P. Czobor,et al.  Selective anxiolysis produced by ocinaplon, a GABA(A) receptor modulator. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[54]  E. Kirkness,et al.  Insensitivity to anaesthetic agents conferred by a class of GABAA receptor subunit , 1997, Nature.

[55]  J. Lambert,et al.  Neurosteroids: endogenous regulators of the GABAA receptor , 2005, Nature Reviews Neuroscience.