A benzodiazepine antagonist, Ro 15-1788, can block the phase-shifting effects of triazolam on the mammalian circadian clock

Abstract

A single injection of the short acting benzodiazepine, triazolam, can induce permanent phase advances as well as phase delays in the onset of the circadian rhythm of wheel running behavior in hamsters free-running under constant environmental conditions. If the phase shifting effects of triazolam on the circadian system are mediated through the benzodiazepine-GABA receptor complex, then it should be possible to block these effects with RO 15-1788, a selective benzodiazepine antagonist, which acts at the benzodiazepine-GABA receptor level. To test this hypothesis, hamsters free running in constant light received an intraperitoneal injection of various doses of Ro 15-1788 15 min before a single i.p. injection of 0.5 mg of triazolam. This dose of triazolam is known to induce maximal phase shifts in the circadian rhythm of wheel running behavior in hamster. Treatment with Ro 15-1788 totally blocked both the phase advancing and phase delaying effects of triazolam, while the administration of Ro 15-1788 alone did not phase shift the activity rhythm. These results support the hypothesis that the phase shifting effects of triazolam are mediated through the benzodiazepine-GABA receptor complex. The absence of any phase shifting effects of Ro 15-1788 when delivered alone suggests that Ro 15-1788 has no partial agonist properties in this experimental paradigm.