Manipulation of a central circadian clock regulating behavioral and endocrine rhythms with a short-acting benzodiazepine used in the treatment of insomnia.

Abnormal circadian rhythms have been linked to at least some forms of depression and to disturbances in the sleep-wake cycle. In addition, mental and physical disorders that are associated with rapid travel across time zones (i.e. the jet-lag syndrome) and with rotating shift-work schedules, are thought to involve a disruption of normal circadian rhythmicity. It might be possible to alleviate some of the adverse effects of abnormal circadian rhythms if pharmacological agents could be used to manipulate the central circadian pacemaker(s) that regulate these rhythms. Studies in our laboratory indicate that treatment with a short-acting benzodiazepine, triazolam, can induce major shifts in both behavioral and endocrine circadian rhythms in hamsters under a variety of experimental conditions. In the absence of a synchronizing light-dark cycle (i.e. during exposure to constant light or constant dark), single or multiple injections of triazolam can induce a permanent phase shift in both the circadian rhythm of locomotor activity and the circadian rhythm of pituitary LH release. In addition, repeated daily injections of triazolam can alter the entrained phase relationship of the circadian activity rhythm to a fixed light-dark cycle, and following a shift in the light-dark cycle, a single injection of triazolam can facilitate the time it takes for the activity rhythm to be resynchronized to the new lighting schedule. Thus, triazolam, or drugs with similar phase-shifting effects on the mammalian circadian system, might be useful in the treatment of various physical and mental illnesses that have been associated with a disorder in circadian time-keeping in humans.