Strain- and model-dependent effects of chlordiazepoxide, L-838,417 and zolpidem on anxiety-like behaviours in laboratory mice

• Published in: Pharmacology, biochemistry and behavior biochemistry and behavior, 2008-07, Vol.90 (1), p.19-36
• Main Authors: Mathiasen, L.S., Mirza, N.R., Rodgers, R.J.
• Format: Article
• Language: English
• Subjects: Animals; Anxiety - psychology; Behavior, Animal - drug effects; Chlordiazepoxide; Chlordiazepoxide - pharmacology; Conflict (Psychology); Darkness; Fluorobenzenes - pharmacology; GABA A receptor; GABA Modulators - pharmacology; Genotype; Hypnotics and Sedatives - pharmacology; L-838,417; Light; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Models of anxiety-like behaviour; Models, Psychological; Mouse; Pyridines - pharmacology; Species Specificity; Triazoles - pharmacology; Zolpidem; α-subunits
• ISSN: 0091-3057; 1873-5177
• DOI: 10.1016/j.pbb.2008.01.014

The promise of subtype-selective GABA A receptor drugs with anxiolytic properties but with a much reduced side-effect burden (compared to benzodiazepines) is an attainable goal. However, its achievement necessitates the availability of in vivo preclinical assays capable of demonstrating differences as well as similarities between subtype-selective agents and non-selective benzodiazepines. In this study, we have compared three mouse strains (NMRI, C57BL/6J and DBA/2) in four models of anxiety-like behaviour (plus-maze, zero-maze, light–dark, and Vogel conflict). Furthermore, in each model, we have contrasted in detail the behavioural responses of each strain to the non-selective benzodiazepine chlordiazepoxide (CDP; 5–20 mg/kg), and the subtype-selective agents L-838,417 (GABA A-α 2/3/5; 3–30 mg/kg) and zolpidem (GABA A-α1; 0.3–3.0 mg/kg). The data show a complex mouse strain × model × pharmacological agent interaction. Most importantly, not all mouse strain × model test systems showed a positive response to CDP or predicted the response to L-838,417. This dissociation between CDP and L-838,417 opens up opportunities for preclinical test systems that differentiate subtype-selective and non-selective GABA A receptor agents, an attribute that might well be important in providing the necessary confidence for further drug development. Present findings suggest the need for a much greater focus on defining test systems appropriate for screening novel chemical entities, rather than self-selection of models or genotypes based on responses to known pharmacological agents. For example, if current data with L-838,417 are confirmed with compounds showing similar selectivity profiles, such agents may in future be best identified and characterised using test systems comprising NMRI mice in the zero-maze and/or C57 mice in the Vogel conflict and/or light–dark tests.