Comparison of benzodiazepine (BZ) receptor agonists in two rodent activity tests.

The effects of four BZ receptor ligands in an operant test were compared with a rotarod test. In the operant test, rats were trained to pull a chain on a schedule that regulates the probability of delivery of food pellets to maintain a steady chain-pulling rate across a 1 h test session. For the rotarod test, mice were trained to remain on a rotarod for 2 min. Diazepam (0.1-3.0 mg/kg, i.p.), FG 8205 (0.1-3.0 mg/kg, i.p.), quazepam (3.0-60.0 mg/kg, i.p.) and zolpidem (0.3-10.0 mg/kg, i.p.) each produced dose-related impairments of performance in both the chain- pulling test and the mouse rotarod test. Furthermore, the impairment in performance induced by FG 8205 (10.0 mg/kg, p.o.) was dose-dependently reversed by the BZ receptor antagonist, flumazenil (1.0-10.0 mg/kg, i.p.), indicating that the chain-pulling deficit was mediated via BZ receptor activation. Diazepam, FG 8205 and quazepam all had comparable potencies in both the rotarod assay and the chain-pulling test. However, zolpidem suppressed the chain-pulling rates at a dose 30-fold lower than that required to induce a significant deficit in the rotarod performance. As zolpidem is a preferentially sedative compound, this pattern of results is consistent with the hypothesis that the chain-pulling test is sensitive to sedation induced by BZ receptor agonists.