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
2013
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Authors
Milić, MarijaTimić, Tamara
Joksimović, Srđan
Biawat, Poonam
Rallapalli, Sundari
Divljaković, Jovana
Radulović, Tamara
Cook, James M.
Savić, Miroslav
Article (Published version)
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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) als...o 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.
Keywords:
GABA / Inverse agonist / Memory / Object recognition / Water mazeSource:
Behavioural Brain Research, 2013, 241, 206-213Publisher:
- Elsevier Science BV, Amsterdam
Funding / projects:
- Behavioral ?ffects following repeated administration of newly synthesized ligands selective for distinct subtypes of GABAA receptor benzodiazepine binding site: comparison with standard psychopharmacologic drugs (RS-MESTD-Basic Research (BR or ON)-175076)
- Lynde and Harry Bradley Foundation
DOI: 10.1016/j.bbr.2012.12.016
ISSN: 0166-4328
PubMed: 23261875
WoS: 000315308700027
Scopus: 2-s2.0-84872037944
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PharmacyTY - 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 . .