Are GABAA Receptors Containing α5 Subunits Contributing to the Sedative Properties of Benzodiazepine Site Agonists?

Classical benzodiazepines (BZs) exert anxiolytic, sedative, hypnotic, muscle relaxant, anticonvulsive, and amnesic effects through potentiation of neurotransmission at GABA_A receptors containing α₁, α₂, α₃ or α₅ subunits. Genetic studies suggest that modulation at the α₁ subunit contributes to much of the adverse effects of BZs, most notably sedation, ataxia, and amnesia. Hence, BZ site ligands functionally inactive at GABA_A receptors containing the α₁ 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 GABA_A 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 α₂-, α₃-, and α₅-containing subtypes of GABA_A receptors (SH-053-S-CH3 and SH-053-S-CH3-2′F) or essentially selective for α₅ 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 α₁ 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 α₅-containing GABA_A receptors. Hence, it could be of importance to avoid substantial agonist activity at α₅ receptors by candidate anxioselective anxiolytics, if clinical sedation is to be avoided.Neuropsychopharmacology (2008) 33, 332–339; doi:10.1038/sj.npp.1301403; published online 28 March 2007 [ABSTRACT FROM AUTHOR]