Anxiogenic-like activity of L-655,708, a selective ligand for the benzodiazepine site of GABAA receptors which contain the alpha-5 subunit, in the elevated plus-maze test

GABA(A) receptor is a transmembrane hetero-oligomeric protein which consists of five subunits, the combination of which confers unique pharmacological properties to the receptor. L-655,708 is a new ligand selective for GABA(A) receptors containing an alpha-5 subunit. It is a partial inverse agonist that exhibits a 100-fold higher affinity for alpha-5 containing receptors, compared with alpha-1 containing receptors. The aim of this study was to examine the effects of L-655,708 (0.625-5 mg/kg ip) on anxiety tested in the elevated plus-maze in male mice. A number of classical parameters were collected: (a) Open arm duration; (b) Closed arm duration; (c) Central platform duration; (d) Open arm frequency; (e) Closed arm frequency, and (f) Total number of entries in the arms. Likewise, different ethological measures were also obtained (rears, head-dipping [HD], stretched attend posture [SAP] and grooming). Mice treated with L-655,708 showed a marked increase in the frequency of entries and the time spent in closed arms, as well as a reduction in the frequency of entries and the time spent in open arms, as compared with the control group. Unprotected HDs were also significantly decreased after treatment with the drug. Overall, these results indicate that L-655,708 could exhibit an anxiogenic-like profile in the elevated plus-maze test. This ligand is selective for GABA(A) receptors containing an alpha-5 subunit, which is mainly expressed over the hippocampal formation, a region which has been involved in the modulation of anxiety. (C) 2002 Elsevier Science Inc. All rights reserved.