TY  - JOUR
AU  - Batinić, Bojan
AU  - Stanković, Tamara
AU  - Stephen, Michael
AU  - Kodali, Revathi
AU  - Tiruveedhula, Veera V.
AU  - Li, Guanguan
AU  - Scholze, Petra
AU  - Marković, Bojan
AU  - Obradović, Aleksandar
AU  - Ernst, Margot
AU  - Cook, James M.
AU  - Savić, Miroslav
PY  - 2018
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3070
AB  - 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.
PB  - Elsevier Science BV, Amsterdam
T2  - European Neuropsychopharmacology
T1  - Attaining in vivo selectivity of positive modulation of alpha 3 ss gamma 2 GABA(A) receptors in rats: A hard task!
VL  - 28
IS  - 8
SP  - 903
EP  - 914
DO  - 10.1016/j.euroneuro.2018.05.014
ER  - 

@article{
author = "Batinić, Bojan and Stanković, Tamara and Stephen, Michael and Kodali, Revathi and Tiruveedhula, Veera V. and Li, Guanguan and Scholze, Petra and Marković, Bojan and Obradović, Aleksandar and Ernst, Margot and Cook, James M. and Savić, Miroslav",
year = "2018",
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.",
publisher = "Elsevier Science BV, Amsterdam",
journal = "European Neuropsychopharmacology",
title = "Attaining in vivo selectivity of positive modulation of alpha 3 ss gamma 2 GABA(A) receptors in rats: A hard task!",
volume = "28",
number = "8",
pages = "903-914",
doi = "10.1016/j.euroneuro.2018.05.014"
}

Batinić, B., Stanković, T., Stephen, M., Kodali, R., Tiruveedhula, V. V., Li, G., Scholze, P., Marković, B., Obradović, A., Ernst, M., Cook, J. M.,& Savić, M.. (2018). Attaining in vivo selectivity of positive modulation of alpha 3 ss gamma 2 GABA(A) receptors in rats: A hard task!. in European Neuropsychopharmacology
Elsevier Science BV, Amsterdam., 28(8), 903-914.
https://doi.org/10.1016/j.euroneuro.2018.05.014

Batinić B, Stanković T, Stephen M, Kodali R, Tiruveedhula VV, Li G, Scholze P, Marković B, Obradović A, Ernst M, Cook JM, Savić M. Attaining in vivo selectivity of positive modulation of alpha 3 ss gamma 2 GABA(A) receptors in rats: A hard task!. in European Neuropsychopharmacology. 2018;28(8):903-914.
doi:10.1016/j.euroneuro.2018.05.014 .

Batinić, Bojan, Stanković, Tamara, Stephen, Michael, Kodali, Revathi, Tiruveedhula, Veera V., Li, Guanguan, Scholze, Petra, Marković, Bojan, Obradović, Aleksandar, Ernst, Margot, Cook, James M., Savić, Miroslav, "Attaining in vivo selectivity of positive modulation of alpha 3 ss gamma 2 GABA(A) receptors in rats: A hard task!" in European Neuropsychopharmacology, 28, no. 8 (2018):903-914,
https://doi.org/10.1016/j.euroneuro.2018.05.014 . .

TY  - JOUR
AU  - Batinić, Bojan
AU  - Santrač, Anja
AU  - Jančić, Ivan
AU  - Li, Guanguan
AU  - Vidojević, Aleksandra
AU  - Marković, Bojan
AU  - Cook, James M.
AU  - Savić, Miroslav
PY  - 2017
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2821
AB  - We previously demonstrated that lipopolysaccharide (LPS) administered intraperitoneally (i.p.) to pregnant Wistar rat dams, at embryonic days 15 and 16 (E15/16), induced a decrease of baseline locomotor activity and diminished reactivity to amphetamine in adult female offspring. In the present study we aimed to assess the duration of LPS-induced maternal immune activation (MIA) and investigate possible changes in levels of main neurotransmitters in fetal brain during MIA. We hypothesized that the observed behavioral changes may be linked with MIA-induced disturbance of prenatal GABAergic system development, especially with alpha 5 GABA(A) receptors (alpha 5GABA(A)Rs), expression of which takes place between E14 and E17. Thereafter, we set to investigate if later potentiation of alpha 5GABA(A)Rs in offspring's preadolescence (from postnatal day 22-28) could prevent the deficit in locomotor reactivity to amphetamine observed in adulthood, at postnatal day P60. The elevation of IL-6 in amniotic fluid 6 h after LPS treatment (100 mu g/kg, i.p.) at E15 was concurrent with a significant increase of GABA and decrease of glutamate concentration in fetal brain. Moreover, repeated administration of MP-III-022, a selective positive allosteric modulator of alpha 5GABA(A)Rs, at a dose (2 mg/kg daily, i.p.) derived from a separate pharmacokinetic study, prevented the LPS-induced decrease in locomotor reactivity to amphetamine (0.5 mg/kg, i.p.) in adult females. These results were not mirrored in the parallel set of experiments with male offspring from LPS-treated rats. The results suggest that pharmacological potentiation of alpha 5GABA(A)Rs activity in preadolescence may ameliorate at least some of adverse consequences of exposure to MIA in utero.
PB  - Pergamon-Elsevier Science Ltd, Oxford
T2  - International Journal of Developmental Neuroscience
T1  - Positive modulation of alpha 5 GABA(A) receptors in preadolescence prevents reduced locomotor response to amphetamine in adult female but not male rats prenatally exposed to lipopolysaccharide
VL  - 61
SP  - 31
EP  - 39
DO  - 10.1016/j.ijdevneu.2017.06.001
ER  - 

@article{
author = "Batinić, Bojan and Santrač, Anja and Jančić, Ivan and Li, Guanguan and Vidojević, Aleksandra and Marković, Bojan and Cook, James M. and Savić, Miroslav",
year = "2017",
abstract = "We previously demonstrated that lipopolysaccharide (LPS) administered intraperitoneally (i.p.) to pregnant Wistar rat dams, at embryonic days 15 and 16 (E15/16), induced a decrease of baseline locomotor activity and diminished reactivity to amphetamine in adult female offspring. In the present study we aimed to assess the duration of LPS-induced maternal immune activation (MIA) and investigate possible changes in levels of main neurotransmitters in fetal brain during MIA. We hypothesized that the observed behavioral changes may be linked with MIA-induced disturbance of prenatal GABAergic system development, especially with alpha 5 GABA(A) receptors (alpha 5GABA(A)Rs), expression of which takes place between E14 and E17. Thereafter, we set to investigate if later potentiation of alpha 5GABA(A)Rs in offspring's preadolescence (from postnatal day 22-28) could prevent the deficit in locomotor reactivity to amphetamine observed in adulthood, at postnatal day P60. The elevation of IL-6 in amniotic fluid 6 h after LPS treatment (100 mu g/kg, i.p.) at E15 was concurrent with a significant increase of GABA and decrease of glutamate concentration in fetal brain. Moreover, repeated administration of MP-III-022, a selective positive allosteric modulator of alpha 5GABA(A)Rs, at a dose (2 mg/kg daily, i.p.) derived from a separate pharmacokinetic study, prevented the LPS-induced decrease in locomotor reactivity to amphetamine (0.5 mg/kg, i.p.) in adult females. These results were not mirrored in the parallel set of experiments with male offspring from LPS-treated rats. The results suggest that pharmacological potentiation of alpha 5GABA(A)Rs activity in preadolescence may ameliorate at least some of adverse consequences of exposure to MIA in utero.",
publisher = "Pergamon-Elsevier Science Ltd, Oxford",
journal = "International Journal of Developmental Neuroscience",
title = "Positive modulation of alpha 5 GABA(A) receptors in preadolescence prevents reduced locomotor response to amphetamine in adult female but not male rats prenatally exposed to lipopolysaccharide",
volume = "61",
pages = "31-39",
doi = "10.1016/j.ijdevneu.2017.06.001"
}

Batinić, B., Santrač, A., Jančić, I., Li, G., Vidojević, A., Marković, B., Cook, J. M.,& Savić, M.. (2017). Positive modulation of alpha 5 GABA(A) receptors in preadolescence prevents reduced locomotor response to amphetamine in adult female but not male rats prenatally exposed to lipopolysaccharide. in International Journal of Developmental Neuroscience
Pergamon-Elsevier Science Ltd, Oxford., 61, 31-39.
https://doi.org/10.1016/j.ijdevneu.2017.06.001

Batinić B, Santrač A, Jančić I, Li G, Vidojević A, Marković B, Cook JM, Savić M. Positive modulation of alpha 5 GABA(A) receptors in preadolescence prevents reduced locomotor response to amphetamine in adult female but not male rats prenatally exposed to lipopolysaccharide. in International Journal of Developmental Neuroscience. 2017;61:31-39.
doi:10.1016/j.ijdevneu.2017.06.001 .

Batinić, Bojan, Santrač, Anja, Jančić, Ivan, Li, Guanguan, Vidojević, Aleksandra, Marković, Bojan, Cook, James M., Savić, Miroslav, "Positive modulation of alpha 5 GABA(A) receptors in preadolescence prevents reduced locomotor response to amphetamine in adult female but not male rats prenatally exposed to lipopolysaccharide" in International Journal of Developmental Neuroscience, 61 (2017):31-39,
https://doi.org/10.1016/j.ijdevneu.2017.06.001 . .