Benzodiazepine-induced spatial learning deficits in rats are regulated by the degree of modulation of α1 GABAA receptors

• Published in: European neuropsychopharmacology Vol. 23; no. 5; pp. 390 - 399
• Main Authors: Joksimović, Srđan, Divljaković, Jovana, Van Linn, Michael L, Varagic, Zdravko, Brajković, Gordana, Milinković, Marija M, Yin, Wenyuan, Timić, Tamara, Sieghart, Werner, Cook, James M, Savić, Miroslav M
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.05.2013
• Subjects: Diazepam; GABAA subtype selective ligand; Internal Medicine; Psychiatry; Two electrode voltage clamp; Water maze; GABA A subtype selective ligand; Two electrode voltage clamp; Diazepam; Water maze; GABAA subtype selective ligand
• ISSN: 0924-977X; 1873-7862
• DOI: 10.1016/j.euroneuro.2012.05.003

Abstract Despite significant advances in understanding the role of benzodiazepine (BZ)-sensitive populations of GABAA receptors, containing the α1 , α2 , α3 or α5 subunit, factual substrates of BZ-induced learning and memory deficits are not yet fully elucidated. It was shown that α1 -subunit affinity-selective antagonist β -CCt almost completely abolished spatial learning deficits induced by diazepam (DZP) in the Morris water maze. We examined a novel, highly (105 fold) α1 -subunit selective ligand—WYS8 (0.2, 1 and 10 mg/kg), on its own and in combination with the non-selective agonist DZP (2 mg/kg) or β -CCt (5 mg/kg) in the water maze in rats. The in vitro efficacy study revealed that WYS8 acts as α1 -subtype selective weak partial positive modulator (40% potentiation at 100 nM). Measurement of concentrations of WYS8 and DZP in rat serum and brain tissues suggested that they did not substantially cross-influence the respective disposition. In the water maze, DZP impaired spatial learning (acquisition trials) and memory (probe trial). WYS8 caused no effect per se , did not affect the overall influence of DZP on the water-maze performance and was devoid of any activity in this task when combined with β -CCt. Nonetheless, an additional analysis of the latency to reach the platform and the total distance swam suggested that WYS8 addition attenuated the run-down of the spatial impairment induced by DZP at the end of acquisition trials. These results demonstrate a clear difference in the influence of an α1 subtype-selective antagonist and a partial agonist on the effects of DZP on the water-maze acquisition.