TY  - JOUR
AU  - Kovacević, Jovana
AU  - Timić, Tamara
AU  - Tiruveedhula, Veera V.
AU  - Batinić, Bojan
AU  - Namjoshi, Ojas A.
AU  - Milić, Marija
AU  - Joksimović, Srđan
AU  - Cook, James M.
AU  - Savić, Miroslav
PY  - 2014
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2205
AB  - Long-term use of benzodiazepine-type drugs may lead to physical dependence, manifested by withdrawal syndrome after abrupt cessation of treatment. The aim of the present study was to investigate the influence of duration of treatment, as well as the role of alpha(1)-containing GABA(A) receptors, in development of physical dependence to diazepam, assessed through the level of anxiety and susceptibility to pentylenetetrazole (PTZ)-induced seizures, 24 h after withdrawal from protracted treatment in rats. Withdrawal of 2 mg/kg diazepam after 28, but not after 14 or 21 days of administration led to an anxiety-like behavior in the elevated plus maze. Antagonism of the diazepam effects at alpha(1)-containing GABA(A) receptors, achieved by daily administration of the neutral modulator beta CCt (5 mg/kg), did not affect the anxiety level during withdrawal. An increased susceptibility to PTZ-induced seizures was observed during diazepam withdrawal after 21 and 28 days of treatment. Daily co-administration of beta CCt further decreased the PTZ-seizure threshold after 21 days of treatment, whilst it prevented the diazepam withdrawal-elicited decrease of the PTZ threshold after 28 days of treatment. In conclusion, the current study suggests that the role of alpha(1)-containing GABA(A) receptors in mediating the development of physical dependence may vary based on the effect being studied and duration of protracted treatment. Moreover, the present data supports previous findings that the lack of activity at alpha(1)-containing GABA(A) receptors is not sufficient to eliminate physical dependence liability of ligands of the benzodiazepine type.
PB  - Pergamon-Elsevier Science Ltd, Oxford
T2  - Brain Research Bulletin
T1  - Duration of treatment and activation of alpha(1)-containing GABA(A) receptors variably affect the level of anxiety and seizure susceptibility after diazepam withdrawal in rats
VL  - 104
SP  - 1
EP  - 6
DO  - 10.1016/j.brainresbull.2014.03.002
ER  - 

@article{
author = "Kovacević, Jovana and Timić, Tamara and Tiruveedhula, Veera V. and Batinić, Bojan and Namjoshi, Ojas A. and Milić, Marija and Joksimović, Srđan and Cook, James M. and Savić, Miroslav",
year = "2014",
abstract = "Long-term use of benzodiazepine-type drugs may lead to physical dependence, manifested by withdrawal syndrome after abrupt cessation of treatment. The aim of the present study was to investigate the influence of duration of treatment, as well as the role of alpha(1)-containing GABA(A) receptors, in development of physical dependence to diazepam, assessed through the level of anxiety and susceptibility to pentylenetetrazole (PTZ)-induced seizures, 24 h after withdrawal from protracted treatment in rats. Withdrawal of 2 mg/kg diazepam after 28, but not after 14 or 21 days of administration led to an anxiety-like behavior in the elevated plus maze. Antagonism of the diazepam effects at alpha(1)-containing GABA(A) receptors, achieved by daily administration of the neutral modulator beta CCt (5 mg/kg), did not affect the anxiety level during withdrawal. An increased susceptibility to PTZ-induced seizures was observed during diazepam withdrawal after 21 and 28 days of treatment. Daily co-administration of beta CCt further decreased the PTZ-seizure threshold after 21 days of treatment, whilst it prevented the diazepam withdrawal-elicited decrease of the PTZ threshold after 28 days of treatment. In conclusion, the current study suggests that the role of alpha(1)-containing GABA(A) receptors in mediating the development of physical dependence may vary based on the effect being studied and duration of protracted treatment. Moreover, the present data supports previous findings that the lack of activity at alpha(1)-containing GABA(A) receptors is not sufficient to eliminate physical dependence liability of ligands of the benzodiazepine type.",
publisher = "Pergamon-Elsevier Science Ltd, Oxford",
journal = "Brain Research Bulletin",
title = "Duration of treatment and activation of alpha(1)-containing GABA(A) receptors variably affect the level of anxiety and seizure susceptibility after diazepam withdrawal in rats",
volume = "104",
pages = "1-6",
doi = "10.1016/j.brainresbull.2014.03.002"
}

Kovacević, J., Timić, T., Tiruveedhula, V. V., Batinić, B., Namjoshi, O. A., Milić, M., Joksimović, S., Cook, J. M.,& Savić, M.. (2014). Duration of treatment and activation of alpha(1)-containing GABA(A) receptors variably affect the level of anxiety and seizure susceptibility after diazepam withdrawal in rats. in Brain Research Bulletin
Pergamon-Elsevier Science Ltd, Oxford., 104, 1-6.
https://doi.org/10.1016/j.brainresbull.2014.03.002

Kovacević J, Timić T, Tiruveedhula VV, Batinić B, Namjoshi OA, Milić M, Joksimović S, Cook JM, Savić M. Duration of treatment and activation of alpha(1)-containing GABA(A) receptors variably affect the level of anxiety and seizure susceptibility after diazepam withdrawal in rats. in Brain Research Bulletin. 2014;104:1-6.
doi:10.1016/j.brainresbull.2014.03.002 .

Kovacević, Jovana, Timić, Tamara, Tiruveedhula, Veera V., Batinić, Bojan, Namjoshi, Ojas A., Milić, Marija, Joksimović, Srđan, Cook, James M., Savić, Miroslav, "Duration of treatment and activation of alpha(1)-containing GABA(A) receptors variably affect the level of anxiety and seizure susceptibility after diazepam withdrawal in rats" in Brain Research Bulletin, 104 (2014):1-6,
https://doi.org/10.1016/j.brainresbull.2014.03.002 . .

TY  - JOUR
AU  - Obradović, Aleksandar
AU  - Joksimović, Srđan
AU  - Poe, Michael M.
AU  - Ramerstorfer, Joachim
AU  - Varagić, Zdravko
AU  - Namjoshi, Ojas A.
AU  - Batinić, Bojan
AU  - Radulović, Tamara
AU  - Marković, Bojan
AU  - Roth, Brian L.
AU  - Sieghart, Werner
AU  - Cook, James M.
AU  - Savić, Miroslav
PY  - 2014
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2200
AB  - Enormous progress in understanding the role of four populations of benzodiazepine-sensitive GABA(A) receptors was paralleled by the puzzling findings suggesting that substantial separation of behavioral effects may be accomplished by apparently nonselective modulators. We report on SH-I-048A, a newly synthesized chiral positive modulator of GABAA receptors characterized by exceptional subnanomolar affinity, high efficacy and non-selectivity. Its influence on behavior was assessed in Wistar rats and contrasted to that obtained with 2 mg/kg diazepam. SH-I-048A reached micromolar concentrations in brain tissue, while the unbound fraction in brain homogenate was around 1.5%. The approximated electrophysiological responses, which estimated free concentrations of SH-I-048A or diazepam are able to elicit, suggested a similarity between the 10 mg/kg dose of the novel ligand and 2 mg/kg diazepam; however, SH-I-048A was relatively more active at and as-containing GABAA receptors. Behaviorally, SH-I-048A induced sedative, muscle relaxant and ataxic effects, reversed mechanical hyperalgesia 24 h after injury, while it was devoid of clear anxiolytic actions and did not affect water-maze performance. While lack of clear anxiolytic actions may be connected with an enhanced potentiation at al-containing GABAA receptors, the observed behavior in the rotarod, water maze and peripheral nerve injury tests was possibly affected by its prominent action at receptors containing the as subunit. The current results encourage further innovative approaches aimed at linking in vitro an in vivo data in order to help define fine-tuning mechanisms at four sensitive receptor populations that underlie subtle differences in behavioral profiles of benzodiazepine site ligands.
PB  - Elsevier Science BV, Amsterdam
T2  - Brain Research
T1  - Sh-I-048A, an in vitro non-selective super-agonist at the benzodiazepine site of GABAA receptors: The approximated activation of receptor subtypes may explain behavioral effects
VL  - 1554
SP  - 36
EP  - 48
DO  - 10.1016/j.brainres.2014.01.036
ER  - 

@article{
author = "Obradović, Aleksandar and Joksimović, Srđan and Poe, Michael M. and Ramerstorfer, Joachim and Varagić, Zdravko and Namjoshi, Ojas A. and Batinić, Bojan and Radulović, Tamara and Marković, Bojan and Roth, Brian L. and Sieghart, Werner and Cook, James M. and Savić, Miroslav",
year = "2014",
abstract = "Enormous progress in understanding the role of four populations of benzodiazepine-sensitive GABA(A) receptors was paralleled by the puzzling findings suggesting that substantial separation of behavioral effects may be accomplished by apparently nonselective modulators. We report on SH-I-048A, a newly synthesized chiral positive modulator of GABAA receptors characterized by exceptional subnanomolar affinity, high efficacy and non-selectivity. Its influence on behavior was assessed in Wistar rats and contrasted to that obtained with 2 mg/kg diazepam. SH-I-048A reached micromolar concentrations in brain tissue, while the unbound fraction in brain homogenate was around 1.5%. The approximated electrophysiological responses, which estimated free concentrations of SH-I-048A or diazepam are able to elicit, suggested a similarity between the 10 mg/kg dose of the novel ligand and 2 mg/kg diazepam; however, SH-I-048A was relatively more active at and as-containing GABAA receptors. Behaviorally, SH-I-048A induced sedative, muscle relaxant and ataxic effects, reversed mechanical hyperalgesia 24 h after injury, while it was devoid of clear anxiolytic actions and did not affect water-maze performance. While lack of clear anxiolytic actions may be connected with an enhanced potentiation at al-containing GABAA receptors, the observed behavior in the rotarod, water maze and peripheral nerve injury tests was possibly affected by its prominent action at receptors containing the as subunit. The current results encourage further innovative approaches aimed at linking in vitro an in vivo data in order to help define fine-tuning mechanisms at four sensitive receptor populations that underlie subtle differences in behavioral profiles of benzodiazepine site ligands.",
publisher = "Elsevier Science BV, Amsterdam",
journal = "Brain Research",
title = "Sh-I-048A, an in vitro non-selective super-agonist at the benzodiazepine site of GABAA receptors: The approximated activation of receptor subtypes may explain behavioral effects",
volume = "1554",
pages = "36-48",
doi = "10.1016/j.brainres.2014.01.036"
}

Obradović, A., Joksimović, S., Poe, M. M., Ramerstorfer, J., Varagić, Z., Namjoshi, O. A., Batinić, B., Radulović, T., Marković, B., Roth, B. L., Sieghart, W., Cook, J. M.,& Savić, M.. (2014). Sh-I-048A, an in vitro non-selective super-agonist at the benzodiazepine site of GABAA receptors: The approximated activation of receptor subtypes may explain behavioral effects. in Brain Research
Elsevier Science BV, Amsterdam., 1554, 36-48.
https://doi.org/10.1016/j.brainres.2014.01.036

Obradović A, Joksimović S, Poe MM, Ramerstorfer J, Varagić Z, Namjoshi OA, Batinić B, Radulović T, Marković B, Roth BL, Sieghart W, Cook JM, Savić M. Sh-I-048A, an in vitro non-selective super-agonist at the benzodiazepine site of GABAA receptors: The approximated activation of receptor subtypes may explain behavioral effects. in Brain Research. 2014;1554:36-48.
doi:10.1016/j.brainres.2014.01.036 .

Obradović, Aleksandar, Joksimović, Srđan, Poe, Michael M., Ramerstorfer, Joachim, Varagić, Zdravko, Namjoshi, Ojas A., Batinić, Bojan, Radulović, Tamara, Marković, Bojan, Roth, Brian L., Sieghart, Werner, Cook, James M., Savić, Miroslav, "Sh-I-048A, an in vitro non-selective super-agonist at the benzodiazepine site of GABAA receptors: The approximated activation of receptor subtypes may explain behavioral effects" in Brain Research, 1554 (2014):36-48,
https://doi.org/10.1016/j.brainres.2014.01.036 . .

TY  - JOUR
AU  - Divljaković, Jovana
AU  - Milić, Marija
AU  - Namjoshi, Ojas A.
AU  - Tiruveedhula, Veera V.
AU  - Timić, Tamara
AU  - Cook, James M.
AU  - Savić, Miroslav
PY  - 2013
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/1931
AB  - The abrupt discontinuation of prolonged benzodiazepine treatment elicits a withdrawal syndrome with increased anxiety as a major symptom. The neural mechanisms underlying benzodiazepine physical dependence are still insufficiently understood. Flumazenil, the non-selective antagonist of the benzodiazepine binding site of GABA(A) receptors was capable of preventing and reversing the increased anxiety during benzodiazepine withdrawal in animals and humans in some, but not all studies. On the other hand, a number of data suggest that GABA(A) receptors containing alpha(1) subunits are critically involved in processes developing during prolonged use of benzodiazepines, such are tolerance to sedative effects, liability to physical dependence and addiction. Hence, we investigated in the elevated plus maze the level of anxiety 24 h following 21 days of diazepam treatment and the influence of flumazenil or a preferential alpha(1)-subunit selective antagonist beta CCt on diazepam withdrawal syndrome in rats. Abrupt cessation of protracted once-daily intraperitoneal administration of 2 mg/kg diazepam induced a withdrawal syndrome, measured by increased anxiety-like behavior in the elevated plus maze 24 h after treatment cessation. Acute challenge with either flumazenil (10 mg/kg) or beta CCt (1.25, 5 and 20 mg/kg) alleviated the diazepam withdrawal-induced anxiety. Moreover, both antagonists induced an anxiolytic-like response close, though not identical, to that seen with acute administration of diazepam. These findings imply that the mechanism by which antagonism at GABA(A) receptors may reverse the withdrawal-induced anxiety involves the alpha(1) subunit and prompt further studies aimed at linking the changes in behavior with possible adaptive changes in subunit expression and function of GABA(A) receptors.
PB  - Pergamon-Elsevier Science Ltd, Oxford
T2  - Brain Research Bulletin
T1  - βCCT, an antagonist selective for α1GABAA receptors, reverses diazepam withdrawal-induced anxiety in rats
VL  - 91
SP  - 1
EP  - 7
DO  - 10.1016/j.brainresbull.2012.10.011
ER  - 

@article{
author = "Divljaković, Jovana and Milić, Marija and Namjoshi, Ojas A. and Tiruveedhula, Veera V. and Timić, Tamara and Cook, James M. and Savić, Miroslav",
year = "2013",
abstract = "The abrupt discontinuation of prolonged benzodiazepine treatment elicits a withdrawal syndrome with increased anxiety as a major symptom. The neural mechanisms underlying benzodiazepine physical dependence are still insufficiently understood. Flumazenil, the non-selective antagonist of the benzodiazepine binding site of GABA(A) receptors was capable of preventing and reversing the increased anxiety during benzodiazepine withdrawal in animals and humans in some, but not all studies. On the other hand, a number of data suggest that GABA(A) receptors containing alpha(1) subunits are critically involved in processes developing during prolonged use of benzodiazepines, such are tolerance to sedative effects, liability to physical dependence and addiction. Hence, we investigated in the elevated plus maze the level of anxiety 24 h following 21 days of diazepam treatment and the influence of flumazenil or a preferential alpha(1)-subunit selective antagonist beta CCt on diazepam withdrawal syndrome in rats. Abrupt cessation of protracted once-daily intraperitoneal administration of 2 mg/kg diazepam induced a withdrawal syndrome, measured by increased anxiety-like behavior in the elevated plus maze 24 h after treatment cessation. Acute challenge with either flumazenil (10 mg/kg) or beta CCt (1.25, 5 and 20 mg/kg) alleviated the diazepam withdrawal-induced anxiety. Moreover, both antagonists induced an anxiolytic-like response close, though not identical, to that seen with acute administration of diazepam. These findings imply that the mechanism by which antagonism at GABA(A) receptors may reverse the withdrawal-induced anxiety involves the alpha(1) subunit and prompt further studies aimed at linking the changes in behavior with possible adaptive changes in subunit expression and function of GABA(A) receptors.",
publisher = "Pergamon-Elsevier Science Ltd, Oxford",
journal = "Brain Research Bulletin",
title = "βCCT, an antagonist selective for α1GABAA receptors, reverses diazepam withdrawal-induced anxiety in rats",
volume = "91",
pages = "1-7",
doi = "10.1016/j.brainresbull.2012.10.011"
}

Divljaković, J., Milić, M., Namjoshi, O. A., Tiruveedhula, V. V., Timić, T., Cook, J. M.,& Savić, M.. (2013). βCCT, an antagonist selective for α1GABAA receptors, reverses diazepam withdrawal-induced anxiety in rats. in Brain Research Bulletin
Pergamon-Elsevier Science Ltd, Oxford., 91, 1-7.
https://doi.org/10.1016/j.brainresbull.2012.10.011

Divljaković J, Milić M, Namjoshi OA, Tiruveedhula VV, Timić T, Cook JM, Savić M. βCCT, an antagonist selective for α1GABAA receptors, reverses diazepam withdrawal-induced anxiety in rats. in Brain Research Bulletin. 2013;91:1-7.
doi:10.1016/j.brainresbull.2012.10.011 .

Divljaković, Jovana, Milić, Marija, Namjoshi, Ojas A., Tiruveedhula, Veera V., Timić, Tamara, Cook, James M., Savić, Miroslav, "βCCT, an antagonist selective for α1GABAA receptors, reverses diazepam withdrawal-induced anxiety in rats" in Brain Research Bulletin, 91 (2013):1-7,
https://doi.org/10.1016/j.brainresbull.2012.10.011 . .