TY  - JOUR
AU  - Santrač, Anja
AU  - Batinić, Bojan
AU  - Timić-Stamenić, Tamara
AU  - Aranđelović, Jovana
AU  - Sharmin, Dishary
AU  - Knutson, Daniel E.
AU  - Cook, James
AU  - Savić, Miroslav
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3968
AB  - Positive allosteric modulators (PAMs) of α5GABAA receptors (α5GABAARs) are emerging as potential therapeutics for a range of neuropsychiatric disorders. However, their role in memory processing of healthy animals is not sufficiently examined. We tested the effects of MP-III-022 (1 mg/kg, 2.5 mg/kg and 10 mg/kg), a PAM known to be selective for α5GABAARs and devoid of prominent side-effects, in different behavioral paradigms (Morris water maze, novel object recognition test and social novelty discrimination) and on GABRA5 expression in Wistar rats, 30 min and 24 h after intraperitoneal treatment administration. The lowest dose tested worsened short-term object memory. The same dose, administered two times in a span of 24 h, improved spatial and impaired object and, at a trend level, social memory. The highest dose had a detrimental effect on all types of long-term memory (object memory at a trend level) and short-term spatial memory, but improved short-term object and social memory. Distinct sets of expression changes were detected in both prefrontal cortex and two regions of the hippocampus, but the latter ones could be assessed as more consequential. An increase of GABRA5 mRNA in CA2 occurred in parallel with improvement of object and social, but impairment of spatial memory, while the opposite happened with a trend level change in CA1. Our study demonstrates the variability of the roles of the α5GABAAR based on its level of expression and localization, in dependence on the type and protocol of cognitive tasks, as well as the respective timing of pharmacological modulation and testing.
PB  - Elsevier B.V.
T2  - Behavioural Brain Research
T1  - Positive modulation of α5GABAA receptors leads to dichotomous effects in rats on memory pattern and GABRA5 expression in prefrontal cortex and hippocampus
VL  - 416
DO  - 10.1016/j.bbr.2021.113578
ER  - 

@article{
author = "Santrač, Anja and Batinić, Bojan and Timić-Stamenić, Tamara and Aranđelović, Jovana and Sharmin, Dishary and Knutson, Daniel E. and Cook, James and Savić, Miroslav",
year = "2022",
abstract = "Positive allosteric modulators (PAMs) of α5GABAA receptors (α5GABAARs) are emerging as potential therapeutics for a range of neuropsychiatric disorders. However, their role in memory processing of healthy animals is not sufficiently examined. We tested the effects of MP-III-022 (1 mg/kg, 2.5 mg/kg and 10 mg/kg), a PAM known to be selective for α5GABAARs and devoid of prominent side-effects, in different behavioral paradigms (Morris water maze, novel object recognition test and social novelty discrimination) and on GABRA5 expression in Wistar rats, 30 min and 24 h after intraperitoneal treatment administration. The lowest dose tested worsened short-term object memory. The same dose, administered two times in a span of 24 h, improved spatial and impaired object and, at a trend level, social memory. The highest dose had a detrimental effect on all types of long-term memory (object memory at a trend level) and short-term spatial memory, but improved short-term object and social memory. Distinct sets of expression changes were detected in both prefrontal cortex and two regions of the hippocampus, but the latter ones could be assessed as more consequential. An increase of GABRA5 mRNA in CA2 occurred in parallel with improvement of object and social, but impairment of spatial memory, while the opposite happened with a trend level change in CA1. Our study demonstrates the variability of the roles of the α5GABAAR based on its level of expression and localization, in dependence on the type and protocol of cognitive tasks, as well as the respective timing of pharmacological modulation and testing.",
publisher = "Elsevier B.V.",
journal = "Behavioural Brain Research",
title = "Positive modulation of α5GABAA receptors leads to dichotomous effects in rats on memory pattern and GABRA5 expression in prefrontal cortex and hippocampus",
volume = "416",
doi = "10.1016/j.bbr.2021.113578"
}

Santrač, A., Batinić, B., Timić-Stamenić, T., Aranđelović, J., Sharmin, D., Knutson, D. E., Cook, J.,& Savić, M.. (2022). Positive modulation of α5GABAA receptors leads to dichotomous effects in rats on memory pattern and GABRA5 expression in prefrontal cortex and hippocampus. in Behavioural Brain Research
Elsevier B.V.., 416.
https://doi.org/10.1016/j.bbr.2021.113578

Santrač A, Batinić B, Timić-Stamenić T, Aranđelović J, Sharmin D, Knutson DE, Cook J, Savić M. Positive modulation of α5GABAA receptors leads to dichotomous effects in rats on memory pattern and GABRA5 expression in prefrontal cortex and hippocampus. in Behavioural Brain Research. 2022;416.
doi:10.1016/j.bbr.2021.113578 .

Santrač, Anja, Batinić, Bojan, Timić-Stamenić, Tamara, Aranđelović, Jovana, Sharmin, Dishary, Knutson, Daniel E., Cook, James, Savić, Miroslav, "Positive modulation of α5GABAA receptors leads to dichotomous effects in rats on memory pattern and GABRA5 expression in prefrontal cortex and hippocampus" in Behavioural Brain Research, 416 (2022),
https://doi.org/10.1016/j.bbr.2021.113578 . .

TY  - JOUR
AU  - Timić-Stamenić, Tamara
AU  - Poe, Michael M.
AU  - Rehman, Sabah
AU  - Santrač, Anja
AU  - Divović, Branka
AU  - Scholze, Petra
AU  - Ernst, Margot
AU  - Cook, James M.
AU  - Savić, Miroslav
PY  - 2016
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2631
AB  - We have synthesized and characterized MP-III-022 ((R)-8-ethynyl 6 (2 fluorophenyl)-N,4-dimethyl4H-benzo[f]imidazo[1,5-alpha][1,4]diazepine-3-carboxamide) in vitro and in vivo as a binding- and efficacy selective positive allosteric modulator of GABA(A) receptors containing the alpha 5 subunit (alpha 5GABA(A)Rs). By approximation of the electrophysiological responses which the estimated free rat brain concentrations can induce, we demonstrated that convenient systemic administration of MP-III-022 in the dose range 110 mg/kg may result in a selective potentiation, over a wide range from mild to moderate to strong, of alpha 5 beta gamma 2 GABA(A) receptors. For eliciting a comparable range of potentiation, the widely studied parent ligand SH-053-2'F-R-CH3 containing an ester moiety needs to be administered over a much wider dose range (10-200 mg/kg), but at the price of activating non-alpha 5 GABA(A)Rs as well as the desired alpha 5GABA(A)Rs at the highest dose. At the dose of 10 mg/kg, which elicits a strong positive modulation of alpha 5GABA(A)Rs, MP-III-022 caused mild, but significant muscle relaxation, while at doses 1-10 mg/kg was devoid of ataxia, sedation or an influence on the anxiety level, characteristic for non-selective benzodiazepines. As an amide compound with improved stability and kinetic properties, MP-III-022 may represent an optimized tool to study the influence of alpha 5GABA(A)Rs on the neuronal pathways related to CNS disorders such as schizophrenia, Alzheimer's disease, Down syndrome or autism.
PB  - Elsevier Science BV, Amsterdam
T2  - European Journal of Pharmacology
T1  - Ester to amide substitution improves selectivity, efficacy and kinetic behavior of a benzodiazepine positive modulator of GABA(A) receptors containing the alpha 5 subunit
VL  - 791
SP  - 433
EP  - 443
DO  - 10.1016/j.ejphar.2016.09.016
ER  - 

@article{
author = "Timić-Stamenić, Tamara and Poe, Michael M. and Rehman, Sabah and Santrač, Anja and Divović, Branka and Scholze, Petra and Ernst, Margot and Cook, James M. and Savić, Miroslav",
year = "2016",
abstract = "We have synthesized and characterized MP-III-022 ((R)-8-ethynyl 6 (2 fluorophenyl)-N,4-dimethyl4H-benzo[f]imidazo[1,5-alpha][1,4]diazepine-3-carboxamide) in vitro and in vivo as a binding- and efficacy selective positive allosteric modulator of GABA(A) receptors containing the alpha 5 subunit (alpha 5GABA(A)Rs). By approximation of the electrophysiological responses which the estimated free rat brain concentrations can induce, we demonstrated that convenient systemic administration of MP-III-022 in the dose range 110 mg/kg may result in a selective potentiation, over a wide range from mild to moderate to strong, of alpha 5 beta gamma 2 GABA(A) receptors. For eliciting a comparable range of potentiation, the widely studied parent ligand SH-053-2'F-R-CH3 containing an ester moiety needs to be administered over a much wider dose range (10-200 mg/kg), but at the price of activating non-alpha 5 GABA(A)Rs as well as the desired alpha 5GABA(A)Rs at the highest dose. At the dose of 10 mg/kg, which elicits a strong positive modulation of alpha 5GABA(A)Rs, MP-III-022 caused mild, but significant muscle relaxation, while at doses 1-10 mg/kg was devoid of ataxia, sedation or an influence on the anxiety level, characteristic for non-selective benzodiazepines. As an amide compound with improved stability and kinetic properties, MP-III-022 may represent an optimized tool to study the influence of alpha 5GABA(A)Rs on the neuronal pathways related to CNS disorders such as schizophrenia, Alzheimer's disease, Down syndrome or autism.",
publisher = "Elsevier Science BV, Amsterdam",
journal = "European Journal of Pharmacology",
title = "Ester to amide substitution improves selectivity, efficacy and kinetic behavior of a benzodiazepine positive modulator of GABA(A) receptors containing the alpha 5 subunit",
volume = "791",
pages = "433-443",
doi = "10.1016/j.ejphar.2016.09.016"
}

Timić-Stamenić, T., Poe, M. M., Rehman, S., Santrač, A., Divović, B., Scholze, P., Ernst, M., Cook, J. M.,& Savić, M.. (2016). Ester to amide substitution improves selectivity, efficacy and kinetic behavior of a benzodiazepine positive modulator of GABA(A) receptors containing the alpha 5 subunit. in European Journal of Pharmacology
Elsevier Science BV, Amsterdam., 791, 433-443.
https://doi.org/10.1016/j.ejphar.2016.09.016

Timić-Stamenić T, Poe MM, Rehman S, Santrač A, Divović B, Scholze P, Ernst M, Cook JM, Savić M. Ester to amide substitution improves selectivity, efficacy and kinetic behavior of a benzodiazepine positive modulator of GABA(A) receptors containing the alpha 5 subunit. in European Journal of Pharmacology. 2016;791:433-443.
doi:10.1016/j.ejphar.2016.09.016 .

Timić-Stamenić, Tamara, Poe, Michael M., Rehman, Sabah, Santrač, Anja, Divović, Branka, Scholze, Petra, Ernst, Margot, Cook, James M., Savić, Miroslav, "Ester to amide substitution improves selectivity, efficacy and kinetic behavior of a benzodiazepine positive modulator of GABA(A) receptors containing the alpha 5 subunit" in European Journal of Pharmacology, 791 (2016):433-443,
https://doi.org/10.1016/j.ejphar.2016.09.016 . .

TY  - JOUR
AU  - Batinić, Bojan
AU  - Santrač, Anja
AU  - Divović, Branka
AU  - Timić, Tamara
AU  - Stanković, Tamara
AU  - Obradović, Aleksandar
AU  - Joksimović, Srđan
AU  - Savić, Miroslav
PY  - 2016
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2558
AB  - Numerous basic and epidemiological studies have connected prenatal maternal immune activation with the occurrence of schizophrenia and/or autism. Depending on subtle differences in protocols of the used animal model, a variety of behavioral abnormalities has been reported. This study investigated behavioral differences in Wistar rat offspring of both genders, exposed to the 100 mu g/kg per day dose of lipopolysaccharide (LPS) in late embryogenesis (embryonic days 15 and 16), while tested at their adolescent and young adult age (postnatal days 40 and 60, respectively). Immune activation was confirmed by detecting high levels of TNF-alpha and IL-6 in dam blood withdrawn 2 h after the first dose of LPS. The animals were assessed in three consecutive trials of locomotor activity (novelty exploration, response to i.p. saline injection and challenge with 0.5 mg/kg amphetamine), Morris water maze and social interaction tests. Overt behavioral dysfunction was perceived in adult rats only, and these changes were gender-distinctive. When compared with control rats, LPS females displayed baseline hypolocomotion and a decreased reactivity to amphetamine, while LPS males exhibited spatial learning (acquisition trials) and memory (probe trial) impairments. Prenatal treatment did not affect the time spent in social interaction. As maternal exposure to LPS in late gestation resulted in behavioral changes in offspring in early adulthood, it may model schizophrenia-like, but not autism-like endophenotypes. However, lack of a potentiated response to amphetamine testified that this model could not mimic positive symptoms, but rather certain traits of cognitive dysfunction and deficit symptoms, in males and females, respectively.
PB  - Elsevier Science BV, Amsterdam
T2  - Behavioural Brain Research
T1  - Lipopolysaccharide exposure during late embryogenesis results in diminished locomotor activity and amphetamine response in females and spatial cognition impairment in males in adult, but not adolescent rat offspring
VL  - 299
SP  - 72
EP  - 80
DO  - 10.1016/j.bbr.2015.11.025
ER  - 

@article{
author = "Batinić, Bojan and Santrač, Anja and Divović, Branka and Timić, Tamara and Stanković, Tamara and Obradović, Aleksandar and Joksimović, Srđan and Savić, Miroslav",
year = "2016",
abstract = "Numerous basic and epidemiological studies have connected prenatal maternal immune activation with the occurrence of schizophrenia and/or autism. Depending on subtle differences in protocols of the used animal model, a variety of behavioral abnormalities has been reported. This study investigated behavioral differences in Wistar rat offspring of both genders, exposed to the 100 mu g/kg per day dose of lipopolysaccharide (LPS) in late embryogenesis (embryonic days 15 and 16), while tested at their adolescent and young adult age (postnatal days 40 and 60, respectively). Immune activation was confirmed by detecting high levels of TNF-alpha and IL-6 in dam blood withdrawn 2 h after the first dose of LPS. The animals were assessed in three consecutive trials of locomotor activity (novelty exploration, response to i.p. saline injection and challenge with 0.5 mg/kg amphetamine), Morris water maze and social interaction tests. Overt behavioral dysfunction was perceived in adult rats only, and these changes were gender-distinctive. When compared with control rats, LPS females displayed baseline hypolocomotion and a decreased reactivity to amphetamine, while LPS males exhibited spatial learning (acquisition trials) and memory (probe trial) impairments. Prenatal treatment did not affect the time spent in social interaction. As maternal exposure to LPS in late gestation resulted in behavioral changes in offspring in early adulthood, it may model schizophrenia-like, but not autism-like endophenotypes. However, lack of a potentiated response to amphetamine testified that this model could not mimic positive symptoms, but rather certain traits of cognitive dysfunction and deficit symptoms, in males and females, respectively.",
publisher = "Elsevier Science BV, Amsterdam",
journal = "Behavioural Brain Research",
title = "Lipopolysaccharide exposure during late embryogenesis results in diminished locomotor activity and amphetamine response in females and spatial cognition impairment in males in adult, but not adolescent rat offspring",
volume = "299",
pages = "72-80",
doi = "10.1016/j.bbr.2015.11.025"
}

Batinić, B., Santrač, A., Divović, B., Timić, T., Stanković, T., Obradović, A., Joksimović, S.,& Savić, M.. (2016). Lipopolysaccharide exposure during late embryogenesis results in diminished locomotor activity and amphetamine response in females and spatial cognition impairment in males in adult, but not adolescent rat offspring. in Behavioural Brain Research
Elsevier Science BV, Amsterdam., 299, 72-80.
https://doi.org/10.1016/j.bbr.2015.11.025

Batinić B, Santrač A, Divović B, Timić T, Stanković T, Obradović A, Joksimović S, Savić M. Lipopolysaccharide exposure during late embryogenesis results in diminished locomotor activity and amphetamine response in females and spatial cognition impairment in males in adult, but not adolescent rat offspring. in Behavioural Brain Research. 2016;299:72-80.
doi:10.1016/j.bbr.2015.11.025 .

Batinić, Bojan, Santrač, Anja, Divović, Branka, Timić, Tamara, Stanković, Tamara, Obradović, Aleksandar, Joksimović, Srđan, Savić, Miroslav, "Lipopolysaccharide exposure during late embryogenesis results in diminished locomotor activity and amphetamine response in females and spatial cognition impairment in males in adult, but not adolescent rat offspring" in Behavioural Brain Research, 299 (2016):72-80,
https://doi.org/10.1016/j.bbr.2015.11.025 . .

TY  - JOUR
AU  - Piantadosi, Sean C.
AU  - French, Beverly J.
AU  - Poe, Michael M.
AU  - Timić, Tamara
AU  - Marković, Bojan
AU  - Pabba, Mohan
AU  - Seney, Marianne L.
AU  - Oh, Hyunjung
AU  - Orser, Beverley A.
AU  - Savić, Miroslav
AU  - Cook, James M.
AU  - Sibille, Etienne
PY  - 2016
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2633
AB  - Rationale: Current first-line treatments for stress related disorders such as major depressive disorder (MDD) act on monoaminergic systems and take weeks to achieve a therapeutic effect with poor response and low remission rates. Recent research has implicated the GABAergic system in the pathophysiology of depression, including deficits in interneurons targeting the dendritic compartment of cortical pyramidal cells. Objectives: The present study evaluates whether SH-053-2'F-R-CH3 (denoted "alpha 5-PAM"), a positive allosteric modulator selective for (alpha 5-subunit containing GABA(A) receptors found predominantly on cortical pyramidal cell dendrites, has anti stress effects. Methods: Female and male C57BL6/J mice were exposed to unpredictable chronic mild stress (UCMS) and treated with alpha 5-PAM acutely (30 min prior to assessing behavior) or chronically before being assessed behaviorally. Results: Acute and chronic alpha 5-PAM treatments produce a pattern of decreased stress induced behaviors (denoted as "behavioral emotionality") across various tests in female, but not in male mice. Behavioral Z-scores calculated across a panel of tests designed to best model the range and heterogeneity of human symptomatology confirmed that acute and chronic alpha 5-PAM treatments consistently produce significant decreases in behavioral emotionality in several independent cohorts of females. The behavioral responses to alpha 5-PAM could not be completely accounted for by differences in drug brain disposition between female and male mice. In mice exposed to UCMS, expression of the Gabra5 gene was increased in the frontal cortex after acute treatment and in the hippocampus after chronic treatment with alpha 5-PAM in females only, and these expression changes correlated with behavioral emotionality. Conclusion: We showed that acute and chronic positive modulation of alpha 5 subunit containing GABA(A) receptors elicit anti-stress effects in a sex-dependent manner, suggesting novel therapeutic modalities.
PB  - Frontiers Media Sa, Lausanne
T2  - Frontiers in Pharmacology
T1  - Sex-Dependent Anti-Stress Effect of an alpha 5 Subunit Containing GABA(A) Receptor Positive Allosteric Modulator
VL  - 7
DO  - 10.3389/fphar.2016.00446
ER  - 

@article{
author = "Piantadosi, Sean C. and French, Beverly J. and Poe, Michael M. and Timić, Tamara and Marković, Bojan and Pabba, Mohan and Seney, Marianne L. and Oh, Hyunjung and Orser, Beverley A. and Savić, Miroslav and Cook, James M. and Sibille, Etienne",
year = "2016",
abstract = "Rationale: Current first-line treatments for stress related disorders such as major depressive disorder (MDD) act on monoaminergic systems and take weeks to achieve a therapeutic effect with poor response and low remission rates. Recent research has implicated the GABAergic system in the pathophysiology of depression, including deficits in interneurons targeting the dendritic compartment of cortical pyramidal cells. Objectives: The present study evaluates whether SH-053-2'F-R-CH3 (denoted "alpha 5-PAM"), a positive allosteric modulator selective for (alpha 5-subunit containing GABA(A) receptors found predominantly on cortical pyramidal cell dendrites, has anti stress effects. Methods: Female and male C57BL6/J mice were exposed to unpredictable chronic mild stress (UCMS) and treated with alpha 5-PAM acutely (30 min prior to assessing behavior) or chronically before being assessed behaviorally. Results: Acute and chronic alpha 5-PAM treatments produce a pattern of decreased stress induced behaviors (denoted as "behavioral emotionality") across various tests in female, but not in male mice. Behavioral Z-scores calculated across a panel of tests designed to best model the range and heterogeneity of human symptomatology confirmed that acute and chronic alpha 5-PAM treatments consistently produce significant decreases in behavioral emotionality in several independent cohorts of females. The behavioral responses to alpha 5-PAM could not be completely accounted for by differences in drug brain disposition between female and male mice. In mice exposed to UCMS, expression of the Gabra5 gene was increased in the frontal cortex after acute treatment and in the hippocampus after chronic treatment with alpha 5-PAM in females only, and these expression changes correlated with behavioral emotionality. Conclusion: We showed that acute and chronic positive modulation of alpha 5 subunit containing GABA(A) receptors elicit anti-stress effects in a sex-dependent manner, suggesting novel therapeutic modalities.",
publisher = "Frontiers Media Sa, Lausanne",
journal = "Frontiers in Pharmacology",
title = "Sex-Dependent Anti-Stress Effect of an alpha 5 Subunit Containing GABA(A) Receptor Positive Allosteric Modulator",
volume = "7",
doi = "10.3389/fphar.2016.00446"
}

Piantadosi, S. C., French, B. J., Poe, M. M., Timić, T., Marković, B., Pabba, M., Seney, M. L., Oh, H., Orser, B. A., Savić, M., Cook, J. M.,& Sibille, E.. (2016). Sex-Dependent Anti-Stress Effect of an alpha 5 Subunit Containing GABA(A) Receptor Positive Allosteric Modulator. in Frontiers in Pharmacology
Frontiers Media Sa, Lausanne., 7.
https://doi.org/10.3389/fphar.2016.00446

Piantadosi SC, French BJ, Poe MM, Timić T, Marković B, Pabba M, Seney ML, Oh H, Orser BA, Savić M, Cook JM, Sibille E. Sex-Dependent Anti-Stress Effect of an alpha 5 Subunit Containing GABA(A) Receptor Positive Allosteric Modulator. in Frontiers in Pharmacology. 2016;7.
doi:10.3389/fphar.2016.00446 .

Piantadosi, Sean C., French, Beverly J., Poe, Michael M., Timić, Tamara, Marković, Bojan, Pabba, Mohan, Seney, Marianne L., Oh, Hyunjung, Orser, Beverley A., Savić, Miroslav, Cook, James M., Sibille, Etienne, "Sex-Dependent Anti-Stress Effect of an alpha 5 Subunit Containing GABA(A) Receptor Positive Allosteric Modulator" in Frontiers in Pharmacology, 7 (2016),
https://doi.org/10.3389/fphar.2016.00446 . .

TY  - CONF
AU  - Timić-Stamenić, Tamara
AU  - Santrač, Anja
AU  - Divović, Branka
AU  - Poe, Michael M.
AU  - Cook, James M.
AU  - Savić, Miroslav
PY  - 2015
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2424
PB  - Elsevier Science BV, Amsterdam
C3  - European Neuropsychopharmacology
T1  - Effects of positive alpha5-selective
modulation of GABA A receptors on
amphetamine-induced hyperlocomotion
VL  - 25
IS  - Supplement 1
SP  - S38
EP  - S39
DO  - 10.1016/S0924-977X(15)30007-9
ER  - 

@conference{
author = "Timić-Stamenić, Tamara and Santrač, Anja and Divović, Branka and Poe, Michael M. and Cook, James M. and Savić, Miroslav",
year = "2015",
publisher = "Elsevier Science BV, Amsterdam",
journal = "European Neuropsychopharmacology",
title = "Effects of positive alpha5-selective
modulation of GABA A receptors on
amphetamine-induced hyperlocomotion",
volume = "25",
number = "Supplement 1",
pages = "S38-S39",
doi = "10.1016/S0924-977X(15)30007-9"
}

Timić-Stamenić, T., Santrač, A., Divović, B., Poe, M. M., Cook, J. M.,& Savić, M.. (2015). Effects of positive alpha5-selective
modulation of GABA A receptors on
amphetamine-induced hyperlocomotion. in European Neuropsychopharmacology
Elsevier Science BV, Amsterdam., 25(Supplement 1), S38-S39.
https://doi.org/10.1016/S0924-977X(15)30007-9

Timić-Stamenić T, Santrač A, Divović B, Poe MM, Cook JM, Savić M. Effects of positive alpha5-selective
modulation of GABA A receptors on
amphetamine-induced hyperlocomotion. in European Neuropsychopharmacology. 2015;25(Supplement 1):S38-S39.
doi:10.1016/S0924-977X(15)30007-9 .

Timić-Stamenić, Tamara, Santrač, Anja, Divović, Branka, Poe, Michael M., Cook, James M., Savić, Miroslav, "Effects of positive alpha5-selective
modulation of GABA A receptors on
amphetamine-induced hyperlocomotion" in European Neuropsychopharmacology, 25, no. Supplement 1 (2015):S38-S39,
https://doi.org/10.1016/S0924-977X(15)30007-9 . .

TY  - CONF
AU  - Timić-Stamenić, Tamara
AU  - Santrač, Anja
AU  - Divović, Branka
AU  - Poe, Michael M.
AU  - James, C. M.
AU  - Savić, Miroslav
PY  - 2015
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2305
PB  - Elsevier Science BV, Amsterdam
C3  - European Neuropsychopharmacology
T1  - Effects of positive α5-selective modulation of GABAA receptors on amphetamine-induced hyperactivation
VL  - 25
SP  - S287
EP  - S288
DO  - 10.1016/S0924-977X(15)30342-4
ER  - 

@conference{
author = "Timić-Stamenić, Tamara and Santrač, Anja and Divović, Branka and Poe, Michael M. and James, C. M. and Savić, Miroslav",
year = "2015",
publisher = "Elsevier Science BV, Amsterdam",
journal = "European Neuropsychopharmacology",
title = "Effects of positive α5-selective modulation of GABAA receptors on amphetamine-induced hyperactivation",
volume = "25",
pages = "S287-S288",
doi = "10.1016/S0924-977X(15)30342-4"
}

Timić-Stamenić, T., Santrač, A., Divović, B., Poe, M. M., James, C. M.,& Savić, M.. (2015). Effects of positive α5-selective modulation of GABAA receptors on amphetamine-induced hyperactivation. in European Neuropsychopharmacology
Elsevier Science BV, Amsterdam., 25, S287-S288.
https://doi.org/10.1016/S0924-977X(15)30342-4

Timić-Stamenić T, Santrač A, Divović B, Poe MM, James CM, Savić M. Effects of positive α5-selective modulation of GABAA receptors on amphetamine-induced hyperactivation. in European Neuropsychopharmacology. 2015;25:S287-S288.
doi:10.1016/S0924-977X(15)30342-4 .

Timić-Stamenić, Tamara, Santrač, Anja, Divović, Branka, Poe, Michael M., James, C. M., Savić, Miroslav, "Effects of positive α5-selective modulation of GABAA receptors on amphetamine-induced hyperactivation" in European Neuropsychopharmacology, 25 (2015):S287-S288,
https://doi.org/10.1016/S0924-977X(15)30342-4 . .

TY  - JOUR
AU  - Đorđević, Sanela
AU  - Cekić, Nebojša
AU  - Savić, Miroslav
AU  - Isailović, Tanja
AU  - Ranđelović, Danijela
AU  - Marković, Bojan
AU  - Savić, Saša R.
AU  - Timić-Stamenić, Tamara
AU  - Daniels, Rolf
AU  - Savić, Snežana
PY  - 2015
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2346
AB  - This paper describes design and evaluation of parenteral lecithin-based nanoemulsions intended for brain delivery of risperidone, a poorly water-soluble psychopharmacological drug. The nanoemulsions were prepared through cold/hot high pressure homogenization and characterized regarding droplet size, polydispersity, surface charge, morphology, drug-vehicle interactions, and physical stability. To estimate the simultaneous influence of nanoemulsion formulation and preparation parameters-co-emulsifier type, aqueous phase type, homogenization temperature-on the critical quality attributes of developed nanoemulsions, a general factorial experimental design was applied. From the established design space and stability data, promising risperidone-loaded nanoemulsions (mean size about 160 nm, size distribution  lt 0.15, zeta potential around -50 mV), containing sodium oleate in the aqueous phase and polysorbate 80, poloxamer 188 or Solutol (R) HS15 as co-emulsifier, were produced by hot homogenization and their ability to improve risperidone delivery to the brain was assessed in rats. Pharmacokinetic study demonstrated erratic brain profiles of risperidone following intraperitoneal administration in selected nanoemulsions, most probably due to their different droplet surface properties (different composition of the stabilizing layer). Namely, polysorbate 80-costabilized nanoemulsion showed increased (1.4-7.4-fold higher) risperidone brain availability compared to other nanoemulsions and drug solution, suggesting this nanoemulsion as a promising carrier worth exploring further for brain targeting.
PB  - Elsevier Science BV, Amsterdam
T2  - International Journal of Pharmaceutics
T1  - Parenteral nanoemulsions as promising carriers for brain delivery of risperidone: Design, characterization and in vivo pharmacokinetic evaluation
VL  - 493
IS  - 1-2
SP  - 40
EP  - 54
DO  - 10.1016/j.ijpharm.2015.07.007
ER  - 

@article{
author = "Đorđević, Sanela and Cekić, Nebojša and Savić, Miroslav and Isailović, Tanja and Ranđelović, Danijela and Marković, Bojan and Savić, Saša R. and Timić-Stamenić, Tamara and Daniels, Rolf and Savić, Snežana",
year = "2015",
abstract = "This paper describes design and evaluation of parenteral lecithin-based nanoemulsions intended for brain delivery of risperidone, a poorly water-soluble psychopharmacological drug. The nanoemulsions were prepared through cold/hot high pressure homogenization and characterized regarding droplet size, polydispersity, surface charge, morphology, drug-vehicle interactions, and physical stability. To estimate the simultaneous influence of nanoemulsion formulation and preparation parameters-co-emulsifier type, aqueous phase type, homogenization temperature-on the critical quality attributes of developed nanoemulsions, a general factorial experimental design was applied. From the established design space and stability data, promising risperidone-loaded nanoemulsions (mean size about 160 nm, size distribution  lt 0.15, zeta potential around -50 mV), containing sodium oleate in the aqueous phase and polysorbate 80, poloxamer 188 or Solutol (R) HS15 as co-emulsifier, were produced by hot homogenization and their ability to improve risperidone delivery to the brain was assessed in rats. Pharmacokinetic study demonstrated erratic brain profiles of risperidone following intraperitoneal administration in selected nanoemulsions, most probably due to their different droplet surface properties (different composition of the stabilizing layer). Namely, polysorbate 80-costabilized nanoemulsion showed increased (1.4-7.4-fold higher) risperidone brain availability compared to other nanoemulsions and drug solution, suggesting this nanoemulsion as a promising carrier worth exploring further for brain targeting.",
publisher = "Elsevier Science BV, Amsterdam",
journal = "International Journal of Pharmaceutics",
title = "Parenteral nanoemulsions as promising carriers for brain delivery of risperidone: Design, characterization and in vivo pharmacokinetic evaluation",
volume = "493",
number = "1-2",
pages = "40-54",
doi = "10.1016/j.ijpharm.2015.07.007"
}

Đorđević, S., Cekić, N., Savić, M., Isailović, T., Ranđelović, D., Marković, B., Savić, S. R., Timić-Stamenić, T., Daniels, R.,& Savić, S.. (2015). Parenteral nanoemulsions as promising carriers for brain delivery of risperidone: Design, characterization and in vivo pharmacokinetic evaluation. in International Journal of Pharmaceutics
Elsevier Science BV, Amsterdam., 493(1-2), 40-54.
https://doi.org/10.1016/j.ijpharm.2015.07.007

Đorđević S, Cekić N, Savić M, Isailović T, Ranđelović D, Marković B, Savić SR, Timić-Stamenić T, Daniels R, Savić S. Parenteral nanoemulsions as promising carriers for brain delivery of risperidone: Design, characterization and in vivo pharmacokinetic evaluation. in International Journal of Pharmaceutics. 2015;493(1-2):40-54.
doi:10.1016/j.ijpharm.2015.07.007 .

Đorđević, Sanela, Cekić, Nebojša, Savić, Miroslav, Isailović, Tanja, Ranđelović, Danijela, Marković, Bojan, Savić, Saša R., Timić-Stamenić, Tamara, Daniels, Rolf, Savić, Snežana, "Parenteral nanoemulsions as promising carriers for brain delivery of risperidone: Design, characterization and in vivo pharmacokinetic evaluation" in International Journal of Pharmaceutics, 493, no. 1-2 (2015):40-54,
https://doi.org/10.1016/j.ijpharm.2015.07.007 . .

TY  - JOUR
AU  - Timić-Stamenić, Tamara
AU  - Joksimović, Srđan
AU  - Biawat, Poonam
AU  - Stanković, Tamara
AU  - Marković, Bojan
AU  - Cook, James M.
AU  - Savić, Miroslav
PY  - 2015
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2314
AB  - Reportedly, negative modulation of alpha(5) GABA(A) receptors may improve cognition in normal and pharmacologically-impaired animals, and such modulation has been proposed as an avenue for treatment of cognitive symptoms in schizophrenia. This study assessed the actions of PWZ-029, administered at doses (2, 5, and 10 mg/kg) at which it reached micromolar concentrations in brain tissue with estimated free concentrations adequate for selective modulation of alpha(5) GABA(A) receptors, in three cognitive tasks in male Wistar rats acutely treated with the noncompetitive N-methyl-D-aspartate receptor antagonist, MK-801 (0.1 mg/kg), as well in tests of locomotor activity potentiated by MK-801 (0.2 mg/kg) or amphetamine (0.5 mg/kg). In a hormetic-like manner, only 5 mg/kg PWZ-029 reversed MK-801-induced deficits in novel object recognition test (visual recognition memory), whereas in the Morris water maze, the 2 mg/kg dose of PWZ-029 exerted partial beneficial effects on spatial learning impairment. PWZ-029 did not affect recognition memory deficits in social novelty discrimination procedure. Motor hyperactivity induced with MK-801 or amphetamine was not preventable by PWZ-029. Our results show that certain MK-801-induced memory deficits can be ameliorated by negative modulation of alpha(5) GABA(A) receptors, and point to the need for further elucidation of their translational relevance to cognitive deterioration in schizophrenia.
PB  - Sage Publications Ltd, London
T2  - Journal of Psychopharmacology
T1  - Negative modulation of alpha(5) GABA(A) receptors in rats may partially prevent memory impairment induced by MK-801, but not amphetamine- or MK-801-elicited hyperlocomotion
VL  - 29
IS  - 9
SP  - 1013
EP  - 1024
DO  - 10.1177/0269881115590601
ER  - 

@article{
author = "Timić-Stamenić, Tamara and Joksimović, Srđan and Biawat, Poonam and Stanković, Tamara and Marković, Bojan and Cook, James M. and Savić, Miroslav",
year = "2015",
abstract = "Reportedly, negative modulation of alpha(5) GABA(A) receptors may improve cognition in normal and pharmacologically-impaired animals, and such modulation has been proposed as an avenue for treatment of cognitive symptoms in schizophrenia. This study assessed the actions of PWZ-029, administered at doses (2, 5, and 10 mg/kg) at which it reached micromolar concentrations in brain tissue with estimated free concentrations adequate for selective modulation of alpha(5) GABA(A) receptors, in three cognitive tasks in male Wistar rats acutely treated with the noncompetitive N-methyl-D-aspartate receptor antagonist, MK-801 (0.1 mg/kg), as well in tests of locomotor activity potentiated by MK-801 (0.2 mg/kg) or amphetamine (0.5 mg/kg). In a hormetic-like manner, only 5 mg/kg PWZ-029 reversed MK-801-induced deficits in novel object recognition test (visual recognition memory), whereas in the Morris water maze, the 2 mg/kg dose of PWZ-029 exerted partial beneficial effects on spatial learning impairment. PWZ-029 did not affect recognition memory deficits in social novelty discrimination procedure. Motor hyperactivity induced with MK-801 or amphetamine was not preventable by PWZ-029. Our results show that certain MK-801-induced memory deficits can be ameliorated by negative modulation of alpha(5) GABA(A) receptors, and point to the need for further elucidation of their translational relevance to cognitive deterioration in schizophrenia.",
publisher = "Sage Publications Ltd, London",
journal = "Journal of Psychopharmacology",
title = "Negative modulation of alpha(5) GABA(A) receptors in rats may partially prevent memory impairment induced by MK-801, but not amphetamine- or MK-801-elicited hyperlocomotion",
volume = "29",
number = "9",
pages = "1013-1024",
doi = "10.1177/0269881115590601"
}

Timić-Stamenić, T., Joksimović, S., Biawat, P., Stanković, T., Marković, B., Cook, J. M.,& Savić, M.. (2015). Negative modulation of alpha(5) GABA(A) receptors in rats may partially prevent memory impairment induced by MK-801, but not amphetamine- or MK-801-elicited hyperlocomotion. in Journal of Psychopharmacology
Sage Publications Ltd, London., 29(9), 1013-1024.
https://doi.org/10.1177/0269881115590601

Timić-Stamenić T, Joksimović S, Biawat P, Stanković T, Marković B, Cook JM, Savić M. Negative modulation of alpha(5) GABA(A) receptors in rats may partially prevent memory impairment induced by MK-801, but not amphetamine- or MK-801-elicited hyperlocomotion. in Journal of Psychopharmacology. 2015;29(9):1013-1024.
doi:10.1177/0269881115590601 .

Timić-Stamenić, Tamara, Joksimović, Srđan, Biawat, Poonam, Stanković, Tamara, Marković, Bojan, Cook, James M., Savić, Miroslav, "Negative modulation of alpha(5) GABA(A) receptors in rats may partially prevent memory impairment induced by MK-801, but not amphetamine- or MK-801-elicited hyperlocomotion" in Journal of Psychopharmacology, 29, no. 9 (2015):1013-1024,
https://doi.org/10.1177/0269881115590601 . .

TY  - CONF
AU  - Timić-Stamenić, Tamara
AU  - Joksimović, Srđan
AU  - Milić, Marija
AU  - Batinić, Bojan
AU  - Poe, Michael M.
AU  - Cook, James M.
AU  - Savić, Miroslav
PY  - 2014
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2106
PB  - Elsevier Science BV, Amsterdam
C3  - European Neuropsychopharmacology
T1  - Positive modulation at alpha(5)GABA(A) receptors is not beneficial for cognitive deficits induced by MK-801 in water maze in rats
VL  - 24
IS  - Supplement 2
SP  - S325
EP  - S325
DO  - 10.1016/S0924-977X(14)70516-4
ER  - 

@conference{
author = "Timić-Stamenić, Tamara and Joksimović, Srđan and Milić, Marija and Batinić, Bojan and Poe, Michael M. and Cook, James M. and Savić, Miroslav",
year = "2014",
publisher = "Elsevier Science BV, Amsterdam",
journal = "European Neuropsychopharmacology",
title = "Positive modulation at alpha(5)GABA(A) receptors is not beneficial for cognitive deficits induced by MK-801 in water maze in rats",
volume = "24",
number = "Supplement 2",
pages = "S325-S325",
doi = "10.1016/S0924-977X(14)70516-4"
}

Timić-Stamenić, T., Joksimović, S., Milić, M., Batinić, B., Poe, M. M., Cook, J. M.,& Savić, M.. (2014). Positive modulation at alpha(5)GABA(A) receptors is not beneficial for cognitive deficits induced by MK-801 in water maze in rats. in European Neuropsychopharmacology
Elsevier Science BV, Amsterdam., 24(Supplement 2), S325-S325.
https://doi.org/10.1016/S0924-977X(14)70516-4

Timić-Stamenić T, Joksimović S, Milić M, Batinić B, Poe MM, Cook JM, Savić M. Positive modulation at alpha(5)GABA(A) receptors is not beneficial for cognitive deficits induced by MK-801 in water maze in rats. in European Neuropsychopharmacology. 2014;24(Supplement 2):S325-S325.
doi:10.1016/S0924-977X(14)70516-4 .

Timić-Stamenić, Tamara, Joksimović, Srđan, Milić, Marija, Batinić, Bojan, Poe, Michael M., Cook, James M., Savić, Miroslav, "Positive modulation at alpha(5)GABA(A) receptors is not beneficial for cognitive deficits induced by MK-801 in water maze in rats" in European Neuropsychopharmacology, 24, no. Supplement 2 (2014):S325-S325,
https://doi.org/10.1016/S0924-977X(14)70516-4 . .

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  - Michael, Poe M.
AU  - Timić, Tamara
AU  - James, Cook M.
AU  - Savić, Miroslav
PY  - 2014
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2284
AB  - The complex clinical picture of mono-neuropathy following injury of peripheral nerve is often accompanied by changes in the patients' affective states. It has been shown that positive allosteric modulators of GABAA receptors can decrease nociceptive transmission in animal pain models. However, recent findings suggest a possibility that at least some of the antinociceptive effects of benzodiazepines, related to neuropathic painful stimuli, may to a significant degree be a consequence of their anxiolytic action. In this study we evaluated the possible delayed effects of SH-I-048A, a newly- synthesized high-efficacy nonselective positive modulator of GABAA receptors, on anxiety-like behavior and locomotor activity in Wistar rats with a previously induced peripheral nerve injury. Assessment of behavioral parameters, using spontaneous locomotor activity and elevated plus maze tests, was performed 48h after completion of single-day three i.p. injections treatment consisting of zero, one, two or three doses of SH-I-048A (10 mg/kg). In general, rats' behavior observed 72 h after a moderate peripheral nerve injury did not indicate the persistence of sequelae of mono-neuropathic pain. The rats treated with three doses of SH-I-048A displayed an enhanced immobility time in the locomotor activity test, without concomitant decrease of the total distance traveled. On the other hand, in the group treated with two doses of SH-I-048A, a decrease in the emotional reactivity in the elevated plus maze test was observed. Subtle changes in the regimen of dosing of SH-I-048A affect locomotor activity and anxiety-related behavior in animals with peripheral nerve injury.
AB  - Kompleksna klinička slika neuropatije nakon povrede perifernog nerva često je praćena i promenama afektivnog stanja pacijenata. U animalnim modelima bola pokazano je da pozitivni alosterni modulatori GABAA receptora mogu da smanje nociceptivnu transmisiju. Međutim, skorašnji nalazi ukazuju i na mogućnost da je prividni antinociceptivni efekat benzodiazepina nakon delovanja akutnog bolnog stimulusa u značajnoj meri posledica anksiolitičnog efekta. U ovoj studiji ispitani su mogući odloženi efekti novosintetisanog, neselektivnog liganda GABAA receptora (SH-I-048A) na lokomotornu aktivnost i ponašanje u vezi sa anksioznošću kod pacova soja Wistar prethodno podvrgnutih povredi perifernog nerva. Procena bihejvioralnih parametara sprovedena je testovima spontane lokomotorne aktivnosti i uzdignutog plus lavirinta 48 sati nakon što su životinje u periodu od 24 sata primile rastvarač, jednu, dve ili tri doze SH-I-048A (10 mg/kg). Generalno, ponašanje pacova praćeno 72 sata nakon umerene povrede perifernog nerva nije ukazivalo na prisustvo perzistentnih posledica neuropatskog bola. Pacovi prethodno tretirani sa tri doze SH-I-048A ispoljili su povećano vreme imobilnosti u testu lokomotorne aktivnosti, bez značajnog smanjenja ukupnog pređenog puta. S druge strane, u grupi koja je tretirana sa dve doze SH-I-048A zapažena je smanjena emocionalna reaktivnost u uzdignutom plus lavirintu. Kod životinja sa povredom perifernog nerva, suptilne razlike u režimu doziranja pozitivnog modulatora GABAA, mogu značajno da utiču na ponašanje vezano za lomotornu aktivnost i nivo anksioznosti.
PB  - Univerzitet u Beogradu - Fakultet veterinarske medicine, Beograd
T2  - Acta veterinaria
T1  - Delayed behavioral effects of SH-I-048A, a novel nonselective positive modulator of GABAA receptors, after peripheral nerve injury in rats
T1  - Odloženi bihejvioralni efekti SH-I-048A, novog neselektivnog pozitivnog modulatora GABAA receptora, nakon povrede perifernog nerva pacova
VL  - 64
IS  - 2
SP  - 189
EP  - 199
DO  - 10.2478/acve-2014-0018
ER  - 

@article{
author = "Obradović, Aleksandar and Joksimović, Srđan and Michael, Poe M. and Timić, Tamara and James, Cook M. and Savić, Miroslav",
year = "2014",
abstract = "The complex clinical picture of mono-neuropathy following injury of peripheral nerve is often accompanied by changes in the patients' affective states. It has been shown that positive allosteric modulators of GABAA receptors can decrease nociceptive transmission in animal pain models. However, recent findings suggest a possibility that at least some of the antinociceptive effects of benzodiazepines, related to neuropathic painful stimuli, may to a significant degree be a consequence of their anxiolytic action. In this study we evaluated the possible delayed effects of SH-I-048A, a newly- synthesized high-efficacy nonselective positive modulator of GABAA receptors, on anxiety-like behavior and locomotor activity in Wistar rats with a previously induced peripheral nerve injury. Assessment of behavioral parameters, using spontaneous locomotor activity and elevated plus maze tests, was performed 48h after completion of single-day three i.p. injections treatment consisting of zero, one, two or three doses of SH-I-048A (10 mg/kg). In general, rats' behavior observed 72 h after a moderate peripheral nerve injury did not indicate the persistence of sequelae of mono-neuropathic pain. The rats treated with three doses of SH-I-048A displayed an enhanced immobility time in the locomotor activity test, without concomitant decrease of the total distance traveled. On the other hand, in the group treated with two doses of SH-I-048A, a decrease in the emotional reactivity in the elevated plus maze test was observed. Subtle changes in the regimen of dosing of SH-I-048A affect locomotor activity and anxiety-related behavior in animals with peripheral nerve injury., Kompleksna klinička slika neuropatije nakon povrede perifernog nerva često je praćena i promenama afektivnog stanja pacijenata. U animalnim modelima bola pokazano je da pozitivni alosterni modulatori GABAA receptora mogu da smanje nociceptivnu transmisiju. Međutim, skorašnji nalazi ukazuju i na mogućnost da je prividni antinociceptivni efekat benzodiazepina nakon delovanja akutnog bolnog stimulusa u značajnoj meri posledica anksiolitičnog efekta. U ovoj studiji ispitani su mogući odloženi efekti novosintetisanog, neselektivnog liganda GABAA receptora (SH-I-048A) na lokomotornu aktivnost i ponašanje u vezi sa anksioznošću kod pacova soja Wistar prethodno podvrgnutih povredi perifernog nerva. Procena bihejvioralnih parametara sprovedena je testovima spontane lokomotorne aktivnosti i uzdignutog plus lavirinta 48 sati nakon što su životinje u periodu od 24 sata primile rastvarač, jednu, dve ili tri doze SH-I-048A (10 mg/kg). Generalno, ponašanje pacova praćeno 72 sata nakon umerene povrede perifernog nerva nije ukazivalo na prisustvo perzistentnih posledica neuropatskog bola. Pacovi prethodno tretirani sa tri doze SH-I-048A ispoljili su povećano vreme imobilnosti u testu lokomotorne aktivnosti, bez značajnog smanjenja ukupnog pređenog puta. S druge strane, u grupi koja je tretirana sa dve doze SH-I-048A zapažena je smanjena emocionalna reaktivnost u uzdignutom plus lavirintu. Kod životinja sa povredom perifernog nerva, suptilne razlike u režimu doziranja pozitivnog modulatora GABAA, mogu značajno da utiču na ponašanje vezano za lomotornu aktivnost i nivo anksioznosti.",
publisher = "Univerzitet u Beogradu - Fakultet veterinarske medicine, Beograd",
journal = "Acta veterinaria",
title = "Delayed behavioral effects of SH-I-048A, a novel nonselective positive modulator of GABAA receptors, after peripheral nerve injury in rats, Odloženi bihejvioralni efekti SH-I-048A, novog neselektivnog pozitivnog modulatora GABAA receptora, nakon povrede perifernog nerva pacova",
volume = "64",
number = "2",
pages = "189-199",
doi = "10.2478/acve-2014-0018"
}

Obradović, A., Joksimović, S., Michael, P. M., Timić, T., James, C. M.,& Savić, M.. (2014). Delayed behavioral effects of SH-I-048A, a novel nonselective positive modulator of GABAA receptors, after peripheral nerve injury in rats. in Acta veterinaria
Univerzitet u Beogradu - Fakultet veterinarske medicine, Beograd., 64(2), 189-199.
https://doi.org/10.2478/acve-2014-0018

Obradović A, Joksimović S, Michael PM, Timić T, James CM, Savić M. Delayed behavioral effects of SH-I-048A, a novel nonselective positive modulator of GABAA receptors, after peripheral nerve injury in rats. in Acta veterinaria. 2014;64(2):189-199.
doi:10.2478/acve-2014-0018 .

Obradović, Aleksandar, Joksimović, Srđan, Michael, Poe M., Timić, Tamara, James, Cook M., Savić, Miroslav, "Delayed behavioral effects of SH-I-048A, a novel nonselective positive modulator of GABAA receptors, after peripheral nerve injury in rats" in Acta veterinaria, 64, no. 2 (2014):189-199,
https://doi.org/10.2478/acve-2014-0018 . .

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 . .

TY  - CONF
AU  - Joksimović, Srđan
AU  - Obradović, Aleksandar
AU  - Timić, Tamara
AU  - Radulović, Tamara
AU  - Biawat, Poonam
AU  - Kovacević, Jovana
AU  - Milić, Marija
AU  - Batinić, Bojan
AU  - Cook, James M.
AU  - Savić, Miroslav
PY  - 2013
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/1888
PB  - Elsevier Science BV, Amsterdam
C3  - European Neuropsychopharmacology
T1  - PWZ-029 alleviates MK-801-induced memory deficits in the rat: implications for the treatment of cognitive impairment in schizophrenia
VL  - 23
IS  - Supplement 2
SP  - S260
EP  - S260
DO  - 10.1016/S0924-977X(13)70406-1
ER  - 

@conference{
author = "Joksimović, Srđan and Obradović, Aleksandar and Timić, Tamara and Radulović, Tamara and Biawat, Poonam and Kovacević, Jovana and Milić, Marija and Batinić, Bojan and Cook, James M. and Savić, Miroslav",
year = "2013",
publisher = "Elsevier Science BV, Amsterdam",
journal = "European Neuropsychopharmacology",
title = "PWZ-029 alleviates MK-801-induced memory deficits in the rat: implications for the treatment of cognitive impairment in schizophrenia",
volume = "23",
number = "Supplement 2",
pages = "S260-S260",
doi = "10.1016/S0924-977X(13)70406-1"
}

Joksimović, S., Obradović, A., Timić, T., Radulović, T., Biawat, P., Kovacević, J., Milić, M., Batinić, B., Cook, J. M.,& Savić, M.. (2013). PWZ-029 alleviates MK-801-induced memory deficits in the rat: implications for the treatment of cognitive impairment in schizophrenia. in European Neuropsychopharmacology
Elsevier Science BV, Amsterdam., 23(Supplement 2), S260-S260.
https://doi.org/10.1016/S0924-977X(13)70406-1

Joksimović S, Obradović A, Timić T, Radulović T, Biawat P, Kovacević J, Milić M, Batinić B, Cook JM, Savić M. PWZ-029 alleviates MK-801-induced memory deficits in the rat: implications for the treatment of cognitive impairment in schizophrenia. in European Neuropsychopharmacology. 2013;23(Supplement 2):S260-S260.
doi:10.1016/S0924-977X(13)70406-1 .

Joksimović, Srđan, Obradović, Aleksandar, Timić, Tamara, Radulović, Tamara, Biawat, Poonam, Kovacević, Jovana, Milić, Marija, Batinić, Bojan, Cook, James M., Savić, Miroslav, "PWZ-029 alleviates MK-801-induced memory deficits in the rat: implications for the treatment of cognitive impairment in schizophrenia" in European Neuropsychopharmacology, 23, no. Supplement 2 (2013):S260-S260,
https://doi.org/10.1016/S0924-977X(13)70406-1 . .

TY  - CONF
AU  - Timić, Tamara
AU  - Joksimović, Srđan
AU  - Obradović, Aleksandar
AU  - Poe, Michael M.
AU  - Biawat, Poonam
AU  - Ramerstorfer, Joachim
AU  - Roth, Brian L.
AU  - Sieghart, Werner
AU  - Cook, James M.
AU  - Savić, Miroslav
PY  - 2013
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/1887
PB  - Elsevier Science BV, Amsterdam
C3  - European Neuropsychopharmacology
T1  - MK-801-induced hyperlocomotion in rats is affected by modulation of alpha(5)-containing GABA(A) receptors
VL  - 23
IS  - Supplement 2
SP  - S259
EP  - S260
DO  - 10.1016/S0924-977X(13)70405-X
ER  - 

@conference{
author = "Timić, Tamara and Joksimović, Srđan and Obradović, Aleksandar and Poe, Michael M. and Biawat, Poonam and Ramerstorfer, Joachim and Roth, Brian L. and Sieghart, Werner and Cook, James M. and Savić, Miroslav",
year = "2013",
publisher = "Elsevier Science BV, Amsterdam",
journal = "European Neuropsychopharmacology",
title = "MK-801-induced hyperlocomotion in rats is affected by modulation of alpha(5)-containing GABA(A) receptors",
volume = "23",
number = "Supplement 2",
pages = "S259-S260",
doi = "10.1016/S0924-977X(13)70405-X"
}

Timić, T., Joksimović, S., Obradović, A., Poe, M. M., Biawat, P., Ramerstorfer, J., Roth, B. L., Sieghart, W., Cook, J. M.,& Savić, M.. (2013). MK-801-induced hyperlocomotion in rats is affected by modulation of alpha(5)-containing GABA(A) receptors. in European Neuropsychopharmacology
Elsevier Science BV, Amsterdam., 23(Supplement 2), S259-S260.
https://doi.org/10.1016/S0924-977X(13)70405-X

Timić T, Joksimović S, Obradović A, Poe MM, Biawat P, Ramerstorfer J, Roth BL, Sieghart W, Cook JM, Savić M. MK-801-induced hyperlocomotion in rats is affected by modulation of alpha(5)-containing GABA(A) receptors. in European Neuropsychopharmacology. 2013;23(Supplement 2):S259-S260.
doi:10.1016/S0924-977X(13)70405-X .

Timić, Tamara, Joksimović, Srđan, Obradović, Aleksandar, Poe, Michael M., Biawat, Poonam, Ramerstorfer, Joachim, Roth, Brian L., Sieghart, Werner, Cook, James M., Savić, Miroslav, "MK-801-induced hyperlocomotion in rats is affected by modulation of alpha(5)-containing GABA(A) receptors" in European Neuropsychopharmacology, 23, no. Supplement 2 (2013):S259-S260,
https://doi.org/10.1016/S0924-977X(13)70405-X . .

TY  - JOUR
AU  - Joksimović, Srđan
AU  - Divljaković, Jovana
AU  - van Linn, Michael
AU  - Varagić, Zdravko
AU  - Brajković, Gordana
AU  - Milinković, Marija M.
AU  - Yin, Wenyuan
AU  - Timić, Tamara
AU  - Sieghart, Werner
AU  - Cook, James M.
AU  - Savić, Miroslav
PY  - 2013
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2028
AB  - 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 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 α 1 -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 α 1 subtype-selective antagonist and a partial agonist on the effects of DZP on the water-maze acquisition.
T2  - European Neuropsychopharmacology
T1  - Benzodiazepine-induced spatial learning deficits in rats are regulated by the degree of modulation of α 1 GABA A receptors
VL  - 23
IS  - 5
SP  - 390
EP  - 399
DO  - 10.1016/j.euroneuro.2012.05.003
ER  - 

@article{
author = "Joksimović, Srđan and Divljaković, Jovana and van Linn, Michael and Varagić, Zdravko and Brajković, Gordana and Milinković, Marija M. and Yin, Wenyuan and Timić, Tamara and Sieghart, Werner and Cook, James M. and Savić, Miroslav",
year = "2013",
abstract = "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 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 α 1 -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 α 1 subtype-selective antagonist and a partial agonist on the effects of DZP on the water-maze acquisition.",
journal = "European Neuropsychopharmacology",
title = "Benzodiazepine-induced spatial learning deficits in rats are regulated by the degree of modulation of α 1 GABA A receptors",
volume = "23",
number = "5",
pages = "390-399",
doi = "10.1016/j.euroneuro.2012.05.003"
}

Joksimović, S., Divljaković, J., van Linn, M., Varagić, Z., Brajković, G., Milinković, M. M., Yin, W., Timić, T., Sieghart, W., Cook, J. M.,& Savić, M.. (2013). Benzodiazepine-induced spatial learning deficits in rats are regulated by the degree of modulation of α 1 GABA A receptors. in European Neuropsychopharmacology, 23(5), 390-399.
https://doi.org/10.1016/j.euroneuro.2012.05.003

Joksimović S, Divljaković J, van Linn M, Varagić Z, Brajković G, Milinković MM, Yin W, Timić T, Sieghart W, Cook JM, Savić M. Benzodiazepine-induced spatial learning deficits in rats are regulated by the degree of modulation of α 1 GABA A receptors. in European Neuropsychopharmacology. 2013;23(5):390-399.
doi:10.1016/j.euroneuro.2012.05.003 .

Joksimović, Srđan, Divljaković, Jovana, van Linn, Michael, Varagić, Zdravko, Brajković, Gordana, Milinković, Marija M., Yin, Wenyuan, Timić, Tamara, Sieghart, Werner, Cook, James M., Savić, Miroslav, "Benzodiazepine-induced spatial learning deficits in rats are regulated by the degree of modulation of α 1 GABA A receptors" in European Neuropsychopharmacology, 23, no. 5 (2013):390-399,
https://doi.org/10.1016/j.euroneuro.2012.05.003 . .

TY  - JOUR
AU  - Milić, Marija
AU  - Timić, Tamara
AU  - Joksimović, Srđan
AU  - Biawat, Poonam
AU  - Rallapalli, Sundari
AU  - Divljaković, Jovana
AU  - Radulović, Tamara
AU  - Cook, James M.
AU  - Savić, Miroslav
PY  - 2013
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/1926
AB  - Inverse agonism at the benzodiazepine site of alpha(5) subunit-containing GABA(A) receptors is an attractive approach for the development of putative cognition-enhancing compounds, which are still far from clinical application. Several ligands with binding and/or functional selectivity for alpha(5) GABA(A) receptors have been synthesized and tested in a few animal models. PWZ-029 is an alpha(5) GABA(A) selective inverse agonist whose memory enhancing effects were demonstrated in the passive avoidance task in rats and in Pavlovian fear conditioning in mice. In the present study we investigated the effects of PWZ-029 administration in novel object recognition test and Morris water maze, in normal and scopolamine-treated rats. All the three doses of PWZ-029 (2,5 and 10 mg/kg) improved object recognition after the 24-h delay period, as shown by significant differences between the exploration times of the novel and old object, and the respective discrimination indices. PWZ-029 (2 mg/kg) also successfully reversed the 0.3 mg/kg scopolamine-induced deficit in recognition memory after the 1-h delay. In the Morris water maze test, PWZ-029 (5,10 and 15 mg/kg) did not significantly influence swim patterns, either during five acquisition days or during the treatment-free probe trial. PWZ-029 (2, 5 and 10 mg/kg) also proved to be ineffective in the reversal of the 1 mg/kg scopolamine-induced memory impairment in the water maze. The present mixed results encourage use of a variety of tests and experimental conditions in order to increase the predictability of preclinical testing of selective as GABA(A) inverse agonists.
PB  - Elsevier Science BV, Amsterdam
T2  - Behavioural Brain Research
T1  - PWZ-029, an inverse agonist selective for alpha(5) GABA(A) receptors, improves object recognition, but not water-maze memory in normal and scopolamine-treated rats
VL  - 241
SP  - 206
EP  - 213
DO  - 10.1016/j.bbr.2012.12.016
ER  - 

@article{
author = "Milić, Marija and Timić, Tamara and Joksimović, Srđan and Biawat, Poonam and Rallapalli, Sundari and Divljaković, Jovana and Radulović, Tamara and Cook, James M. and Savić, Miroslav",
year = "2013",
abstract = "Inverse agonism at the benzodiazepine site of alpha(5) subunit-containing GABA(A) receptors is an attractive approach for the development of putative cognition-enhancing compounds, which are still far from clinical application. Several ligands with binding and/or functional selectivity for alpha(5) GABA(A) receptors have been synthesized and tested in a few animal models. PWZ-029 is an alpha(5) GABA(A) selective inverse agonist whose memory enhancing effects were demonstrated in the passive avoidance task in rats and in Pavlovian fear conditioning in mice. In the present study we investigated the effects of PWZ-029 administration in novel object recognition test and Morris water maze, in normal and scopolamine-treated rats. All the three doses of PWZ-029 (2,5 and 10 mg/kg) improved object recognition after the 24-h delay period, as shown by significant differences between the exploration times of the novel and old object, and the respective discrimination indices. PWZ-029 (2 mg/kg) also successfully reversed the 0.3 mg/kg scopolamine-induced deficit in recognition memory after the 1-h delay. In the Morris water maze test, PWZ-029 (5,10 and 15 mg/kg) did not significantly influence swim patterns, either during five acquisition days or during the treatment-free probe trial. PWZ-029 (2, 5 and 10 mg/kg) also proved to be ineffective in the reversal of the 1 mg/kg scopolamine-induced memory impairment in the water maze. The present mixed results encourage use of a variety of tests and experimental conditions in order to increase the predictability of preclinical testing of selective as GABA(A) inverse agonists.",
publisher = "Elsevier Science BV, Amsterdam",
journal = "Behavioural Brain Research",
title = "PWZ-029, an inverse agonist selective for alpha(5) GABA(A) receptors, improves object recognition, but not water-maze memory in normal and scopolamine-treated rats",
volume = "241",
pages = "206-213",
doi = "10.1016/j.bbr.2012.12.016"
}

Milić, M., Timić, T., Joksimović, S., Biawat, P., Rallapalli, S., Divljaković, J., Radulović, T., Cook, J. M.,& Savić, M.. (2013). PWZ-029, an inverse agonist selective for alpha(5) GABA(A) receptors, improves object recognition, but not water-maze memory in normal and scopolamine-treated rats. in Behavioural Brain Research
Elsevier Science BV, Amsterdam., 241, 206-213.
https://doi.org/10.1016/j.bbr.2012.12.016

Milić M, Timić T, Joksimović S, Biawat P, Rallapalli S, Divljaković J, Radulović T, Cook JM, Savić M. PWZ-029, an inverse agonist selective for alpha(5) GABA(A) receptors, improves object recognition, but not water-maze memory in normal and scopolamine-treated rats. in Behavioural Brain Research. 2013;241:206-213.
doi:10.1016/j.bbr.2012.12.016 .

Milić, Marija, Timić, Tamara, Joksimović, Srđan, Biawat, Poonam, Rallapalli, Sundari, Divljaković, Jovana, Radulović, Tamara, Cook, James M., Savić, Miroslav, "PWZ-029, an inverse agonist selective for alpha(5) GABA(A) receptors, improves object recognition, but not water-maze memory in normal and scopolamine-treated rats" in Behavioural Brain Research, 241 (2013):206-213,
https://doi.org/10.1016/j.bbr.2012.12.016 . .

TY  - JOUR
AU  - Joksimović, Srđan
AU  - Varagić, Zdravko
AU  - Kovacević, Jovana
AU  - van Linn, Michael
AU  - Milić, Marija
AU  - Rallapalli, Sundari
AU  - Timić, Tamara
AU  - Sieghart, Werner
AU  - Cook, James M.
AU  - Savić, Miroslav
PY  - 2013
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/1839
AB  - Synthesis of ligands inactive or with low activity at alpha(1) GABA(A) receptors has become the key concept for development of novel, more tolerable benzodiazepine (BZ)-like drugs. WYS8, a remarkably (105 times) alpha(1)-subtype selective partial positive modulator, may serve as a pharmacological tool for refining the role of alpha(1) GABA(A) receptors in mediation of BZs' effects. Here, the effects of WYS8 on GABA-induced currents and on diazepam-induced potentiation of recombinant BZ-sensitive GABA(A) receptors were studied in more detail. In addition, the behavioral profile of WYS8 (0.2, 1, and 10 mg/kg i.p.), on its own and in combination with diazepam, was tested in the spontaneous locomotor activity, elevated plus maze, grip strength, rotarod, and pentylenetetrazole tests. WYS8, applied at an in vivo attainable concentration of 100 nM, reduced the stimulation of GABA currents by 1 mu M diazepam by 57 % at alpha(1)beta(3)gamma(2), but not at alpha(2)beta(3)gamma(2), alpha(3)beta(3)gamma(2), or alpha(5)beta(3)gamma(2) GABA(A) receptors. The administration of WYS8 alone induced negligible behavioral consequences. When combined with diazepam, WYS8 caused a reduction in sedation, muscle relaxation, and anticonvulsant activity, as compared with this BZ alone, whereas ataxia was preserved, and the anxiolytic effect of 2 mg/kg diazepam was unmasked. Hence, a partial instead of full activation at alpha(1) GABA(A) receptors did not necessarily result in the attenuation of the effects assumed to be mediated by activation of these receptors, or in the full preservation of the effects mediated by activation of other GABA(A) receptors. Thus, the role of alpha(1) GABA(A) receptors appears more complex than that proposed by genetic studies.
PB  - Springer, New York
T2  - QSAR & Combinatorial Science
T1  - Insights into functional pharmacology of alpha(1) GABA(A) receptors: how much does partial activation at the benzodiazepine site matter?
VL  - 230
IS  - 1
SP  - 113
EP  - 123
DO  - 10.1007/s00213-013-3143-4
ER  - 

@article{
author = "Joksimović, Srđan and Varagić, Zdravko and Kovacević, Jovana and van Linn, Michael and Milić, Marija and Rallapalli, Sundari and Timić, Tamara and Sieghart, Werner and Cook, James M. and Savić, Miroslav",
year = "2013",
abstract = "Synthesis of ligands inactive or with low activity at alpha(1) GABA(A) receptors has become the key concept for development of novel, more tolerable benzodiazepine (BZ)-like drugs. WYS8, a remarkably (105 times) alpha(1)-subtype selective partial positive modulator, may serve as a pharmacological tool for refining the role of alpha(1) GABA(A) receptors in mediation of BZs' effects. Here, the effects of WYS8 on GABA-induced currents and on diazepam-induced potentiation of recombinant BZ-sensitive GABA(A) receptors were studied in more detail. In addition, the behavioral profile of WYS8 (0.2, 1, and 10 mg/kg i.p.), on its own and in combination with diazepam, was tested in the spontaneous locomotor activity, elevated plus maze, grip strength, rotarod, and pentylenetetrazole tests. WYS8, applied at an in vivo attainable concentration of 100 nM, reduced the stimulation of GABA currents by 1 mu M diazepam by 57 % at alpha(1)beta(3)gamma(2), but not at alpha(2)beta(3)gamma(2), alpha(3)beta(3)gamma(2), or alpha(5)beta(3)gamma(2) GABA(A) receptors. The administration of WYS8 alone induced negligible behavioral consequences. When combined with diazepam, WYS8 caused a reduction in sedation, muscle relaxation, and anticonvulsant activity, as compared with this BZ alone, whereas ataxia was preserved, and the anxiolytic effect of 2 mg/kg diazepam was unmasked. Hence, a partial instead of full activation at alpha(1) GABA(A) receptors did not necessarily result in the attenuation of the effects assumed to be mediated by activation of these receptors, or in the full preservation of the effects mediated by activation of other GABA(A) receptors. Thus, the role of alpha(1) GABA(A) receptors appears more complex than that proposed by genetic studies.",
publisher = "Springer, New York",
journal = "QSAR & Combinatorial Science",
title = "Insights into functional pharmacology of alpha(1) GABA(A) receptors: how much does partial activation at the benzodiazepine site matter?",
volume = "230",
number = "1",
pages = "113-123",
doi = "10.1007/s00213-013-3143-4"
}

Joksimović, S., Varagić, Z., Kovacević, J., van Linn, M., Milić, M., Rallapalli, S., Timić, T., Sieghart, W., Cook, J. M.,& Savić, M.. (2013). Insights into functional pharmacology of alpha(1) GABA(A) receptors: how much does partial activation at the benzodiazepine site matter?. in QSAR & Combinatorial Science
Springer, New York., 230(1), 113-123.
https://doi.org/10.1007/s00213-013-3143-4

Joksimović S, Varagić Z, Kovacević J, van Linn M, Milić M, Rallapalli S, Timić T, Sieghart W, Cook JM, Savić M. Insights into functional pharmacology of alpha(1) GABA(A) receptors: how much does partial activation at the benzodiazepine site matter?. in QSAR & Combinatorial Science. 2013;230(1):113-123.
doi:10.1007/s00213-013-3143-4 .

Joksimović, Srđan, Varagić, Zdravko, Kovacević, Jovana, van Linn, Michael, Milić, Marija, Rallapalli, Sundari, Timić, Tamara, Sieghart, Werner, Cook, James M., Savić, Miroslav, "Insights into functional pharmacology of alpha(1) GABA(A) receptors: how much does partial activation at the benzodiazepine site matter?" in QSAR & Combinatorial Science, 230, no. 1 (2013):113-123,
https://doi.org/10.1007/s00213-013-3143-4 . .

TY  - JOUR
AU  - Timić, Tamara
AU  - Joksimović, Srđan
AU  - Milić, Marija
AU  - Divljaković, Jovana
AU  - Batinić, Bojan
AU  - Savić, Miroslav
PY  - 2013
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/1957
AB  - Amnesia is one of the most discussed properties of the benzodiazepine class of drugs. The effects of benzodiazepines on human memory are usually anterograde, while changes in retrograde memory functions were seldom reported. Such inconsistent findings have prompted numerous animal studies investigating the influences of these positive modulators of inhibitory neurotransmission on different stages of memory. Among the benzodiazepines, memory effects of midazolam are of special interest due to its many and varied clinical applications. The present Morris water maze study in adult male Wistar rats was performed in three experiments in which midazolam was administered at doses of 0.5, 1 and 2 mg/kg intraperitoneally, before or immediately after each of five daily learning sessions, with two trials in a session, as well as before the probe test. Midazolam impaired acquisition and subsequent retention of spatial learning of the position of the hidden platform even at a pre-training dose of 0.5 mg/kg. This low dose was not associated with impairment of the procedural component of learning, manifested by increased time spent in the periphery of the pool. The lack of midazolam effect on consolidation has not been confounded by the observed below-chance performance of the control group since our additional experiment using diazepam also administered immediately after each of five learning sessions has revealed a similar pattern of results. Finally, midazolam administered before the probe test impaired retrieval of reference memory at all tested doses. Hence, induction of retrograde, besides anterograde amnesia should be kept in mind as a possibility when midazolam is used in clinical settings.
PB  - Elsevier Science BV, Amsterdam
T2  - Behavioural Brain Research
T1  - Midazolam impairs acquisition and retrieval, but not consolidation of reference memory in the Morris water maze
VL  - 241
SP  - 198
EP  - 205
DO  - 10.1016/j.bbr.2012.12.014
ER  - 

@article{
author = "Timić, Tamara and Joksimović, Srđan and Milić, Marija and Divljaković, Jovana and Batinić, Bojan and Savić, Miroslav",
year = "2013",
abstract = "Amnesia is one of the most discussed properties of the benzodiazepine class of drugs. The effects of benzodiazepines on human memory are usually anterograde, while changes in retrograde memory functions were seldom reported. Such inconsistent findings have prompted numerous animal studies investigating the influences of these positive modulators of inhibitory neurotransmission on different stages of memory. Among the benzodiazepines, memory effects of midazolam are of special interest due to its many and varied clinical applications. The present Morris water maze study in adult male Wistar rats was performed in three experiments in which midazolam was administered at doses of 0.5, 1 and 2 mg/kg intraperitoneally, before or immediately after each of five daily learning sessions, with two trials in a session, as well as before the probe test. Midazolam impaired acquisition and subsequent retention of spatial learning of the position of the hidden platform even at a pre-training dose of 0.5 mg/kg. This low dose was not associated with impairment of the procedural component of learning, manifested by increased time spent in the periphery of the pool. The lack of midazolam effect on consolidation has not been confounded by the observed below-chance performance of the control group since our additional experiment using diazepam also administered immediately after each of five learning sessions has revealed a similar pattern of results. Finally, midazolam administered before the probe test impaired retrieval of reference memory at all tested doses. Hence, induction of retrograde, besides anterograde amnesia should be kept in mind as a possibility when midazolam is used in clinical settings.",
publisher = "Elsevier Science BV, Amsterdam",
journal = "Behavioural Brain Research",
title = "Midazolam impairs acquisition and retrieval, but not consolidation of reference memory in the Morris water maze",
volume = "241",
pages = "198-205",
doi = "10.1016/j.bbr.2012.12.014"
}

Timić, T., Joksimović, S., Milić, M., Divljaković, J., Batinić, B.,& Savić, M.. (2013). Midazolam impairs acquisition and retrieval, but not consolidation of reference memory in the Morris water maze. in Behavioural Brain Research
Elsevier Science BV, Amsterdam., 241, 198-205.
https://doi.org/10.1016/j.bbr.2012.12.014

Timić T, Joksimović S, Milić M, Divljaković J, Batinić B, Savić M. Midazolam impairs acquisition and retrieval, but not consolidation of reference memory in the Morris water maze. in Behavioural Brain Research. 2013;241:198-205.
doi:10.1016/j.bbr.2012.12.014 .

Timić, Tamara, Joksimović, Srđan, Milić, Marija, Divljaković, Jovana, Batinić, Bojan, Savić, Miroslav, "Midazolam impairs acquisition and retrieval, but not consolidation of reference memory in the Morris water maze" in Behavioural Brain Research, 241 (2013):198-205,
https://doi.org/10.1016/j.bbr.2012.12.014 . .

TY  - CONF
AU  - Divljaković, Jovana
AU  - Timić, Tamara
AU  - Milinković, Marija M.
AU  - Batinić, Bojan
AU  - van Linn, Michael
AU  - Cook, James M.
AU  - Savić, Miroslav
PY  - 2012
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/1661
AB  - Objective : Despite a half century of clinical use and the recognized
potential of benzodiazepine dependence, the mechanisms under-
lying benzodiazepine withdrawal remain insufficiently understood.
The aim of the present study was to assess the influence of the non-
selective antagonist (flumazenil) and the preferential a1-subunit
selective antagonist (bCCt) on the anxiety level after diazepam with-
drawal.
Methods : The male Wistar rats were protractedly treated during
21 days with diazepam (2 mg/kg) or solvent. On the testing day,
24 hours after the last injection, animals from the diazepam-treated
groups received either antagonist (flumazenil or bCCt) or solvent, and
animals from the solvent-treated groups received solvent or diaze-
pam. Twenty minutes after administration of treatment on the testing
day, single animals were placed in the elevated plus maze in order to
assess the level of anxiety.
Results : Two-way ANOVA revealed that animals withdrawn from
diazepam spent significantly less time on the open arms than control
animals (p=0.023). One-way ANOVA, followed by post hoc test, re-
vealed that administration of flumazenil (10 mg/kg) or bCCt (1.25,
5 or 20 mg/kg) reversed the diazepam withdrawal-induced anxiety
(percentage of open arm time : p=0.003, p=0.032, p=0.031 and
p=0.014 compared to the diazepam-withdrawn group, respectively).
Concomitant administration of antagonists (10 mg/kg flumazenil,
or 1.25, 5 or 20 mg/kg bCCt) induced an anxiolytic effect comparable
to that observed after acutely administrated diazepam (percentage of
open arm time : p=0.142, p=0.187, p=0.243 and p=0.290, respect-
ively).
Conclusion : The present study demonstrated that administration
of the a1-selective antagonist bCCt or non-selective antagonist
flumazenil could prevent the withdrawal-induced anxiety and also
induce an anxiolytic-like effect. Moreover, presented results have
suggested that mechanism of preventing the withdrawal-induced
anxiety involves the antagonism at a1-containing GABAA receptors.
PB  - Oxford Univ Press, Oxford
C3  - International Journal of Neuropsychopharmacology
T1  - Beta CCT as well as flumazenil prevent the diazepam withdrawal-induced anxiety in the elevated plus maze in rats
VL  - 15
IS  - Supplement 1
SP  - 201
EP  - 201
DO  - 10.1017/S1461145712000508
UR  - https://hdl.handle.net/21.15107/rcub_farfar_1661
ER  - 

@conference{
author = "Divljaković, Jovana and Timić, Tamara and Milinković, Marija M. and Batinić, Bojan and van Linn, Michael and Cook, James M. and Savić, Miroslav",
year = "2012",
abstract = "Objective : Despite a half century of clinical use and the recognized
potential of benzodiazepine dependence, the mechanisms under-
lying benzodiazepine withdrawal remain insufficiently understood.
The aim of the present study was to assess the influence of the non-
selective antagonist (flumazenil) and the preferential a1-subunit
selective antagonist (bCCt) on the anxiety level after diazepam with-
drawal.
Methods : The male Wistar rats were protractedly treated during
21 days with diazepam (2 mg/kg) or solvent. On the testing day,
24 hours after the last injection, animals from the diazepam-treated
groups received either antagonist (flumazenil or bCCt) or solvent, and
animals from the solvent-treated groups received solvent or diaze-
pam. Twenty minutes after administration of treatment on the testing
day, single animals were placed in the elevated plus maze in order to
assess the level of anxiety.
Results : Two-way ANOVA revealed that animals withdrawn from
diazepam spent significantly less time on the open arms than control
animals (p=0.023). One-way ANOVA, followed by post hoc test, re-
vealed that administration of flumazenil (10 mg/kg) or bCCt (1.25,
5 or 20 mg/kg) reversed the diazepam withdrawal-induced anxiety
(percentage of open arm time : p=0.003, p=0.032, p=0.031 and
p=0.014 compared to the diazepam-withdrawn group, respectively).
Concomitant administration of antagonists (10 mg/kg flumazenil,
or 1.25, 5 or 20 mg/kg bCCt) induced an anxiolytic effect comparable
to that observed after acutely administrated diazepam (percentage of
open arm time : p=0.142, p=0.187, p=0.243 and p=0.290, respect-
ively).
Conclusion : The present study demonstrated that administration
of the a1-selective antagonist bCCt or non-selective antagonist
flumazenil could prevent the withdrawal-induced anxiety and also
induce an anxiolytic-like effect. Moreover, presented results have
suggested that mechanism of preventing the withdrawal-induced
anxiety involves the antagonism at a1-containing GABAA receptors.",
publisher = "Oxford Univ Press, Oxford",
journal = "International Journal of Neuropsychopharmacology",
title = "Beta CCT as well as flumazenil prevent the diazepam withdrawal-induced anxiety in the elevated plus maze in rats",
volume = "15",
number = "Supplement 1",
pages = "201-201",
doi = "10.1017/S1461145712000508",
url = "https://hdl.handle.net/21.15107/rcub_farfar_1661"
}

Divljaković, J., Timić, T., Milinković, M. M., Batinić, B., van Linn, M., Cook, J. M.,& Savić, M.. (2012). Beta CCT as well as flumazenil prevent the diazepam withdrawal-induced anxiety in the elevated plus maze in rats. in International Journal of Neuropsychopharmacology
Oxford Univ Press, Oxford., 15(Supplement 1), 201-201.
https://doi.org/10.1017/S1461145712000508
https://hdl.handle.net/21.15107/rcub_farfar_1661

Divljaković J, Timić T, Milinković MM, Batinić B, van Linn M, Cook JM, Savić M. Beta CCT as well as flumazenil prevent the diazepam withdrawal-induced anxiety in the elevated plus maze in rats. in International Journal of Neuropsychopharmacology. 2012;15(Supplement 1):201-201.
doi:10.1017/S1461145712000508
https://hdl.handle.net/21.15107/rcub_farfar_1661 .

Divljaković, Jovana, Timić, Tamara, Milinković, Marija M., Batinić, Bojan, van Linn, Michael, Cook, James M., Savić, Miroslav, "Beta CCT as well as flumazenil prevent the diazepam withdrawal-induced anxiety in the elevated plus maze in rats" in International Journal of Neuropsychopharmacology, 15, no. Supplement 1 (2012):201-201,
https://doi.org/10.1017/S1461145712000508 .,
https://hdl.handle.net/21.15107/rcub_farfar_1661 .

TY  - CONF
AU  - Milinković, Marija M.
AU  - Timić, Tamara
AU  - Divljaković, Jovana
AU  - Joksimović, Srđan
AU  - Rallapalli, Sundari
AU  - Cook, James M.
AU  - Savić, Miroslav
PY  - 2012
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/1660
AB  - Objective : The impairing effects of diazepam in Morris water maze
(MWM) could be partially antagonized with co-administration of an
a5 subunit selective antagonist XLi093 (Savic ́ et al., 2009). In order
to further assess the role of the a5GABAA receptors population
in mediating amnesic effects in rats, the present study examined
effects of an a5GABAA selective agonist XLi356 on the MWM
performance.
Methods : Male Wistar rats were given vehicle or 5, 10 and 20 mg/
kg of XLI356 intraperitoneally 20 minutes before the testing. A single-
day water maze task had three swimming blocks, each consisting of
4 trials, lasting a maximum time of 60 s each. Afterwards, a probe trial
was given and a number of standard parameters was calculated.
Additionally, rats were tested in spontaneous locomotor activity
(SLA) and elevated plus maze (EPM) tests, where the sedative and
anxiolytic effects were assessed.
Results : Results were analyzed using one-way ANOVA with post
hoc Student-Newman-Keuls test where applicable. XLi356 signifi-
cantly increased latency to platform (F(3,444)=3.1287, p=0.026) ; post
hoc test revealed that the dose of 20 mg/kg was significantly different
from vehicle. The same dose of XLi356 significantly increased cumu-
lative distance from the platform zone (p=0.028) and the time spent
in the periphery ring (p=0.009), while the path efficiency was on the
control level. On the other hand, XLi356 did not show behavioral
activity in SLA and EPM tests at either of three doses tested.
Conclusion : The present results suggest that ligands with ap-
preciable agonist activity at GABAA receptors containing a5 subunits
may impair memory acquisition in Morris water maze task, without
discernible effects on general behavior. Thus the activity of the ben-
zodiazepine type drugs at a5GABAA receptors should be decreased if
the amnesic effects are to avoid.
PB  - Oxford Univ Press, Oxford
C3  - International Journal of Neuropsychopharmacology
T1  - The influence of an a5GABAA selective agonist XLi356 on rats' performance in morris water maze
VL  - 15
IS  - Supplement 1
SP  - 231
EP  - 231
DO  - 10.1017/S1461145712000508
UR  - https://hdl.handle.net/21.15107/rcub_farfar_1660
ER  - 

@conference{
author = "Milinković, Marija M. and Timić, Tamara and Divljaković, Jovana and Joksimović, Srđan and Rallapalli, Sundari and Cook, James M. and Savić, Miroslav",
year = "2012",
abstract = "Objective : The impairing effects of diazepam in Morris water maze
(MWM) could be partially antagonized with co-administration of an
a5 subunit selective antagonist XLi093 (Savic ́ et al., 2009). In order
to further assess the role of the a5GABAA receptors population
in mediating amnesic effects in rats, the present study examined
effects of an a5GABAA selective agonist XLi356 on the MWM
performance.
Methods : Male Wistar rats were given vehicle or 5, 10 and 20 mg/
kg of XLI356 intraperitoneally 20 minutes before the testing. A single-
day water maze task had three swimming blocks, each consisting of
4 trials, lasting a maximum time of 60 s each. Afterwards, a probe trial
was given and a number of standard parameters was calculated.
Additionally, rats were tested in spontaneous locomotor activity
(SLA) and elevated plus maze (EPM) tests, where the sedative and
anxiolytic effects were assessed.
Results : Results were analyzed using one-way ANOVA with post
hoc Student-Newman-Keuls test where applicable. XLi356 signifi-
cantly increased latency to platform (F(3,444)=3.1287, p=0.026) ; post
hoc test revealed that the dose of 20 mg/kg was significantly different
from vehicle. The same dose of XLi356 significantly increased cumu-
lative distance from the platform zone (p=0.028) and the time spent
in the periphery ring (p=0.009), while the path efficiency was on the
control level. On the other hand, XLi356 did not show behavioral
activity in SLA and EPM tests at either of three doses tested.
Conclusion : The present results suggest that ligands with ap-
preciable agonist activity at GABAA receptors containing a5 subunits
may impair memory acquisition in Morris water maze task, without
discernible effects on general behavior. Thus the activity of the ben-
zodiazepine type drugs at a5GABAA receptors should be decreased if
the amnesic effects are to avoid.",
publisher = "Oxford Univ Press, Oxford",
journal = "International Journal of Neuropsychopharmacology",
title = "The influence of an a5GABAA selective agonist XLi356 on rats' performance in morris water maze",
volume = "15",
number = "Supplement 1",
pages = "231-231",
doi = "10.1017/S1461145712000508",
url = "https://hdl.handle.net/21.15107/rcub_farfar_1660"
}

Milinković, M. M., Timić, T., Divljaković, J., Joksimović, S., Rallapalli, S., Cook, J. M.,& Savić, M.. (2012). The influence of an a5GABAA selective agonist XLi356 on rats' performance in morris water maze. in International Journal of Neuropsychopharmacology
Oxford Univ Press, Oxford., 15(Supplement 1), 231-231.
https://doi.org/10.1017/S1461145712000508
https://hdl.handle.net/21.15107/rcub_farfar_1660

Milinković MM, Timić T, Divljaković J, Joksimović S, Rallapalli S, Cook JM, Savić M. The influence of an a5GABAA selective agonist XLi356 on rats' performance in morris water maze. in International Journal of Neuropsychopharmacology. 2012;15(Supplement 1):231-231.
doi:10.1017/S1461145712000508
https://hdl.handle.net/21.15107/rcub_farfar_1660 .

Milinković, Marija M., Timić, Tamara, Divljaković, Jovana, Joksimović, Srđan, Rallapalli, Sundari, Cook, James M., Savić, Miroslav, "The influence of an a5GABAA selective agonist XLi356 on rats' performance in morris water maze" in International Journal of Neuropsychopharmacology, 15, no. Supplement 1 (2012):231-231,
https://doi.org/10.1017/S1461145712000508 .,
https://hdl.handle.net/21.15107/rcub_farfar_1660 .

TY  - CONF
AU  - Timić, Tamara
AU  - Divljaković, Jovana
AU  - Milinković, Marija M.
AU  - Rallapalli, Sundari
AU  - Cook, James M.
AU  - Savić, Miroslav
PY  - 2012
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/1685
AB  - Objective : It is well known that benzodiazepine binding site ligands
influence learning and memory and that the a5 subunit is significantly
involved in cognition enhancement mediated by the negative modu-
lation of GABAA receptor function. PWZ-029, a moderately selective
a5GABA A receptor inverse agonist, improved learning in passive but
not in active avoidance test, without effects on anxiety or muscle tone.
The aim of this study was to investigate effects of PWZ-029 and
DMCM, a non-selective inverse agonist, on learning ability and short-
term memory in Morris water-maze (MWM) test.
Methods : MWM test was conducted 20 minutes after in-
traperitoneal administration of treatments (solvent, 5, 15 or 30 mg/kg
PWZ-029 or 2 mg/kg DMCM) to male Wistar rats. The single-day
MWM task consisted of 3 consecutive blocks of 4 trials lasting maxi-
mally 60 s each and a probe trial. During spatial learning the platform
was hidden in the middle of the NE quadrant.
Results : Two-way ANOVA with one repeated measure (block) and
animals nested in treatment has shown that latency to find the plat-
form, path efficiency and total distance travelled were on the control
level for DMCM and all doses of PWZ-029. Factors block and treat-
ment were significant only for latency to first entry to the NE quadrant
[block effect : F(2,386)=10.50, p<0.001, treatment effect : F(4,31)=3.10,
p<0.05]. Tukey’s post-hoc test revealed that animals treated with
DMCM and 5 mg/kg of PWZ-029 had longer latency to first entry
to the target quadrant than those treated with solvent (p=0.001,
p<0.001, respectively). Probe trial performance did not differ signifi-
cantly between treatments.
Conclusion : These results suggest that neither non-selective nor b5
subunit-selective negative modulation of GABA A receptors is suf-
ficient to enhance learning and short-term memory in the single-day
MWM spatial task.
PB  - Oxford Univ Press, Oxford
C3  - International Journal of Neuropsychopharmacology
T1  - Non-selective and a(5) subunit-selective negative modulators of GABA(A) receptors in a single-day morris water maze task in rats
VL  - 15
IS  - Supplement 1
SP  - 231
EP  - 231
DO  - 10.1017/S1461145712000508
UR  - https://hdl.handle.net/21.15107/rcub_farfar_1685
ER  - 

@conference{
author = "Timić, Tamara and Divljaković, Jovana and Milinković, Marija M. and Rallapalli, Sundari and Cook, James M. and Savić, Miroslav",
year = "2012",
abstract = "Objective : It is well known that benzodiazepine binding site ligands
influence learning and memory and that the a5 subunit is significantly
involved in cognition enhancement mediated by the negative modu-
lation of GABAA receptor function. PWZ-029, a moderately selective
a5GABA A receptor inverse agonist, improved learning in passive but
not in active avoidance test, without effects on anxiety or muscle tone.
The aim of this study was to investigate effects of PWZ-029 and
DMCM, a non-selective inverse agonist, on learning ability and short-
term memory in Morris water-maze (MWM) test.
Methods : MWM test was conducted 20 minutes after in-
traperitoneal administration of treatments (solvent, 5, 15 or 30 mg/kg
PWZ-029 or 2 mg/kg DMCM) to male Wistar rats. The single-day
MWM task consisted of 3 consecutive blocks of 4 trials lasting maxi-
mally 60 s each and a probe trial. During spatial learning the platform
was hidden in the middle of the NE quadrant.
Results : Two-way ANOVA with one repeated measure (block) and
animals nested in treatment has shown that latency to find the plat-
form, path efficiency and total distance travelled were on the control
level for DMCM and all doses of PWZ-029. Factors block and treat-
ment were significant only for latency to first entry to the NE quadrant
[block effect : F(2,386)=10.50, p<0.001, treatment effect : F(4,31)=3.10,
p<0.05]. Tukey’s post-hoc test revealed that animals treated with
DMCM and 5 mg/kg of PWZ-029 had longer latency to first entry
to the target quadrant than those treated with solvent (p=0.001,
p<0.001, respectively). Probe trial performance did not differ signifi-
cantly between treatments.
Conclusion : These results suggest that neither non-selective nor b5
subunit-selective negative modulation of GABA A receptors is suf-
ficient to enhance learning and short-term memory in the single-day
MWM spatial task.",
publisher = "Oxford Univ Press, Oxford",
journal = "International Journal of Neuropsychopharmacology",
title = "Non-selective and a(5) subunit-selective negative modulators of GABA(A) receptors in a single-day morris water maze task in rats",
volume = "15",
number = "Supplement 1",
pages = "231-231",
doi = "10.1017/S1461145712000508",
url = "https://hdl.handle.net/21.15107/rcub_farfar_1685"
}

Timić, T., Divljaković, J., Milinković, M. M., Rallapalli, S., Cook, J. M.,& Savić, M.. (2012). Non-selective and a(5) subunit-selective negative modulators of GABA(A) receptors in a single-day morris water maze task in rats. in International Journal of Neuropsychopharmacology
Oxford Univ Press, Oxford., 15(Supplement 1), 231-231.
https://doi.org/10.1017/S1461145712000508
https://hdl.handle.net/21.15107/rcub_farfar_1685

Timić T, Divljaković J, Milinković MM, Rallapalli S, Cook JM, Savić M. Non-selective and a(5) subunit-selective negative modulators of GABA(A) receptors in a single-day morris water maze task in rats. in International Journal of Neuropsychopharmacology. 2012;15(Supplement 1):231-231.
doi:10.1017/S1461145712000508
https://hdl.handle.net/21.15107/rcub_farfar_1685 .

Timić, Tamara, Divljaković, Jovana, Milinković, Marija M., Rallapalli, Sundari, Cook, James M., Savić, Miroslav, "Non-selective and a(5) subunit-selective negative modulators of GABA(A) receptors in a single-day morris water maze task in rats" in International Journal of Neuropsychopharmacology, 15, no. Supplement 1 (2012):231-231,
https://doi.org/10.1017/S1461145712000508 .,
https://hdl.handle.net/21.15107/rcub_farfar_1685 .

TY  - CONF
AU  - Joksimović, Srđan
AU  - Timić, Tamara
AU  - Radulović, Tamara
AU  - Rallapalli, Sundari
AU  - Milinković, Marija M.
AU  - Divljaković, Jovana
AU  - Batinić, Bojan
AU  - Cook, James M.
AU  - Savić, Miroslav
PY  - 2012
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/1673
PB  - Elsevier Science BV, Amsterdam
C3  - European Neuropsychopharmacology
T1  - Effects of PWZ-029, an alpha(5)GABA(A) receptor inverse agonist, on scopolamine-induced spatial learning deficits in the water maze
VL  - 22
IS  - Supplement 2
SP  - S190
EP  - S191
DO  - 10.1016/S0924-977X(12)70274-2
ER  - 

@conference{
author = "Joksimović, Srđan and Timić, Tamara and Radulović, Tamara and Rallapalli, Sundari and Milinković, Marija M. and Divljaković, Jovana and Batinić, Bojan and Cook, James M. and Savić, Miroslav",
year = "2012",
publisher = "Elsevier Science BV, Amsterdam",
journal = "European Neuropsychopharmacology",
title = "Effects of PWZ-029, an alpha(5)GABA(A) receptor inverse agonist, on scopolamine-induced spatial learning deficits in the water maze",
volume = "22",
number = "Supplement 2",
pages = "S190-S191",
doi = "10.1016/S0924-977X(12)70274-2"
}

Joksimović, S., Timić, T., Radulović, T., Rallapalli, S., Milinković, M. M., Divljaković, J., Batinić, B., Cook, J. M.,& Savić, M.. (2012). Effects of PWZ-029, an alpha(5)GABA(A) receptor inverse agonist, on scopolamine-induced spatial learning deficits in the water maze. in European Neuropsychopharmacology
Elsevier Science BV, Amsterdam., 22(Supplement 2), S190-S191.
https://doi.org/10.1016/S0924-977X(12)70274-2

Joksimović S, Timić T, Radulović T, Rallapalli S, Milinković MM, Divljaković J, Batinić B, Cook JM, Savić M. Effects of PWZ-029, an alpha(5)GABA(A) receptor inverse agonist, on scopolamine-induced spatial learning deficits in the water maze. in European Neuropsychopharmacology. 2012;22(Supplement 2):S190-S191.
doi:10.1016/S0924-977X(12)70274-2 .

Joksimović, Srđan, Timić, Tamara, Radulović, Tamara, Rallapalli, Sundari, Milinković, Marija M., Divljaković, Jovana, Batinić, Bojan, Cook, James M., Savić, Miroslav, "Effects of PWZ-029, an alpha(5)GABA(A) receptor inverse agonist, on scopolamine-induced spatial learning deficits in the water maze" in European Neuropsychopharmacology, 22, no. Supplement 2 (2012):S190-S191,
https://doi.org/10.1016/S0924-977X(12)70274-2 . .

TY  - JOUR
AU  - Milić, Marija
AU  - Divljaković, Jovana
AU  - Rallapalli, Sundari
AU  - van Linn, Michael
AU  - Timić, Tamara
AU  - Cook, James M.
AU  - Savić, Miroslav
PY  - 2012
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/1698
AB  - Benzodiazepines negatively affect motor coordination and balance and produce myorelaxation. The aim of the present study was to examine the extent to which populations of gamma-aminobutyric acid A (GABA(A)) receptors containing alpha(1) and alpha(5) subunits contribute to these motor-impairing effects in rats. We used the nonselective agonist diazepam and the alpha(1)-selective agonist zolpidem, as well as nonselective, alpha(1)-subunit and alpha(5)-subunit-selective antagonists flumazenil, beta CCt, and XLi093, respectively. Ataxia and muscle relaxation were assessed by rotarod and grip strength tests performed 20 min after intraperitoneal treatment. Diazepam (2 mg/kg) induced significant ataxia and muscle relaxation, which were completely prevented by pretreatment with flumazenil (10mg/kg) and beta CCt (20 mg/kg). XLi093 antagonized the myorelaxant, but not the ataxic actions of diazepam. All three doses of zolpidem (1, 2, and 5 mg/kg) produced ataxia, but only the highest dose (5 mg/kg) significantly decreased the grip strength. These effects of zolpidem were reversed by beta CCt at doses of 5 and 10 mg/kg, respectively. The present study demonstrates that alpha(1) GABA(A) receptors mediate ataxia and indirectly contribute to myorelaxation in rats, whereas alpha(5) GABA(A) receptors contribute significantly, although not dominantly, to muscle relaxation but not ataxia. Behavioural Pharmacology 23:191-197
PB  - Lippincott Williams & Wilkins, Philadelphia
T2  - Behavioural Pharmacology
T1  - The role of alpha(1) and alpha(5) subunit-containing GABA(A) receptors in motor impairment induced by benzodiazepines in rats
VL  - 23
IS  - 2
SP  - 191
EP  - 197
DO  - 10.1097/FBP.0b013e3283512c85
ER  - 

@article{
author = "Milić, Marija and Divljaković, Jovana and Rallapalli, Sundari and van Linn, Michael and Timić, Tamara and Cook, James M. and Savić, Miroslav",
year = "2012",
abstract = "Benzodiazepines negatively affect motor coordination and balance and produce myorelaxation. The aim of the present study was to examine the extent to which populations of gamma-aminobutyric acid A (GABA(A)) receptors containing alpha(1) and alpha(5) subunits contribute to these motor-impairing effects in rats. We used the nonselective agonist diazepam and the alpha(1)-selective agonist zolpidem, as well as nonselective, alpha(1)-subunit and alpha(5)-subunit-selective antagonists flumazenil, beta CCt, and XLi093, respectively. Ataxia and muscle relaxation were assessed by rotarod and grip strength tests performed 20 min after intraperitoneal treatment. Diazepam (2 mg/kg) induced significant ataxia and muscle relaxation, which were completely prevented by pretreatment with flumazenil (10mg/kg) and beta CCt (20 mg/kg). XLi093 antagonized the myorelaxant, but not the ataxic actions of diazepam. All three doses of zolpidem (1, 2, and 5 mg/kg) produced ataxia, but only the highest dose (5 mg/kg) significantly decreased the grip strength. These effects of zolpidem were reversed by beta CCt at doses of 5 and 10 mg/kg, respectively. The present study demonstrates that alpha(1) GABA(A) receptors mediate ataxia and indirectly contribute to myorelaxation in rats, whereas alpha(5) GABA(A) receptors contribute significantly, although not dominantly, to muscle relaxation but not ataxia. Behavioural Pharmacology 23:191-197",
publisher = "Lippincott Williams & Wilkins, Philadelphia",
journal = "Behavioural Pharmacology",
title = "The role of alpha(1) and alpha(5) subunit-containing GABA(A) receptors in motor impairment induced by benzodiazepines in rats",
volume = "23",
number = "2",
pages = "191-197",
doi = "10.1097/FBP.0b013e3283512c85"
}

Milić, M., Divljaković, J., Rallapalli, S., van Linn, M., Timić, T., Cook, J. M.,& Savić, M.. (2012). The role of alpha(1) and alpha(5) subunit-containing GABA(A) receptors in motor impairment induced by benzodiazepines in rats. in Behavioural Pharmacology
Lippincott Williams & Wilkins, Philadelphia., 23(2), 191-197.
https://doi.org/10.1097/FBP.0b013e3283512c85

Milić M, Divljaković J, Rallapalli S, van Linn M, Timić T, Cook JM, Savić M. The role of alpha(1) and alpha(5) subunit-containing GABA(A) receptors in motor impairment induced by benzodiazepines in rats. in Behavioural Pharmacology. 2012;23(2):191-197.
doi:10.1097/FBP.0b013e3283512c85 .

Milić, Marija, Divljaković, Jovana, Rallapalli, Sundari, van Linn, Michael, Timić, Tamara, Cook, James M., Savić, Miroslav, "The role of alpha(1) and alpha(5) subunit-containing GABA(A) receptors in motor impairment induced by benzodiazepines in rats" in Behavioural Pharmacology, 23, no. 2 (2012):191-197,
https://doi.org/10.1097/FBP.0b013e3283512c85 . .

TY  - JOUR
AU  - Divljaković, Jovana
AU  - Milić, Marija
AU  - Timić, Tamara
AU  - Savić, Miroslav
PY  - 2012
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/1668
AB  - Background: Behavioral effects of benzodiazepines following repeated exposure vary according to the intrinsic efficacy of the benzodiazepine studied, treatment schedule and the behavioral parameters evaluated. Methods: We applied the behavioral paradigms of spontaneous locomotor activity, elevated plus maze and grip strength to investigate the sedative, anxiolyfic and myorelaxant effect of acute challenge with 2 mg/kg diazepam administered after 14 days of protracted treatment with 0.5, 2 or 10 mg/kg of diazepam. In addition, we studied the effects of everyday handling and intraperitoneal (ip) administration on animal behavior. Results: Tolerance to the sedative effect of 2 mg/kg diszepam ensued after 14 days of protracted treatment with 2 and 10 mg/kg of diazepam. In contrast, treatment with the lowest dose (0.5 mg/kg) of diazepam resulted in potentiation of the sedative effect of acute challenge with 2 mg/kg diazepam thus confounding the detection of the anxiolytic effect of diazepam. A sensitization-like response to the anxiolytic action of 2 mg/kg diazepam was seen after protracted treatment with the intermediate dose (2 mg/kg); however, anxiolytic effect was absent after protracted administration of the highest dose. Partial tolerance to the muscle relaxant effect of 2 mg/kg diazepam ensued after protracted treatment with diazepam regardless of the dose. Daily handling or ip administration did not alter the behavioral response to acute challenge with 2 mg/kg diazepam in all the three behavioral paradigms studied. Conclusion: The presented results showed that behavioral effects of acute challenge with diazepam were differently affected by the dose administered during protracted treatment.
PB  - Polish Acad Sciences Inst Pharmacology, Krakow
T2  - Pharmacological Reports
T1  - Tolerance liability of diazepam is dependent on the dose used for protracted treatment
VL  - 64
IS  - 5
SP  - 1116
EP  - 1125
DO  - 10.1016/S1734-1140(12)70908-8
ER  - 

@article{
author = "Divljaković, Jovana and Milić, Marija and Timić, Tamara and Savić, Miroslav",
year = "2012",
abstract = "Background: Behavioral effects of benzodiazepines following repeated exposure vary according to the intrinsic efficacy of the benzodiazepine studied, treatment schedule and the behavioral parameters evaluated. Methods: We applied the behavioral paradigms of spontaneous locomotor activity, elevated plus maze and grip strength to investigate the sedative, anxiolyfic and myorelaxant effect of acute challenge with 2 mg/kg diazepam administered after 14 days of protracted treatment with 0.5, 2 or 10 mg/kg of diazepam. In addition, we studied the effects of everyday handling and intraperitoneal (ip) administration on animal behavior. Results: Tolerance to the sedative effect of 2 mg/kg diszepam ensued after 14 days of protracted treatment with 2 and 10 mg/kg of diazepam. In contrast, treatment with the lowest dose (0.5 mg/kg) of diazepam resulted in potentiation of the sedative effect of acute challenge with 2 mg/kg diazepam thus confounding the detection of the anxiolytic effect of diazepam. A sensitization-like response to the anxiolytic action of 2 mg/kg diazepam was seen after protracted treatment with the intermediate dose (2 mg/kg); however, anxiolytic effect was absent after protracted administration of the highest dose. Partial tolerance to the muscle relaxant effect of 2 mg/kg diazepam ensued after protracted treatment with diazepam regardless of the dose. Daily handling or ip administration did not alter the behavioral response to acute challenge with 2 mg/kg diazepam in all the three behavioral paradigms studied. Conclusion: The presented results showed that behavioral effects of acute challenge with diazepam were differently affected by the dose administered during protracted treatment.",
publisher = "Polish Acad Sciences Inst Pharmacology, Krakow",
journal = "Pharmacological Reports",
title = "Tolerance liability of diazepam is dependent on the dose used for protracted treatment",
volume = "64",
number = "5",
pages = "1116-1125",
doi = "10.1016/S1734-1140(12)70908-8"
}

Divljaković, J., Milić, M., Timić, T.,& Savić, M.. (2012). Tolerance liability of diazepam is dependent on the dose used for protracted treatment. in Pharmacological Reports
Polish Acad Sciences Inst Pharmacology, Krakow., 64(5), 1116-1125.
https://doi.org/10.1016/S1734-1140(12)70908-8

Divljaković J, Milić M, Timić T, Savić M. Tolerance liability of diazepam is dependent on the dose used for protracted treatment. in Pharmacological Reports. 2012;64(5):1116-1125.
doi:10.1016/S1734-1140(12)70908-8 .

Divljaković, Jovana, Milić, Marija, Timić, Tamara, Savić, Miroslav, "Tolerance liability of diazepam is dependent on the dose used for protracted treatment" in Pharmacological Reports, 64, no. 5 (2012):1116-1125,
https://doi.org/10.1016/S1734-1140(12)70908-8 . .

TY  - JOUR
AU  - Trisović, Nemanja
AU  - Timić, Tamara
AU  - Divljaković, Jovana
AU  - Rogan, Jelena
AU  - Poleti, Dejan
AU  - Savić, Miroslav
AU  - Uscumlić, Gordana
PY  - 2012
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/1649
AB  - Considering the importance of hydantoin derivatives in treatment of status epilepticus, four 5-phenylhydantoins, whose lipophilicities were estimated to be similar to that of phenytoin, were synthesized. Evaluation of their anticonvulsant activities was performed on rats by subcutaneous pentylenetetrazol seizure test and intravenous pentylenetetrazol threshold test, and spontaneous locomotor activity test was used to assess possible sedative effects. X-ray analysis of three compounds suggested that certain analogies might be drawn between interactions in crystal packing and biological interactions responsible for their anticonvulsant activity. It was found that 5-ethyl-5-phenyl-3-propylhydantoin exhibits the most favorable pharmacological properties among the synthesized compounds, i.e., anticonvulsant activity comparable to phenytoin with lower liability for induction of sedation in rats.
PB  - Springer Wien, Wien
T2  - Monatshefte für Chemie Chemical Monthly
T1  - Synthesis, structural and biological characterization of 5-phenylhydantoin derivatives as potential anticonvulsant agents
VL  - 143
IS  - 10
SP  - 1451
EP  - 1457
DO  - 10.1007/s00706-012-0791-8
ER  - 

@article{
author = "Trisović, Nemanja and Timić, Tamara and Divljaković, Jovana and Rogan, Jelena and Poleti, Dejan and Savić, Miroslav and Uscumlić, Gordana",
year = "2012",
abstract = "Considering the importance of hydantoin derivatives in treatment of status epilepticus, four 5-phenylhydantoins, whose lipophilicities were estimated to be similar to that of phenytoin, were synthesized. Evaluation of their anticonvulsant activities was performed on rats by subcutaneous pentylenetetrazol seizure test and intravenous pentylenetetrazol threshold test, and spontaneous locomotor activity test was used to assess possible sedative effects. X-ray analysis of three compounds suggested that certain analogies might be drawn between interactions in crystal packing and biological interactions responsible for their anticonvulsant activity. It was found that 5-ethyl-5-phenyl-3-propylhydantoin exhibits the most favorable pharmacological properties among the synthesized compounds, i.e., anticonvulsant activity comparable to phenytoin with lower liability for induction of sedation in rats.",
publisher = "Springer Wien, Wien",
journal = "Monatshefte für Chemie Chemical Monthly",
title = "Synthesis, structural and biological characterization of 5-phenylhydantoin derivatives as potential anticonvulsant agents",
volume = "143",
number = "10",
pages = "1451-1457",
doi = "10.1007/s00706-012-0791-8"
}

Trisović, N., Timić, T., Divljaković, J., Rogan, J., Poleti, D., Savić, M.,& Uscumlić, G.. (2012). Synthesis, structural and biological characterization of 5-phenylhydantoin derivatives as potential anticonvulsant agents. in Monatshefte für Chemie Chemical Monthly
Springer Wien, Wien., 143(10), 1451-1457.
https://doi.org/10.1007/s00706-012-0791-8

Trisović N, Timić T, Divljaković J, Rogan J, Poleti D, Savić M, Uscumlić G. Synthesis, structural and biological characterization of 5-phenylhydantoin derivatives as potential anticonvulsant agents. in Monatshefte für Chemie Chemical Monthly. 2012;143(10):1451-1457.
doi:10.1007/s00706-012-0791-8 .

Trisović, Nemanja, Timić, Tamara, Divljaković, Jovana, Rogan, Jelena, Poleti, Dejan, Savić, Miroslav, Uscumlić, Gordana, "Synthesis, structural and biological characterization of 5-phenylhydantoin derivatives as potential anticonvulsant agents" in Monatshefte für Chemie Chemical Monthly, 143, no. 10 (2012):1451-1457,
https://doi.org/10.1007/s00706-012-0791-8 . .