title: Behavioral effects of the benzodiazepine-positive allosteric modulator SH-053-2'F-S-CH₃ in an immune-mediated neurodevelopmental disruption model.
abstract: BACKGROUND
  Impaired γ-aminobutyric acid (GABA) signaling may contribute to the emergence of cognitive deficits and subcortical dopaminergic hyperactivity in patients with schizophrenia and related psychotic disorders. Against this background, it has been proposed that pharmacological interventions targeting GABAergic dysfunctions may prove useful in correcting such cognitive impairments and dopaminergic imbalances.
  
  
  METHODS
  Here, we explored possible beneficial effects of the benzodiazepine-positive allosteric modulator SH-053-2'F-S-CH₃, with partial selectivity at the α2, α3, and α5 subunits of the GABAA receptor in an immune-mediated neurodevelopmental disruption model. The model is based on prenatal administration of the viral mimetic polyriboinosinic-polyribocytidilic acid [poly(I:C)] in mice, which is known to capture various GABAergic, dopamine-related, and cognitive abnormalities implicated in schizophrenia and related disorders.
  
  
  RESULTS
  Real-time polymerase chain reaction analyses confirmed the expected alterations in GABAA receptor α subunit gene expression in the medial prefrontal cortices and ventral hippocampi of adult poly(I:C) offspring relative to control offspring. Systemic administration of SH-053-2'F-S-CH₃ failed to normalize the poly(I:C)-induced deficits in working memory and social interaction, but instead impaired performance in these cognitive and behavioral domains both in control and poly(I:C) offspring. In contrast, SH-053-2'F-S-CH₃ was highly effective in mitigating the poly(I:C)-induced amphetamine hypersensitivity phenotype without causing side effects in control offspring.
  
  
  CONCLUSIONS
  Our preclinical data suggest that benzodiazepine-like positive allosteric modulators with activity at the α2, α3, and α5 subunits of the GABAA receptor may be particularly useful in correcting pathological overactivity of the dopaminergic system, but they may be ineffective in targeting multiple pathological domains that involve the co-existence of psychotic, social, and cognitive dysfunctions.
authors: Center of Neuropharmacology, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy (Drs Richetto and Riva); Physiology and Behavior Laboratory, ETH Zurich, Schorenstrasse 16, 8603 Schwerzenbach, Switzerland (Drs Labouesse and Meyer); Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI (Drs Poe and Cook); Departments of Neuroscience, Psychiatry and Psychology, University of Pittsburgh, Pittsburgh, PA (Dr Grace); Center of Excellence on Neurodegenerative Diseases, Università degli Studi di Milano, Milan, Italy (Dr Riva).
authors: Juliet
authors: J
authors: Richetto
authors: Center of Neuropharmacology, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy (Drs Richetto and Riva); Physiology and Behavior Laboratory, ETH Zurich, Schorenstrasse 16, 8603 Schwerzenbach, Switzerland (Drs Labouesse and Meyer); Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI (Drs Poe and Cook); Departments of Neuroscience, Psychiatry and Psychology, University of Pittsburgh, Pittsburgh, PA (Dr Grace); Center of Excellence on Neurodegenerative Diseases, Università degli Studi di Milano, Milan, Italy (Dr Riva).
authors: Marie A
authors: MA
authors: Labouesse
authors: Center of Neuropharmacology, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy (Drs Richetto and Riva); Physiology and Behavior Laboratory, ETH Zurich, Schorenstrasse 16, 8603 Schwerzenbach, Switzerland (Drs Labouesse and Meyer); Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI (Drs Poe and Cook); Departments of Neuroscience, Psychiatry and Psychology, University of Pittsburgh, Pittsburgh, PA (Dr Grace); Center of Excellence on Neurodegenerative Diseases, Università degli Studi di Milano, Milan, Italy (Dr Riva).
authors: Michael M
authors: MM
authors: Poe
authors: Center of Neuropharmacology, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy (Drs Richetto and Riva); Physiology and Behavior Laboratory, ETH Zurich, Schorenstrasse 16, 8603 Schwerzenbach, Switzerland (Drs Labouesse and Meyer); Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI (Drs Poe and Cook); Departments of Neuroscience, Psychiatry and Psychology, University of Pittsburgh, Pittsburgh, PA (Dr Grace); Center of Excellence on Neurodegenerative Diseases, Università degli Studi di Milano, Milan, Italy (Dr Riva).
authors: James M
authors: JM
authors: Cook
authors: Center of Neuropharmacology, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy (Drs Richetto and Riva); Physiology and Behavior Laboratory, ETH Zurich, Schorenstrasse 16, 8603 Schwerzenbach, Switzerland (Drs Labouesse and Meyer); Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI (Drs Poe and Cook); Departments of Neuroscience, Psychiatry and Psychology, University of Pittsburgh, Pittsburgh, PA (Dr Grace); Center of Excellence on Neurodegenerative Diseases, Università degli Studi di Milano, Milan, Italy (Dr Riva).
authors: Anthony A
authors: AA
authors: Grace
authors: Center of Neuropharmacology, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy (Drs Richetto and Riva); Physiology and Behavior Laboratory, ETH Zurich, Schorenstrasse 16, 8603 Schwerzenbach, Switzerland (Drs Labouesse and Meyer); Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI (Drs Poe and Cook); Departments of Neuroscience, Psychiatry and Psychology, University of Pittsburgh, Pittsburgh, PA (Dr Grace); Center of Excellence on Neurodegenerative Diseases, Università degli Studi di Milano, Milan, Italy (Dr Riva).
authors: Marco A
authors: MA
authors: Riva
authors: Center of Neuropharmacology, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy (Drs Richetto and Riva); Physiology and Behavior Laboratory, ETH Zurich, Schorenstrasse 16, 8603 Schwerzenbach, Switzerland (Drs Labouesse and Meyer); Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI (Drs Poe and Cook); Departments of Neuroscience, Psychiatry and Psychology, University of Pittsburgh, Pittsburgh, PA (Dr Grace); Center of Excellence on Neurodegenerative Diseases, Università degli Studi di Milano, Milan, Italy (Dr Riva). urmeyer@ethz.ch.
authors: Urs
authors: U
authors: Meyer
mesh_terms: D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology*; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D003072:Cognition Disorders / Q000188:drug therapy* / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D018682:GABA Agents / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects / Q000502:physiology; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D011119:Polynucleotides; D017397:Prefrontal Cortex / Q000187:drug effects / Q000503:physiopathology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011619:Psychotropic Drugs / Q000494:pharmacology*; D011963:Receptors, GABA-A / Q000378:metabolism; D012919:Social Behavior
chemical_list: D000697:Central Nervous System Stimulants; D018682:GABA Agents; D011119:Polynucleotides; D011619:Psychotropic Drugs; D011963:Receptors, GABA-A; D001569:Benzodiazepines; C049667:poly(rI).poly(dC); D000661:Amphetamine
keywords: GABA; autism; infection; poly(I:C); schizophrenia
references: J Neurosci. 2002 Jul 1;22(13):5572-80
references: 12097508
references: Methods. 2001 Dec;25(4):402-8
references: 11846609
references: Neuropsychopharmacology. 2003 Oct;28(10):1778-89
references: 12865897
references: Brain Res. 1992 Aug 14;588(1):132-9
references: 1393562
references: Dev Psychobiol. 1997 Mar;30(2):141-50
references: 9068968
references: Mol Psychiatry. 2005 Feb;10(2):201-7
references: 15263904
references: Psychopharmacology (Berl). 2005 Jul;180(2):191-205
references: 15864560
references: Neurosci Biobehav Rev. 2005;29(6):913-47
references: 15964075
references: J Pharmacol Exp Ther. 2006 Mar;316(3):1335-45
references: 16326923
references: Biol Psychiatry. 2006 Mar 15;59(6):546-54
references: 16256957
references: Arch Neurol. 2006 Oct;63(10):1372-6
references: 17030651
references: Neuroscience. 2006 Nov 17;143(1):51-62
references: 17045750
references: Neurobiol Learn Mem. 2008 Feb;89(2):87-94
references: 17638582
references: Mol Psychiatry. 2008 Feb;13(2):147-61
references: 17471287
references: Neuropsychopharmacology. 2001 Jul;25(1):1-27
references: 11377916
references: Brain Res Brain Res Rev. 2000 Mar;31(2-3):371-84
references: 10719165
references: Proc Natl Acad Sci U S A. 2002 Jun 25;99(13):8980-5
references: 12084936
references: Am J Psychiatry. 2008 Apr;165(4):479-89
references: 18281411
references: Brain Behav Immun. 2008 May;22(4):469-86
references: 18023140
references: Cereb Cortex. 2008 Jul;18(7):1575-87
references: 18203698
references: Am J Psychiatry. 2008 Dec;165(12):1585-93
references: 18923067
references: Biol Psychiatry. 2009 Dec 1;66(11):1038-46
references: 19726031
references: Psychopharmacology (Berl). 2010 Mar;208(4):531-43
references: 20041229
references: Neural Plast. 2011;2011:723184
references: 21904685
references: J Neurosci. 2010 Feb 17;30(7):2547-58
references: 20164340
references: Prog Neuropsychopharmacol Biol Psychiatry. 2010 Mar 17;34(2):376-86
references: 20074611
references: Am J Psychiatry. 2010 Mar;167(3):261-80
references: 20123911
references: Schizophr Bull. 2010 Mar;36(2):359-69
references: 18644851
references: Prog Neurobiol. 2010 Mar;90(3):285-326
references: 19857543
references: Biol Psychiatry. 2010 May 15;67(10):998-1001
references: 20189164
references: J Psychiatr Res. 2010 Jul;44(10):673-81
references: 20100621
references: Int J Neuropsychopharmacol. 2010 Sep;13(8):981-96
references: 20219156
references: Psychiatry Res. 2010 Sep 30;183(3):187-94
references: 20702070
references: Neurotox Res. 2010 Nov;18(3-4):367-76
references: 20143199
references: Neuropsychopharmacology. 2010 Nov;35(12):2462-78
references: 20736993
references: Neuropharmacology. 2010 Dec;59(7-8):612-8
references: 20727364
references: Am J Psychiatry. 2010 Dec;167(12):1479-88
references: 21041246
references: Biol Psychiatry. 2011 Mar 1;69(5):442-9
references: 21145041
references: Cereb Cortex. 2011 May;21(5):999-1011
references: 20843900
references: PLoS One. 2011;6(6):e21328
references: 21712993
references: Neuropsychopharmacology. 2011 Aug;36(9):1903-11
references: 21562483
references: Schizophr Res. 2011 Sep;131(1-3):165-73
references: 21745723
references: Anat Rec (Hoboken). 2011 Oct;294(10):1646-52
references: 21901839
references: Biol Psychiatry. 2011 Nov 1;70(9):842-51
references: 21816387
references: Trends Neurosci. 2012 Jan;35(1):57-67
references: 22154068
references: Neuropsychopharmacology. 2012 Feb;37(3):746-58
references: 22012473
references: Brain Behav Immun. 2012 Feb;26(2):353-63
references: 22154704
references: Neuropharmacology. 2012 Mar;62(3):1342-8
references: 21621548
references: Psychopharmacology (Berl). 2012 Jun;221(3):451-68
references: 22124672
references: Curr Pharm Biotechnol. 2012 Jun;13(8):1557-62
references: 22283765
references: Schizophr Res. 2012 Sep;140(1-3):175-84
references: 22804924
references: Schizophr Bull. 2012 Sep;38(5):950-7
references: 22355184
references: Behav Brain Res. 2013 Mar 15;241:206-13
references: 23261875
references: Brain Behav Immun. 2013 Oct;33:190-200
references: 23876745
references: Biol Psychiatry. 2014 Feb 15;75(4):307-15
references: 23938317
references: Schizophr Bull. 2014 Mar;40(2):351-61
references: 23328159
references: Brain Behav Immun. 2014 Aug;40:48-54
references: 24859043
references: Neuroscience. 2013 Sep 17;248:154-64
references: 23769891
references: Trends Pharmacol Sci. 2011 Sep;32(9):507-13
references: 21700346
references: J Psychopharmacol. 1999 Dec;13(4):358-71
references: 10667612
references: Cereb Cortex. 2002 Oct;12(10):1063-70
references: 12217970