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Limited anxiolytic-like effects of non-benzodiazepine hypnotics in rodents

CNS Research Department, Synthélabo Recherche, 31 avenue Paul Vaillant-Couturier; 92220 Bagneux, France

Ghislaine Perrault

CNS Research Department, Synthélabo Recherche, 31 avenue Paul Vaillant-Couturier; 92220 Bagneux, France

David J. Sanger

CNS Research Department, Synthélabo Recherche, 31 avenue Paul Vaillant-Couturier; 92220 Bagneux, France

The present experiments compared the anxiolytic-like effects of the benzodiazepine (BZD) hypnotic triazolam with those of four non-BZD hypnotics including one non-selective (zopiclone) and three ₁-BZD selective (zolpidem, zaleplon and SX-3228) receptor ligands, in classical animal models including conflict tests (punished lever pressing and punished drinking tests in rats) and exploratory models (elevated plus-maze test in rats and light/dark choice test in mice), and a recently developed mouse defence test battery (MDTB) which has been validated for the screening of anxiolytic drugs. Results from both conflict procedures showed that zopiclone (0.3-10 mg/kg) produced anxiolytic-like effects comparable to those of triazolam (0.1-3 mg/kg), whereas the selective ₁-BZD receptor hypnotics zolpidem (0.3-3 mg/kg), zaleplon (0.1-3 mg/kg) and SX-3228 (0.1-1 mg/kg) displayed weaker and/or non-specific anxiolytic-like effects. Similarly, in the light/dark test in mice, zolpidem (0.1-1 mg/kg), zaleplon (0.3-10 mg/kg) and SX-3228 (0.03-0.3 mg/kg) showed a reduced potential to produce anxiolytic-like effects as compared to the non-selective -BZD receptor hypnotics triazolam (0.03-1 mg/kg) and zopiclone (1-30 mg/kg). In the elevated plus-maze test, zopiclone (1-10 mg/kg), zolpidem (0.1-1 mg/kg), zaleplon (0.3-3 mg/kg) and SX-3228 (0.1-1 mg/kg) displayed anxiolytic-like activity at doses close to those producing behavioural impairment, whereas triazolam (0.03-1 mg/kg) exhibited anxiolytic-like effects over a wide dose range in the absence of decreases in general activity. In the MDTB, zaleplon (0.3-10 mg/kg) decreased all defensive responses, a profile which was similar to that of triazolam (0.03-1 mg/kg), while zopiclone (1-30 mg/kg), zolpidem (0.3-10 mg/kg) and SX-3228 (0.03-1 mg/kg) had fewer effects on defensive behaviours with several effects occurring only at motor-impairing doses. Taken together, these results demonstrate that, although selective ₁-BZD receptor hypnotics display anxiolytic-like activity, the effects are generally weaker than those observed with non-selective -BZD receptor selective hypnotics such as triazolam or zopiclone. In particular, the anxiety-reducing potential of the ₁-BZD receptor selective compounds is limited to certain anxiety measures and may be confounded and/or masked by behavioural suppression.

Key Words: anxiety • conflict procedures • hypnotics • SX-3228 • triazolam • zaleplon • zolpidem • zopiclone

Journal of Psychopharmacology, Vol. 12, No. 4, 356-365 (1998)
DOI: 10.1177/026988119801200405


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