Benzodiazepine-induced spatial learning deficits in rats are regulated by the degree of modulation of [alpha]1 GABAA receptors

• Published in: European neuropsychopharmacology 2013-05, Vol.23 (5), p.390-399
• Main Authors: Joksimovic, SrAan, Divljakovic, Jovana, Van Linn, Michael L, Varagic, Zdravko, Brajkovic, Gordana, Milinkovic, Marija M, Yin, Wenyuan, Timic, Tamara, Sieghart, Werner, Cook, James M, Savic, Miroslav M
• Format: Article
• Language: English
• ISSN: 0924-977X

Despite significant advances in understanding the role of benzodiazepine (BZ)-sensitive populations of GABAA receptors, containing the [alpha]1, [alpha]2, [alpha]3 or [alpha]5 subunit, factual substrates of BZ-induced learning and memory deficits are not yet fully elucidated. It was shown that [alpha]1-subunit affinity-selective antagonist [beta]-CCt almost completely abolished spatial learning deficits induced by diazepam (DZP) in the Morris water maze. We examined a novel, highly (105 fold) [alpha]1-subunit selective ligandaWYS8 (0.2, 1 and 10 mg/kg), on its own and in combination with the non-selective agonist DZP (2 mg/kg) or [beta]-CCt (5 mg/kg) in the water maze in rats. The in vitro efficacy study revealed that WYS8 acts as [alpha]1-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 [beta]-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 [alpha]1 subtype-selective antagonist and a partial agonist on the effects of DZP on the water-maze acquisition.