Strain- and model-dependent effects of chlordiazepoxide, L-838,417 and zolpidem on anxiety-like behaviours in laboratory mice.
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)-alpha(2/3/5); 3-30 mg/kg) and zolpidem (GABA(A)-alpha1; 0.3-3.0 mg/kg). The data show a complex mouse strainxmodelxpharmacological agent interaction. Most importantly, not all mouse strainxmodel 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.
Mathiasen
L S
LS
Behavioural Neuroscience Laboratory, Institute of Psychological Sciences, Leeds University, Leeds LS2 9JT, Leeds, UK.
Mirza
N R
NR
Rodgers
R J
RJ
D000818:Animals; D001007:Anxiety / Q000523:psychology*; D001522:Behavior, Animal / Q000187:drug effects*; D002707:Chlordiazepoxide / Q000494:pharmacology*; D003220:Conflict, Psychological; D003624:Darkness; D005464:Fluorobenzenes / Q000494:pharmacology*; D018757:GABA Modulators / Q000494:pharmacology*; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D008027:Light; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008960:Models, Psychological; D011725:Pyridines / Q000494:pharmacology*; D013045:Species Specificity; D014230:Triazoles / Q000494:pharmacology*; D000077334:Zolpidem
D005464:Fluorobenzenes; D018757:GABA Modulators; D006993:Hypnotics and Sedatives; D011725:Pyridines; D014230:Triazoles; D002707:Chlordiazepoxide; D000077334:Zolpidem; C409903:L 838,417