title: Negative modulation of GABAA α5 receptors by RO4938581 attenuates discrete sub-chronic and early postnatal phencyclidine (PCP)-induced cognitive deficits in rats.
abstract: BACKGROUND
  A growing body of evidence suggests that negative modulation of γ-aminobutyric acid (GABA) GABA(A) α5 receptors may be a promising strategy for the treatment of certain facets of cognitive impairment; however, selective modulators of GABA(A) α5 receptors have not yet been tested in "schizophrenia-relevant" cognitive assay/model systems in animals.
  
  
  OBJECTIVE
  The objectives of this study were to investigate the potential of RO4938581, a negative modulator of GABA(A) α5 receptors, and to attenuate cognitive impairments induced following sub-chronic (sub-PCP) and early postnatal PCP (neo-PCP) administration in the novel object recognition (NOR) and intra-extradimensional shift (ID/ED) paradigms in rats. Complementary in vitro, ex vivo and in vivo studies were performed to confirm negative modulatory activity of RO4938581 and to investigate animal model validity, concept validity and potential side effect issues, respectively.
  
  
  RESULTS
  In vitro studies confirmed the reported negative modulatory activity of RO4938581, whilst immunohistochemical analyses revealed significantly reduced parvalbumin-positive cells in the prefrontal cortex of sub-PCP- and neo-PCP-treated rats. RO4938581 (1 mg/kg) ameliorated both sub-PCP- and neo-PCP-induced cognitive deficits in NOR and ID/ED performance, respectively. In contrast, QH-II-066 (1 and 3 mg/kg), a GABA(A) α5 receptor positive modulator, impaired cognitive performance in the NOR task when administered to vehicle-treated animals. Additional studies revealed that both RO4938581 (1 mg/kg) and QH-II-066 (1 and 3 mg/kg) attenuated amphetamine-induced hyperactivity in rats.
  
  
  CONCLUSIONS
  Taken together, these novel findings suggest that negative modulation of GABA(A) α5 receptors may represent an attractive treatment option for the cognitive impairments, and potentially positive symptoms, associated with schizophrenia.
authors: Synaptic Transmission I, Neuroscience Research DK, H Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark. JOPR@Lundbeck.com
authors: John P
authors: JP
authors: Redrobe
authors: Lisbeth
authors: L
authors: Elster
authors: Kristen
authors: K
authors: Frederiksen
authors: Christoffer
authors: C
authors: Bundgaard
authors: Inge E M
authors: IE
authors: de Jong
authors: Garrick P
authors: GP
authors: Smith
authors: Anne Techau
authors: AT
authors: Bruun
authors: Peter H
authors: PH
authors: Larsen
authors: Michael
authors: M
authors: Didriksen
mesh_terms: D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology*; D016466:CHO Cells; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D003072:Cognition Disorders / Q000139:chemically induced / Q000188:drug therapy*; D006224:Cricetinae; D003412:Cricetulus; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006948:Hyperkinesis / Q000139:chemically induced; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D009865:Oocytes; D010320:Parvalbumins / Q000378:metabolism; D010622:Phencyclidine / Q000008:administration & dosage / Q000633:toxicity*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000187:drug effects*; D012559:Schizophrenia / Q000188:drug therapy / Q000503:physiopathology; D014982:Xenopus laevis
chemical_list: C542509:3-bromo-10-difluoromethyl-9H-imidazo(1,5-a)(1,2,4)triazolo(1,5-d)(1,4)benzodiazepine; D000697:Central Nervous System Stimulants; C511535:Gabra5 protein, rat; D007093:Imidazoles; D010320:Parvalbumins; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D000661:Amphetamine; D010622:Phencyclidine