Benzodiazepine-induced spatial learning deficits in rats are regulated by the degree of modulation of α1 GABAA receptors
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 affini...
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Published in | European neuropsychopharmacology Vol. 23; no. 5; pp. 390 - 399 |
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Main Authors | , , , , , , , , , , |
Format | Journal Article |
Language | English |
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Elsevier B.V
01.05.2013
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Abstract | 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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AbstractList | 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 10mg/kg), on its own and in combination with the non-selective agonist DZP (2mg/kg) or β-CCt (5mg/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 100nM). 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. Despite significant advances in understanding the role of benzodiazepine (BZ)-sensitive populations of GABA A receptors, containing the α 1 , α 2 , α 3 or α 5 subunit, factual substrates of BZ-induced learning and memory deficits are not yet fully elucidated. It was shown that α 1 -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) α 1 -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 α 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 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 α 1 subtype-selective antagonist and a partial agonist on the effects of DZP on the water-maze acquisition. 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. |
Author | Milinković, Marija M Yin, Wenyuan Savić, Miroslav M Joksimović, Srđan Brajković, Gordana Van Linn, Michael L Varagic, Zdravko Divljaković, Jovana Cook, James M Timić, Tamara Sieghart, Werner |
AuthorAffiliation | a Medicines and Medical Devices Agency of Serbia, Biological Laboratory - Pharmacology, Belgrade, Serbia e National Poison Center, Military Medical Academy, Crnotravska 17, 11000 Belgrade, Serbia c Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, P.O. Box 413, Milwaukee, Wisconsin 53201, USA b Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11221 Belgrade, Serbia d Center for Brain Research, Medical University Vienna, Vienna, Austria |
AuthorAffiliation_xml | – name: a Medicines and Medical Devices Agency of Serbia, Biological Laboratory - Pharmacology, Belgrade, Serbia – name: d Center for Brain Research, Medical University Vienna, Vienna, Austria – name: c Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, P.O. Box 413, Milwaukee, Wisconsin 53201, USA – name: e National Poison Center, Military Medical Academy, Crnotravska 17, 11000 Belgrade, Serbia – name: b Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11221 Belgrade, Serbia |
Author_xml | – sequence: 1 fullname: Joksimović, Srđan – sequence: 2 fullname: Divljaković, Jovana – sequence: 3 fullname: Van Linn, Michael L – sequence: 4 fullname: Varagic, Zdravko – sequence: 5 fullname: Brajković, Gordana – sequence: 6 fullname: Milinković, Marija M – sequence: 7 fullname: Yin, Wenyuan – sequence: 8 fullname: Timić, Tamara – sequence: 9 fullname: Sieghart, Werner – sequence: 10 fullname: Cook, James M – sequence: 11 fullname: Savić, Miroslav M |
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Keywords | GABA A subtype selective ligand Two electrode voltage clamp Diazepam Water maze GABAA subtype selective ligand |
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Snippet | Abstract Despite significant advances in understanding the role of benzodiazepine (BZ)-sensitive populations of GABAA receptors, containing the α1 , α2 , α3 or... Despite significant advances in understanding the role of benzodiazepine (BZ)-sensitive populations of GABAA receptors, containing the α1, α2, α3 or α5... Despite significant advances in understanding the role of benzodiazepine (BZ)-sensitive populations of GABA A receptors, containing the α 1 , α 2 , α 3 or α 5... |
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SubjectTerms | Diazepam GABAA subtype selective ligand Internal Medicine Psychiatry Two electrode voltage clamp Water maze |
Title | Benzodiazepine-induced spatial learning deficits in rats are regulated by the degree of modulation of α1 GABAA receptors |
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