title: Negative modulation of α₅ GABAA receptors in rats may partially prevent memory impairment induced by MK-801, but not amphetamine- or MK-801-elicited hyperlocomotion.
abstract: Reportedly, negative modulation of α5 GABAA receptors may improve cognition in normal and pharmacologically-impaired animals, and such modulation has been proposed as an avenue for treatment of cognitive symptoms in schizophrenia. This study assessed the actions of PWZ-029, administered at doses (2, 5, and 10 mg/kg) at which it reached micromolar concentrations in brain tissue with estimated free concentrations adequate for selective modulation of α5 GABAA receptors, in three cognitive tasks in male Wistar rats acutely treated with the noncompetitive N-methyl-d-aspartate receptor antagonist, MK-801 (0.1 mg/kg), as well in tests of locomotor activity potentiated by MK-801 (0.2 mg/kg) or amphetamine (0.5 mg/kg). In a hormetic-like manner, only 5 mg/kg PWZ-029 reversed MK-801-induced deficits in novel object recognition test (visual recognition memory), whereas in the Morris water maze, the 2 mg/kg dose of PWZ-029 exerted partial beneficial effects on spatial learning impairment. PWZ-029 did not affect recognition memory deﬁcits in social novelty discrimination procedure. Motor hyperactivity induced with MK-801 or amphetamine was not preventable by PWZ-029. Our results show that certain MK-801-induced memory deficits can be ameliorated by negative modulation of α5 GABAA receptors, and point to the need for further elucidation of their translational relevance to cognitive deterioration in schizophrenia.
authors.affiliation: Department of Pharmacology, University of Belgrade, Belgrade, Serbia.
authors.forename: Tamara
authors.initials: T
authors.lastname: Timić Stamenić
authors.affiliation: Department of Pharmacology, University of Belgrade, Belgrade, Serbia.
authors.forename: Srdjan
authors.initials: S
authors.lastname: Joksimović
authors.affiliation: Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI, USA.
authors.forename: Poonam
authors.initials: P
authors.lastname: Biawat
authors.affiliation: Department of Pharmacology, University of Belgrade, Belgrade, Serbia.
authors.forename: Tamara
authors.initials: T
authors.lastname: Stanković
authors.affiliation: Department of Pharmaceutical Chemistry, University of Belgrade, Belgrade, Serbia.
authors.forename: Bojan
authors.initials: B
authors.lastname: Marković
authors.affiliation: Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Cook
authors.affiliation: Department of Pharmacology, University of Belgrade, Belgrade, Serbia miroslav@pharmacy.bg.ac.rs.
authors.forename: Miroslav M
authors.initials: MM
authors.lastname: Savić
mesh_terms: D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001569:Benzodiazepines / Q000494:pharmacology; D003072:Cognition Disorders / Q000139:chemically induced / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D006948:Hyperkinesis / Q000139:chemically induced* / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000139:chemically induced* / Q000378:metabolism / Q000517:prevention & control*; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012559:Schizophrenia / Q000378:metabolism
chemical_list: C531941:PWZ-029; D011963:Receptors, GABA-A; D016194:Receptors, N-Methyl-D-Aspartate; D001569:Benzodiazepines; D016291:Dizocilpine Maleate; D000661:Amphetamine
keywords: Morris water maze; PWZ-029; amphetamine; dizocilpine; free brain concentration; novel object recognition test; social novelty discrimination procedure