Administering triazolam on a circardian basis entrains the activity rhythm of hamsters

A single injection of the short-acting benzodiazepine, triazolam, can induce permanent phase shifts in the circadian rhythm of locomotor activity in free-running hamsters, with the direction and magnitude of the phase shifts being dependent on the circadian time of treatment. The shape of the 'phase-response curve' to triazolam injections is totally different from that of for light pulses. These findings raise the possibility that repeated injections of triazolam on a circadian basis might be capable of entraining the circadian pacemaker underlying the activity rhythm of hamsters and that the entrainment pattern might differ from that observed in animals entrained to light pulses. To test this hypotheses, blind hamsters received intraperitoneal injections of triazolam (or vehicle) every 23.34, 23.72, 24.00 or 24.66 h for 19-20 days, and the effect of these injections on the period of the rhythm of wheel-running behavior was determined during and after treatment. Repeated injections of 0.1 mg triazolam at these time intervals resulted in the entrainment of the activity rhythm in 36 of 40 animals, whereas 0 of 40 animals entrained to vehicle injections. Importantly, the phase relationship between triazolam injections and the circadian activity rhythm was dependent on the period of drug treatment and could be predicted from the phase-response curve to single injections of triazolam. These phase relationships are dramatically different from those observed between the activity rhythm and 1-h light pulses presented at similar circadian intervals. Thus a central clock underlying the activity rhythm of hamsters can be entrained by repeated injections of a short-acting benzodiazepine, and similar to the response to light, the phase relationship between the entraining stimulus and the pacemaker can be predicted from the phase-response curve to single-pulse perturbations.