Are GABAA receptors containing alpha5 subunits contributing to the sedative properties of benzodiazepine site agonists?

Full Abstract

Classical benzodiazepines (BZs) exert anxiolytic, sedative, hypnotic, muscle relaxant, anticonvulsive, and amnesic effects through potentiation of neurotransmission at GABA(A) receptors containing alpha(1), alpha(2), alpha(3) or alpha(5) subunits. Genetic studies suggest that modulation at the alpha(1) 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 alpha(1) 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 alpha(2)-, alpha(3)-, and alpha(5)-containing subtypes of GABA(A) receptors (SH-053-S-CH3 and SH-053-S-CH3-2'F) or essentially selective for alpha(5) 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 alpha(1) 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 alpha(5)-containing GABA(A) receptors. Hence, it could be of importance to avoid substantial agonist activity at alpha(5) receptors by candidate anxioselective anxiolytics, if clinical sedation is to be avoided.

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Author information

Author/s: Savic, Miroslav M (MM); Huang, Shengming (S); Furtmüller, Roman (R); Clayton, Terry (T); Huck, Sigismund (S); Obradovic, Dragan I (DI); Ugresic, Nenad D (ND); Sieghart, Werner (W); Bokonjic, Dubravko R (DR); Cook, James M (JM);

Affiliation: Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia. miroslav(-atsign-)pharmacy.bg.ac.yu

Grants: MH 46851 (Agency:NIMH NIH HHS)

Journal and publication information

Publication Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't

Journal: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology (Neuropsychopharmacology), published in United States. (Language: eng)

Reference: 2008-Jan; vol 33 (issue 2) : pp 332-9

Dates: Created 2007/12/11; Completed 2008/02/06; Revised 2008/11/21;

PMID: 17392731, status: MEDLINE (last retrieval date: 12/26/2008)

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Analysis of Variance
Animals
Benzodiazepines - pharmacology
Male
Maze Learning - drug effects

Motor Activity - drug effects
Protein Subunits - drug effects; physiology
Rats
Rats, Wistar
Receptors, GABA-A - drug effects; physiology

Associated Chemicals: Protein Subunits (0) ; Receptors, GABA-A (0) ; Benzodiazepines (12794-10-4)

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