Discriminative stimulus properties of anxiolytic and sedative drugs: pharmacological specificity

In the first set of experiments rats were trained to discriminate a dose of 5 mg/kg chlordiazepoxide from saline. The chlordiazepoxide cue was antagonized by flumazepil (Ro 15-1788) and by CGS 8216, and generalized to a variety of anxiolytic and sedative drugs including the benzodiazepine receptor ligands zopiclone, suriclone, CL 218,872, CGS 9896, and ZK 91296. The novel imidazopyridine hypnotic, zolpidem, which also displaces benzodiazepines from their binding sites, failed to produce high levels of responding on the chlordiazepoxide-associated level except at a dose which greatly reduced rates of lever pressing. In further experiments rats were trained to discriminate a dose of 2 mg/kg zolpidem from saline. This dose produced reductions in response rates but an attempt to establish a lower dose of zolpidem as a discriminative stimulus was largely unsuccessful. Zolpidem-appropriate responding was produced by pentobarbital, chlordiazepoxide, triazolam, CL 218,872, clorazepate, lorazepam, quazepam, and zopiclone but only at doses which reduced response rates. The zolpidem cue was antagonized by flumazepil, CGS 9896, and ZK 91296. While the discriminative stimulus produced by chlordiazepoxide may be related to its anxiolytic action, the zolpidem stimulus is probably more closely associated with sedation. It was also tentatively concluded that the stimulus properties of chlordiazepoxide and zolpidem are produced by activity at different subtypes of benzodiazepine receptors.