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  - 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  - Savić, Miroslav
AU  - Majumder, Samarpan
AU  - Huang, Shengming
AU  - Edwankar, Rahul V.
AU  - Furtmueller, Roman
AU  - Joksimović, Srđan
AU  - Clayton, Terry
AU  - Ramerstorfer, Joachim
AU  - Milinković, Marija M.
AU  - Roth, Bryan L.
AU  - Sieghart, Werner
AU  - Cook, James M.
PY  - 2010
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/1380
AB  - Over the last years, genetic studies have greatly improved Our knowledge on the receptor subtypes mediating various pharmacological effects of positive allosteric modulators at GABA(A) receptors. This stimulated the development of new benzodiazepine (BZ)-like ligands, especially those inactive/low-active at GABA(A) receptors containing the alpha(1) subunit, with the aim of generating more selective drugs. Hereby, the affinity and efficacy of four recently synthesized BZ site ligands: SH-053-2'N, SH-053-S-CH3-2'F, SH-053-R-CH3-2'F and JY-XHe-053 were assessed. They were also studied in behavioral tests of spontaneous locomotor activity, elevated plus maze, and water maze in rats, which are considered predictive of. respectively, the sedative, anxiolytic, and amnesic influence of BZs. The novel ligands had moderately low to low affinity and mild to partial agonistic efficacy at GABA(A) receptors containing the a, subunit, with variable, but more pronounced efficacy at other BZ-sensitive binding sites. While presumably alpha(1) receptor-mediated sedative effects of GABA(A) modulation were not fully eliminated with any of the ligands tested, only SH-053-2'N and SH-053-S-CH3-2'F, both dosed at 30 mg/kg, exerted anxiolytic effects. The lack of clear anxiolytic-like activity of JY-XHe-053, despite its efficacy at alpha(2)- and alpha(3)-GABA(A) receptors, may have been partly connected with its preferential affinity at alpha(5)-GABA(A) receptors coupled with weak agonist activity at alpha(1)-containing subtypes. The memory impairment in water-maze experiments, generally reported with BZ site agonists, was completely circumvented with all four ligands. The results suggest that a substantial amount of activity at a I GABA(A) receptors is needed for affecting spatial learning and memory impairments, while much weaker activity at alpha(1) and alpha(5)-GABA(A) receptors is sufficient for eliciting sedation.
PB  - Pergamon-Elsevier Science Ltd, Oxford
T2  - Progress in Nutrition
T1  - Novel positive allosteric modulators of GABAA receptors: Do subtle differences in activity at alpha 1 plus alpha 5 versus alpha 2 plus alpha 3 subunits account for dissimilarities in behavioral effects in rats?
VL  - 34
IS  - 2
SP  - 376
EP  - 386
DO  - 10.1016/j.pnpbp.2010.01.004
ER  - 

@article{
author = "Savić, Miroslav and Majumder, Samarpan and Huang, Shengming and Edwankar, Rahul V. and Furtmueller, Roman and Joksimović, Srđan and Clayton, Terry and Ramerstorfer, Joachim and Milinković, Marija M. and Roth, Bryan L. and Sieghart, Werner and Cook, James M.",
year = "2010",
abstract = "Over the last years, genetic studies have greatly improved Our knowledge on the receptor subtypes mediating various pharmacological effects of positive allosteric modulators at GABA(A) receptors. This stimulated the development of new benzodiazepine (BZ)-like ligands, especially those inactive/low-active at GABA(A) receptors containing the alpha(1) subunit, with the aim of generating more selective drugs. Hereby, the affinity and efficacy of four recently synthesized BZ site ligands: SH-053-2'N, SH-053-S-CH3-2'F, SH-053-R-CH3-2'F and JY-XHe-053 were assessed. They were also studied in behavioral tests of spontaneous locomotor activity, elevated plus maze, and water maze in rats, which are considered predictive of. respectively, the sedative, anxiolytic, and amnesic influence of BZs. The novel ligands had moderately low to low affinity and mild to partial agonistic efficacy at GABA(A) receptors containing the a, subunit, with variable, but more pronounced efficacy at other BZ-sensitive binding sites. While presumably alpha(1) receptor-mediated sedative effects of GABA(A) modulation were not fully eliminated with any of the ligands tested, only SH-053-2'N and SH-053-S-CH3-2'F, both dosed at 30 mg/kg, exerted anxiolytic effects. The lack of clear anxiolytic-like activity of JY-XHe-053, despite its efficacy at alpha(2)- and alpha(3)-GABA(A) receptors, may have been partly connected with its preferential affinity at alpha(5)-GABA(A) receptors coupled with weak agonist activity at alpha(1)-containing subtypes. The memory impairment in water-maze experiments, generally reported with BZ site agonists, was completely circumvented with all four ligands. The results suggest that a substantial amount of activity at a I GABA(A) receptors is needed for affecting spatial learning and memory impairments, while much weaker activity at alpha(1) and alpha(5)-GABA(A) receptors is sufficient for eliciting sedation.",
publisher = "Pergamon-Elsevier Science Ltd, Oxford",
journal = "Progress in Nutrition",
title = "Novel positive allosteric modulators of GABAA receptors: Do subtle differences in activity at alpha 1 plus alpha 5 versus alpha 2 plus alpha 3 subunits account for dissimilarities in behavioral effects in rats?",
volume = "34",
number = "2",
pages = "376-386",
doi = "10.1016/j.pnpbp.2010.01.004"
}

Savić, M., Majumder, S., Huang, S., Edwankar, R. V., Furtmueller, R., Joksimović, S., Clayton, T., Ramerstorfer, J., Milinković, M. M., Roth, B. L., Sieghart, W.,& Cook, J. M.. (2010). Novel positive allosteric modulators of GABAA receptors: Do subtle differences in activity at alpha 1 plus alpha 5 versus alpha 2 plus alpha 3 subunits account for dissimilarities in behavioral effects in rats?. in Progress in Nutrition
Pergamon-Elsevier Science Ltd, Oxford., 34(2), 376-386.
https://doi.org/10.1016/j.pnpbp.2010.01.004

Savić M, Majumder S, Huang S, Edwankar RV, Furtmueller R, Joksimović S, Clayton T, Ramerstorfer J, Milinković MM, Roth BL, Sieghart W, Cook JM. Novel positive allosteric modulators of GABAA receptors: Do subtle differences in activity at alpha 1 plus alpha 5 versus alpha 2 plus alpha 3 subunits account for dissimilarities in behavioral effects in rats?. in Progress in Nutrition. 2010;34(2):376-386.
doi:10.1016/j.pnpbp.2010.01.004 .

Savić, Miroslav, Majumder, Samarpan, Huang, Shengming, Edwankar, Rahul V., Furtmueller, Roman, Joksimović, Srđan, Clayton, Terry, Ramerstorfer, Joachim, Milinković, Marija M., Roth, Bryan L., Sieghart, Werner, Cook, James M., "Novel positive allosteric modulators of GABAA receptors: Do subtle differences in activity at alpha 1 plus alpha 5 versus alpha 2 plus alpha 3 subunits account for dissimilarities in behavioral effects in rats?" in Progress in Nutrition, 34, no. 2 (2010):376-386,
https://doi.org/10.1016/j.pnpbp.2010.01.004 . .

TY  - JOUR
AU  - Savić, Miroslav
AU  - Milinković, Marija M.
AU  - Rallapalli, Sundari
AU  - Clayton, Terry
AU  - Joksimović, Srđan
AU  - van Linn, Michael
AU  - Cook, James M.
PY  - 2009
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/1176
AB  - The clinical use of benzodiazepines (BZs) is hampered by sedation and cognitive deterioration. Although genetic and pharmacological studies suggest that alpha(1)- and alpha(5)-containing GABA(A) receptors mediate and/or modulate these effects, their molecular substrate is not fully elucidated. By the use of two selective ligands: the alpha(1)-subunit affinity-selective antagonist beta-CCt, and the alpha(5)-subunit affinity- and efficacy-selective antagonist XLi093, we examined the mechanisms of behavioural effects of diazepam in the tests of spontaneous locomotor activity and water-maze acquisition and recall, the two paradigms indicative of sedative- and cognition-impairing effects of BZs, respectively. The locomotor-activity decreasing propensity of diazepam (significant at 1.5 and 5 mg/kg) was antagonized by beta-CCt (5 and 15 mg/kg), while it tended to be potentiated by XLi093 in doses of 10 mg/kg, and especially 20 mg/kg. Diazepam decreased acquisition and recall in the water maze, with a minimum effective dose of 1.5 mg/kg. Both antagonists reversed the thigmotaxis induced by 2 mg/kg diazepam throughout the test, suggesting that both GABA(A) receptor subtypes participate in BZ effects on the procedural component of the task. Diazepam-induced impairment in the declarative component of the task, as assessed by path efficiency, the latency and distance before finding the platform across acquisition trials, and also by the spatial parameters in the probe trial, was partially prevented by both, 15 mg/kg beta-CCt and 10 mg/kg XLi093. Combining a BZ with beta-CCt results in the near to control level of performance of a cognitive task, without sedation, and may be worth testing on human subjects.
PB  - Oxford Univ Press, Oxford
T2  - International Journal of Neuropsychopharmacology
T1  - The differential role of alpha(1)- and alpha(5)-containing GABA(A) receptors in mediating diazepam effects on spontaneous locomotor activity and water-maze learning and memory in rats
VL  - 12
IS  - 9
SP  - 1179
EP  - 1193
DO  - 10.1017/S1461145709000108
ER  - 

@article{
author = "Savić, Miroslav and Milinković, Marija M. and Rallapalli, Sundari and Clayton, Terry and Joksimović, Srđan and van Linn, Michael and Cook, James M.",
year = "2009",
abstract = "The clinical use of benzodiazepines (BZs) is hampered by sedation and cognitive deterioration. Although genetic and pharmacological studies suggest that alpha(1)- and alpha(5)-containing GABA(A) receptors mediate and/or modulate these effects, their molecular substrate is not fully elucidated. By the use of two selective ligands: the alpha(1)-subunit affinity-selective antagonist beta-CCt, and the alpha(5)-subunit affinity- and efficacy-selective antagonist XLi093, we examined the mechanisms of behavioural effects of diazepam in the tests of spontaneous locomotor activity and water-maze acquisition and recall, the two paradigms indicative of sedative- and cognition-impairing effects of BZs, respectively. The locomotor-activity decreasing propensity of diazepam (significant at 1.5 and 5 mg/kg) was antagonized by beta-CCt (5 and 15 mg/kg), while it tended to be potentiated by XLi093 in doses of 10 mg/kg, and especially 20 mg/kg. Diazepam decreased acquisition and recall in the water maze, with a minimum effective dose of 1.5 mg/kg. Both antagonists reversed the thigmotaxis induced by 2 mg/kg diazepam throughout the test, suggesting that both GABA(A) receptor subtypes participate in BZ effects on the procedural component of the task. Diazepam-induced impairment in the declarative component of the task, as assessed by path efficiency, the latency and distance before finding the platform across acquisition trials, and also by the spatial parameters in the probe trial, was partially prevented by both, 15 mg/kg beta-CCt and 10 mg/kg XLi093. Combining a BZ with beta-CCt results in the near to control level of performance of a cognitive task, without sedation, and may be worth testing on human subjects.",
publisher = "Oxford Univ Press, Oxford",
journal = "International Journal of Neuropsychopharmacology",
title = "The differential role of alpha(1)- and alpha(5)-containing GABA(A) receptors in mediating diazepam effects on spontaneous locomotor activity and water-maze learning and memory in rats",
volume = "12",
number = "9",
pages = "1179-1193",
doi = "10.1017/S1461145709000108"
}

Savić, M., Milinković, M. M., Rallapalli, S., Clayton, T., Joksimović, S., van Linn, M.,& Cook, J. M.. (2009). The differential role of alpha(1)- and alpha(5)-containing GABA(A) receptors in mediating diazepam effects on spontaneous locomotor activity and water-maze learning and memory in rats. in International Journal of Neuropsychopharmacology
Oxford Univ Press, Oxford., 12(9), 1179-1193.
https://doi.org/10.1017/S1461145709000108

Savić M, Milinković MM, Rallapalli S, Clayton T, Joksimović S, van Linn M, Cook JM. The differential role of alpha(1)- and alpha(5)-containing GABA(A) receptors in mediating diazepam effects on spontaneous locomotor activity and water-maze learning and memory in rats. in International Journal of Neuropsychopharmacology. 2009;12(9):1179-1193.
doi:10.1017/S1461145709000108 .

Savić, Miroslav, Milinković, Marija M., Rallapalli, Sundari, Clayton, Terry, Joksimović, Srđan, van Linn, Michael, Cook, James M., "The differential role of alpha(1)- and alpha(5)-containing GABA(A) receptors in mediating diazepam effects on spontaneous locomotor activity and water-maze learning and memory in rats" in International Journal of Neuropsychopharmacology, 12, no. 9 (2009):1179-1193,
https://doi.org/10.1017/S1461145709000108 . .

TY  - JOUR
AU  - Savić, Miroslav
AU  - Clayton, Terry
AU  - Furtmueller, Roman
AU  - Gaurilović, Ivana
AU  - Samardžić, Janko
AU  - Savić, Snežana
AU  - Huck, Sigismund
AU  - Sieghart, Werner
AU  - Cook, James M.
PY  - 2008
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/1081
AB  - Benzodiazepine (BZ) site ligands affect vigilance, anxiety, memory processes, muscle tone and epileptogenic propensity through modulation of neurotransmission at GABA(A) receptors containing alpha 1, alpha 2, alpha 3 or alpha 5 subunits, and may have numerous experimental and clinical applications. The ability of non-selective BZ site inverse agonists to enhance cognition, documented in animal models and human studies, is clinically not feasible due to potentially unacceptable psychomotor effects. Most investigations to date have proposed the alpha 1 and/or alpha 5 subunit-containing GABA(A) receptors as comprising the memory-modulating population of these receptors. The novel ligand PWZ-029, which we synthesized and characterized electrophysiologically, possesses in vitro binding selectivity and moderate inverse agonist functional selectivity at alpha 5-containing GABA(A) receptors. This ligand has also been examined in rats in the passive and active avoidance, spontaneous locomotor activity, elevated plus maze and grip strength tests, primarily predictive of the effects on the memory acquisition, basal locomotor activity, anxiety level and muscle tone, respectively. The improvement of task learning was detected at the dose of 5 mg/kg in the passive, but not active avoidance test. The inverse agonist PWZ-029 had no effect on anxiety or muscle tone, whereas at higher doses (10 and 20 mg/kg) it decreased locomotor activity. This effect was antagonized by flumazenil. and also by the lower (but not the higher) dose of an agonist (SH-053-R-CH3-2'F) selective for GABA(A) receptors containing the alpha 5 subunit. The hypolocomotor effect of PWZ-029 was not antagonized by the antagonist beta-CCt exhibiting a preferential affinity for alpha 1-subunit-containing receptors. These data suggest that moderate negative modulation at GABA(A) receptors containing the alpha 5 subunit is a sufficient condition for eliciting enhanced encoding/consolidation of declarative memory, while the influence of higher doses of modulators at these receptors on motor activity shows an intricate pattern whose relevance and mechanism await to be defined.
PB  - Elsevier Science BV, Amsterdam
T2  - Brain Research
T1  - PWZ-029, a compound with moderate inverse agonist functional selectivity at GABA(A) receptors containing alpha 5 subunits, improves passive, but not active, avoidance learning in rats
VL  - 1208
SP  - 150
EP  - 159
DO  - 10.1016/j.brainres.2008.02.020
ER  - 

@article{
author = "Savić, Miroslav and Clayton, Terry and Furtmueller, Roman and Gaurilović, Ivana and Samardžić, Janko and Savić, Snežana and Huck, Sigismund and Sieghart, Werner and Cook, James M.",
year = "2008",
abstract = "Benzodiazepine (BZ) site ligands affect vigilance, anxiety, memory processes, muscle tone and epileptogenic propensity through modulation of neurotransmission at GABA(A) receptors containing alpha 1, alpha 2, alpha 3 or alpha 5 subunits, and may have numerous experimental and clinical applications. The ability of non-selective BZ site inverse agonists to enhance cognition, documented in animal models and human studies, is clinically not feasible due to potentially unacceptable psychomotor effects. Most investigations to date have proposed the alpha 1 and/or alpha 5 subunit-containing GABA(A) receptors as comprising the memory-modulating population of these receptors. The novel ligand PWZ-029, which we synthesized and characterized electrophysiologically, possesses in vitro binding selectivity and moderate inverse agonist functional selectivity at alpha 5-containing GABA(A) receptors. This ligand has also been examined in rats in the passive and active avoidance, spontaneous locomotor activity, elevated plus maze and grip strength tests, primarily predictive of the effects on the memory acquisition, basal locomotor activity, anxiety level and muscle tone, respectively. The improvement of task learning was detected at the dose of 5 mg/kg in the passive, but not active avoidance test. The inverse agonist PWZ-029 had no effect on anxiety or muscle tone, whereas at higher doses (10 and 20 mg/kg) it decreased locomotor activity. This effect was antagonized by flumazenil. and also by the lower (but not the higher) dose of an agonist (SH-053-R-CH3-2'F) selective for GABA(A) receptors containing the alpha 5 subunit. The hypolocomotor effect of PWZ-029 was not antagonized by the antagonist beta-CCt exhibiting a preferential affinity for alpha 1-subunit-containing receptors. These data suggest that moderate negative modulation at GABA(A) receptors containing the alpha 5 subunit is a sufficient condition for eliciting enhanced encoding/consolidation of declarative memory, while the influence of higher doses of modulators at these receptors on motor activity shows an intricate pattern whose relevance and mechanism await to be defined.",
publisher = "Elsevier Science BV, Amsterdam",
journal = "Brain Research",
title = "PWZ-029, a compound with moderate inverse agonist functional selectivity at GABA(A) receptors containing alpha 5 subunits, improves passive, but not active, avoidance learning in rats",
volume = "1208",
pages = "150-159",
doi = "10.1016/j.brainres.2008.02.020"
}

Savić, M., Clayton, T., Furtmueller, R., Gaurilović, I., Samardžić, J., Savić, S., Huck, S., Sieghart, W.,& Cook, J. M.. (2008). PWZ-029, a compound with moderate inverse agonist functional selectivity at GABA(A) receptors containing alpha 5 subunits, improves passive, but not active, avoidance learning in rats. in Brain Research
Elsevier Science BV, Amsterdam., 1208, 150-159.
https://doi.org/10.1016/j.brainres.2008.02.020

Savić M, Clayton T, Furtmueller R, Gaurilović I, Samardžić J, Savić S, Huck S, Sieghart W, Cook JM. PWZ-029, a compound with moderate inverse agonist functional selectivity at GABA(A) receptors containing alpha 5 subunits, improves passive, but not active, avoidance learning in rats. in Brain Research. 2008;1208:150-159.
doi:10.1016/j.brainres.2008.02.020 .

Savić, Miroslav, Clayton, Terry, Furtmueller, Roman, Gaurilović, Ivana, Samardžić, Janko, Savić, Snežana, Huck, Sigismund, Sieghart, Werner, Cook, James M., "PWZ-029, a compound with moderate inverse agonist functional selectivity at GABA(A) receptors containing alpha 5 subunits, improves passive, but not active, avoidance learning in rats" in Brain Research, 1208 (2008):150-159,
https://doi.org/10.1016/j.brainres.2008.02.020 . .

TY  - JOUR
AU  - Savić, Miroslav
AU  - Huang, Shengming
AU  - Furtmueller, Roman
AU  - Clayton, Terry
AU  - Huck, Sigismund
AU  - Obradović, Dragan I.
AU  - Ugrešić, Nenad
AU  - Sieghart, Werner
AU  - Bokonjić, Dubravko
AU  - Cook, James M.
PY  - 2008
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/1048
AB  - Classical benzodiazepines (BZs) exert anxiolytic, sedative, hypnotic, muscle relaxant, anticonvulsive, and amnesic effects through potentiation of neurotransmission at GABA(A) receptors containing alpha(1), alpha(2), alpha(3) or alpha(5) subunits. Genetic studies suggest that modulation at the alpha(1) subunit contributes to much of the adverse effects of BZs, most notably sedation, ataxia, and amnesia. Hence, BZ site ligands functionally inactive at GABAA receptors containing the alpha(1) subunit are considered to be promising leads for novel, anxioselective anxiolytics devoid of sedative properties. In pursuing this approach, we used two-electrode voltage clamp experiments in Xenopus oocytes expressing recombinant GABAA receptor subtypes to investigate functional selectivity of three newly synthesized BZ site ligands and also compared their in vivo behavioral profiles. The compounds were functionally selective for alpha(2)-, alpha(3)-, and alpha(5)-containing subtypes of GABA(A) receptors (SH-053-S-CH3 and SH-053-S-CH3-2'F) or essentially selective for alpha(5) subtypes (SH-053-R-CH3). Possible influences on behavioral measures were tested in the elevated plus maze, spontaneous locomotor activity, and rotarod test, which are considered primarily predictive of the anxiolytic, sedative, and ataxic influence of BZs, respectively. The results confirmed the substantially diminished ataxic potential of BZ site agonists devoid of alpha(1) subunit-mediated effects, with preserved anti-anxiety effects at 30 mg/kg of SH-053-S-CH3 and SH-053-S-CH3-2'F. However, all three ligands, dosed at 30 mg/kg, decreased spontaneous locomotor activity, suggesting that sedation may be partly dependent on activity mediated by alpha(5)-containing GABAA receptors. Hence, it could be of importance to avoid substantial agonist activity at alpha(5) receptors by candidate anxioselective anxiolytics, if clinical sedation is to be avoided.
PB  - Nature Publishing Group, London
T2  - Neuropsychopharmacology
T1  - Are GABA(A) receptors containing alpha 5 Subunits contributing to the sedative properties of benzodiazepine site agonists?
VL  - 33
IS  - 2
SP  - 332
EP  - 339
DO  - 10.1038/sj.npp.1301403
ER  - 

@article{
author = "Savić, Miroslav and Huang, Shengming and Furtmueller, Roman and Clayton, Terry and Huck, Sigismund and Obradović, Dragan I. and Ugrešić, Nenad and Sieghart, Werner and Bokonjić, Dubravko and Cook, James M.",
year = "2008",
abstract = "Classical benzodiazepines (BZs) exert anxiolytic, sedative, hypnotic, muscle relaxant, anticonvulsive, and amnesic effects through potentiation of neurotransmission at GABA(A) receptors containing alpha(1), alpha(2), alpha(3) or alpha(5) subunits. Genetic studies suggest that modulation at the alpha(1) subunit contributes to much of the adverse effects of BZs, most notably sedation, ataxia, and amnesia. Hence, BZ site ligands functionally inactive at GABAA receptors containing the alpha(1) subunit are considered to be promising leads for novel, anxioselective anxiolytics devoid of sedative properties. In pursuing this approach, we used two-electrode voltage clamp experiments in Xenopus oocytes expressing recombinant GABAA receptor subtypes to investigate functional selectivity of three newly synthesized BZ site ligands and also compared their in vivo behavioral profiles. The compounds were functionally selective for alpha(2)-, alpha(3)-, and alpha(5)-containing subtypes of GABA(A) receptors (SH-053-S-CH3 and SH-053-S-CH3-2'F) or essentially selective for alpha(5) subtypes (SH-053-R-CH3). Possible influences on behavioral measures were tested in the elevated plus maze, spontaneous locomotor activity, and rotarod test, which are considered primarily predictive of the anxiolytic, sedative, and ataxic influence of BZs, respectively. The results confirmed the substantially diminished ataxic potential of BZ site agonists devoid of alpha(1) subunit-mediated effects, with preserved anti-anxiety effects at 30 mg/kg of SH-053-S-CH3 and SH-053-S-CH3-2'F. However, all three ligands, dosed at 30 mg/kg, decreased spontaneous locomotor activity, suggesting that sedation may be partly dependent on activity mediated by alpha(5)-containing GABAA receptors. Hence, it could be of importance to avoid substantial agonist activity at alpha(5) receptors by candidate anxioselective anxiolytics, if clinical sedation is to be avoided.",
publisher = "Nature Publishing Group, London",
journal = "Neuropsychopharmacology",
title = "Are GABA(A) receptors containing alpha 5 Subunits contributing to the sedative properties of benzodiazepine site agonists?",
volume = "33",
number = "2",
pages = "332-339",
doi = "10.1038/sj.npp.1301403"
}

Savić, M., Huang, S., Furtmueller, R., Clayton, T., Huck, S., Obradović, D. I., Ugrešić, N., Sieghart, W., Bokonjić, D.,& Cook, J. M.. (2008). Are GABA(A) receptors containing alpha 5 Subunits contributing to the sedative properties of benzodiazepine site agonists?. in Neuropsychopharmacology
Nature Publishing Group, London., 33(2), 332-339.
https://doi.org/10.1038/sj.npp.1301403

Savić M, Huang S, Furtmueller R, Clayton T, Huck S, Obradović DI, Ugrešić N, Sieghart W, Bokonjić D, Cook JM. Are GABA(A) receptors containing alpha 5 Subunits contributing to the sedative properties of benzodiazepine site agonists?. in Neuropsychopharmacology. 2008;33(2):332-339.
doi:10.1038/sj.npp.1301403 .

Savić, Miroslav, Huang, Shengming, Furtmueller, Roman, Clayton, Terry, Huck, Sigismund, Obradović, Dragan I., Ugrešić, Nenad, Sieghart, Werner, Bokonjić, Dubravko, Cook, James M., "Are GABA(A) receptors containing alpha 5 Subunits contributing to the sedative properties of benzodiazepine site agonists?" in Neuropsychopharmacology, 33, no. 2 (2008):332-339,
https://doi.org/10.1038/sj.npp.1301403 . .