Приказ основних података о документу
Attaining in vivo selectivity of positive modulation of alpha 3 ss gamma 2 GABA(A) receptors in rats: A hard task!
dc.creator | Batinić, Bojan | |
dc.creator | Stanković, Tamara | |
dc.creator | Stephen, Michael | |
dc.creator | Kodali, Revathi | |
dc.creator | Tiruveedhula, Veera V. | |
dc.creator | Li, Guanguan | |
dc.creator | Scholze, Petra | |
dc.creator | Marković, Bojan | |
dc.creator | Obradović, Aleksandar | |
dc.creator | Ernst, Margot | |
dc.creator | Cook, James M. | |
dc.creator | Savić, Miroslav | |
dc.date.accessioned | 2019-09-02T12:04:00Z | |
dc.date.available | 2019-09-02T12:04:00Z | |
dc.date.issued | 2018 | |
dc.identifier.issn | 0924-977X | |
dc.identifier.uri | https://farfar.pharmacy.bg.ac.rs/handle/123456789/3070 | |
dc.description.abstract | It is unclear whether GABA(A) receptors (GABA(A)Rs) that contain the alpha 3-subunit are substantially involved in the anxiolytic effects of benzodiazepines (BDZs). In the present study, we tested YT-III-31, a newer BDZ ligand with functional preference for alpha 3 ss gamma 2 GABA(A) Rs, in two paradigms of unconditioned anxiety, the open field and elevated plus maze in rats. The effective dose of YT-III-31 (2 mg/kg) displayed a clear anxiolytic-like profile, unhampered by sedative action, in both tests. At a higher dose (10 mg/kg), YT-III-31 induced ataxia in the rotarod and sedation in spontaneous locomotor activity test. The latter effect was preventable by flumazenil and ss CCt, the non-selective and alpha 1 ss gamma 2 GABA(A)R affinity-selective antagonist, respectively, demonstrating that sedative properties of YT-III-31, when attained, are mediated by the alpha 1 gamma 2 site. To elucidate the receptor substrate of subtle behavioral differences between YT-III-31 and diazepam, we approximated in vivo receptor potentiation for both ligands, based on estimated unbound concentrations in rat brains. Far different from diazepam, YT-III-31 has significantly lower affinity for the alpha 1 gamma 2 over other BDZ-sensitive sites, and at lower doses (1-2 mg/kg) was devoid of potentiation at alpha 1 ss gamma 2 GABA(A)Rs. The approximation approach revealed a modest selectivity of YT-III-31 for alpha 3 gamma 2- in comparison to alpha 2 gamma 2 and alpha 5 gamma 2 binding sites, suggesting that its anxiolytic-like activity may not necessarily or predominantly reflect potentiation at alpha 3 ss gamma 2 GABA(A)Rs. Nonetheless, as the anxiolytic effects are achievable at a dose devoid of any sedative potential, and having favorable safety (cytotoxicity) and metabolic stability profile, YT-III-31 represents a valuable candidate for further translational research. | en |
dc.publisher | Elsevier Science BV, Amsterdam | |
dc.relation | info:eu-repo/grantAgreement/MESTD/Basic Research (BR or ON)/175076/RS// | |
dc.rights | restrictedAccess | |
dc.source | European Neuropsychopharmacology | |
dc.subject | Sedation | en |
dc.subject | Anxiolysis | en |
dc.subject | Free brain concentration | en |
dc.subject | Binding study | en |
dc.subject | Open field | en |
dc.subject | Elevated plus maze | en |
dc.title | Attaining in vivo selectivity of positive modulation of alpha 3 ss gamma 2 GABA(A) receptors in rats: A hard task! | en |
dc.type | article | |
dc.rights.license | ARR | |
dcterms.abstract | Станковић, Тамара; Цоок, Јамес М.; Сцхолзе, Петра; Ли, Гуангуан; Тирувеедхула, Веера В.; Кодали, Реватхи; Марковић, Бојан; Ернст, Маргот; Степхен, Мицхаел; Батинић, Бојан; Обрадовић, Aлександар; Савић, Мирослав; | |
dc.citation.volume | 28 | |
dc.citation.issue | 8 | |
dc.citation.spage | 903 | |
dc.citation.epage | 914 | |
dc.citation.other | 28(8): 903-914 | |
dc.citation.rank | M21 | |
dc.identifier.wos | 000441875900003 | |
dc.identifier.doi | 10.1016/j.euroneuro.2018.05.014 | |
dc.identifier.pmid | 29891214 | |
dc.identifier.scopus | 2-s2.0-85048182641 | |
dc.type.version | publishedVersion |