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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
European neuropsychopharmacology, 05/2013, Letnik: 23, Številka: 5Journal Article
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.
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