TY  - CONF
AU  - Filipovć, Vladimir
AU  - Ugrenović, Vladan
AU  - Maksimović, Zoran
AU  - Dimitrijević, Snežana
AU  - Popović, Vera
AU  - Mihajlovski, Katarina
AU  - Milić, Marija
PY  - 2021
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5092
AB  - This study has explored the effect of three phytohormones application, based on α-naphthyl acetic acid, named INCIT 1, INCIT 8 and INCIT K, on the root system growing potential and rooting stimulation of Thymus pannonicus All. cuttings. This plant is highly reputable not only in a folk medicine, but also recognized in the business sector, due to a multiple uses and beneficial effects on human health.
The research was located in Veliko Središte, Vršac (Serbia) and conducted in May, 2021. The cuttings were dipped in a powdered formulation of phytohormones and placed in plastic containers pre-filled with commercial substrate. The phytohormone-free variant was taken as a control. After 2 months, the cuttings were removed and the morphological and biological properties (polyphenols content and antioxidant activity by DPPH radical and FRAP method) were measured.
Based on the morphological results, all of treated samples showed satisfactory behaviour, whereby the most suitable phytohormone to stimulate the growth of cuttings was INCIT 8, in which the average weight of the aboveground vegetative part of the plant and root mass were higher for more than 60% in relation to the control; the number of roots were about 25% higher, whereby the mass of the whole plant was almost 3 times increased. Considering the biological activities in a 5% aqueous infusions of the samples, it was found that the polyphenols content and the antioxidant activity were lowered in treated samples, with relation to the control, excluding the sample INCIT 8 where the FRAP value was slightly increased, while the inhibition of DPPH radicals was higher by around 15%.
The applied phytohormone treatment may ensure economically viable yields of standard or even improved plant quality. In the following period, it is expected that all of treated adult plants will have a higher content of biologically active substances.
PB  - University of Belgrade
C3  - UNIFOOD conference, Belgrade, September 24-25, 2021, Book of Abstracts
T1  - The effect of phytohormones application on morphological and biological properties of Thymus pannonicus All.
SP  - 151
EP  - 151
UR  - https://hdl.handle.net/21.15107/rcub_farfar_5092
ER  - 

@conference{
author = "Filipovć, Vladimir and Ugrenović, Vladan and Maksimović, Zoran and Dimitrijević, Snežana and Popović, Vera and Mihajlovski, Katarina and Milić, Marija",
year = "2021",
abstract = "This study has explored the effect of three phytohormones application, based on α-naphthyl acetic acid, named INCIT 1, INCIT 8 and INCIT K, on the root system growing potential and rooting stimulation of Thymus pannonicus All. cuttings. This plant is highly reputable not only in a folk medicine, but also recognized in the business sector, due to a multiple uses and beneficial effects on human health.
The research was located in Veliko Središte, Vršac (Serbia) and conducted in May, 2021. The cuttings were dipped in a powdered formulation of phytohormones and placed in plastic containers pre-filled with commercial substrate. The phytohormone-free variant was taken as a control. After 2 months, the cuttings were removed and the morphological and biological properties (polyphenols content and antioxidant activity by DPPH radical and FRAP method) were measured.
Based on the morphological results, all of treated samples showed satisfactory behaviour, whereby the most suitable phytohormone to stimulate the growth of cuttings was INCIT 8, in which the average weight of the aboveground vegetative part of the plant and root mass were higher for more than 60% in relation to the control; the number of roots were about 25% higher, whereby the mass of the whole plant was almost 3 times increased. Considering the biological activities in a 5% aqueous infusions of the samples, it was found that the polyphenols content and the antioxidant activity were lowered in treated samples, with relation to the control, excluding the sample INCIT 8 where the FRAP value was slightly increased, while the inhibition of DPPH radicals was higher by around 15%.
The applied phytohormone treatment may ensure economically viable yields of standard or even improved plant quality. In the following period, it is expected that all of treated adult plants will have a higher content of biologically active substances.",
publisher = "University of Belgrade",
journal = "UNIFOOD conference, Belgrade, September 24-25, 2021, Book of Abstracts",
title = "The effect of phytohormones application on morphological and biological properties of Thymus pannonicus All.",
pages = "151-151",
url = "https://hdl.handle.net/21.15107/rcub_farfar_5092"
}

Filipovć, V., Ugrenović, V., Maksimović, Z., Dimitrijević, S., Popović, V., Mihajlovski, K.,& Milić, M.. (2021). The effect of phytohormones application on morphological and biological properties of Thymus pannonicus All.. in UNIFOOD conference, Belgrade, September 24-25, 2021, Book of Abstracts
University of Belgrade., 151-151.
https://hdl.handle.net/21.15107/rcub_farfar_5092

Filipovć V, Ugrenović V, Maksimović Z, Dimitrijević S, Popović V, Mihajlovski K, Milić M. The effect of phytohormones application on morphological and biological properties of Thymus pannonicus All.. in UNIFOOD conference, Belgrade, September 24-25, 2021, Book of Abstracts. 2021;:151-151.
https://hdl.handle.net/21.15107/rcub_farfar_5092 .

Filipovć, Vladimir, Ugrenović, Vladan, Maksimović, Zoran, Dimitrijević, Snežana, Popović, Vera, Mihajlovski, Katarina, Milić, Marija, "The effect of phytohormones application on morphological and biological properties of Thymus pannonicus All." in UNIFOOD conference, Belgrade, September 24-25, 2021, Book of Abstracts (2021):151-151,
https://hdl.handle.net/21.15107/rcub_farfar_5092 .

TY  - CONF
AU  - Batinić, Bojan
AU  - Santrač, Anja
AU  - Jančić, Ivan
AU  - Marković, Bojan
AU  - Milić, Marija
AU  - Savić, Miroslav
PY  - 2017
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2872
PB  - Elsevier Science BV, Amsterdam
C3  - European Neuropsychopharmacology
T1  - GABA-A alpha 5 receptor potentiation in preadolescence prevents hyporeactivity to amphetamine induced by prenatal lipopolysaccharide treatment in rat females
VL  - 27
SP  - S610
EP  - S611
UR  - https://hdl.handle.net/21.15107/rcub_farfar_2872
ER  - 

@conference{
author = "Batinić, Bojan and Santrač, Anja and Jančić, Ivan and Marković, Bojan and Milić, Marija and Savić, Miroslav",
year = "2017",
publisher = "Elsevier Science BV, Amsterdam",
journal = "European Neuropsychopharmacology",
title = "GABA-A alpha 5 receptor potentiation in preadolescence prevents hyporeactivity to amphetamine induced by prenatal lipopolysaccharide treatment in rat females",
volume = "27",
pages = "S610-S611",
url = "https://hdl.handle.net/21.15107/rcub_farfar_2872"
}

Batinić, B., Santrač, A., Jančić, I., Marković, B., Milić, M.,& Savić, M.. (2017). GABA-A alpha 5 receptor potentiation in preadolescence prevents hyporeactivity to amphetamine induced by prenatal lipopolysaccharide treatment in rat females. in European Neuropsychopharmacology
Elsevier Science BV, Amsterdam., 27, S610-S611.
https://hdl.handle.net/21.15107/rcub_farfar_2872

Batinić B, Santrač A, Jančić I, Marković B, Milić M, Savić M. GABA-A alpha 5 receptor potentiation in preadolescence prevents hyporeactivity to amphetamine induced by prenatal lipopolysaccharide treatment in rat females. in European Neuropsychopharmacology. 2017;27:S610-S611.
https://hdl.handle.net/21.15107/rcub_farfar_2872 .

Batinić, Bojan, Santrač, Anja, Jančić, Ivan, Marković, Bojan, Milić, Marija, Savić, Miroslav, "GABA-A alpha 5 receptor potentiation in preadolescence prevents hyporeactivity to amphetamine induced by prenatal lipopolysaccharide treatment in rat females" in European Neuropsychopharmacology, 27 (2017):S610-S611,
https://hdl.handle.net/21.15107/rcub_farfar_2872 .

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  - 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  - 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  - 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 . .