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.
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.
['Timić Stamenić|Tamara|T|', 'Joksimović|Srdjan|S|', 'Biawat|Poonam|P|', 'Stanković|Tamara|T|', 'Marković|Bojan|B|', 'Cook|James M|JM|', 'Savić|Miroslav M|MM|']
D000661:Amphetamine D000818:Animals D001522:Behavior, Animal D001569:Benzodiazepines D003072:Cognition Disorders D016291:Dizocilpine Maleate D006948:Hyperkinesis D008297:Male D018782:Maze Learning D008569:Memory Disorders D051381:Rats D017208:Rats, Wistar D011963:Receptors, GABA-A D016194:Receptors, N-Methyl-D-Aspartate D012559:Schizophrenia
PWZ-029 amphetamine novel object recognition test Morris water maze social novelty discrimination procedure dizocilpine free brain concentration