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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

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2009
1174.pdf (215.5Kb)
Authors
Savić, Miroslav
Milinković, Marija M.
Rallapalli, Sundari
Clayton, Terry
Joksimović, Srđan
van Linn, Michael
Cook, James M.
Article (Published version)
Metadata
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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.

Keywords:
Benzodiazepine / GABA(A) subtype / learning / memory / sedation
Source:
International Journal of Neuropsychopharmacology, 2009, 12, 9, 1179-1193
Publisher:
  • Oxford Univ Press, Oxford
Funding / projects:
  • NIMH NIH HHS 46851
  • Harry Bradley Foundation

DOI: 10.1017/S1461145709000108

ISSN: 1461-1457

PubMed: 19265570

WoS: 000270373500004

Scopus: 2-s2.0-77649270051
[ Google Scholar ]
42
39
URI
https://farfar.pharmacy.bg.ac.rs/handle/123456789/1176
Collections
  • Radovi istraživača / Researchers’ publications
Institution/Community
Pharmacy
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 . .

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