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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

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2013
1924.pdf (958.2Kb)
Authors
Milić, Marija
Timić, Tamara
Joksimović, Srđan
Biawat, Poonam
Rallapalli, Sundari
Divljaković, Jovana
Radulović, Tamara
Cook, James M.
Savić, Miroslav
Article (Published version)
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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) 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 maze
Source:
Behavioural Brain Research, 2013, 241, 206-213
Publisher:
  • Elsevier Science BV, Amsterdam
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-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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URI
http://farfar.pharmacy.bg.ac.rs/handle/123456789/1926
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  • Radovi istraživača / Researchers’ publications
Institution
Pharmacy

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