Phase response curves to light in young and old hamsters.

The phase-shifting effects of 1-h light pulses on the circadian rhythm of locomotor activity were measured in young (less than 12 mo old) and old (greater than 16 mo old) hamsters. Phase response curves (PRCs) for both age groups showed an inactive region [approximately circadian time (CT) 0 through CT12], a delay region (CT12 through CT16), and an advance region (CT16 through CT24) as has been reported for young animals. Significant age group differences in the amplitude of phase shifts were measured, with older animals showing larger shifts limited to the region of the "break point" at CT16.

The effects of short periods of immobilization on the hamster circadian clock.

Recent findings indicate that stimuli which induce an acute increase in locomotor activity can induce phase shifts in the circadian clock of hamsters. Support for the actual role of the acute increase in activity in the mediation of these phase shifts is provided by the observation that immobilization can totally block phase shifts in the activity rhythm that are normally induced in response to exposure to two of these stimuli, either a pulse of darkness or an injection of a benzodiazepine. In order to further examine the effects of immobilization on the circadian system of hamsters, 3 studies were carried out.

Bicuculline and picrotoxin block phase advances induced by GABA agonists in the circadian rhythm of locomotor activity in the golden hamster by a phaclofen-insensitive mechanism.

Permanent phase shifts in the free-running rhythm of locomotor activity of the golden hamster were induced with microinjections of the gamma-aminobutyric acid (GABA) agonists muscimol or baclofen in the hypothalamic suprachiasmatic nuclei. Muscimol and baclofen exhibit relatively high binding affinities for GABAA and GABAB receptors, respectively. Microinjections of the GABA antagonists, bicuculline methobromide or picrotoxinin, thought to block the actions of GABA at GABAA receptors, could block phase shifts induced by muscimol but not the benzodiazepine, triazolam.

Daily injections of triazolam induce long-term changes in hamster circadian period.

Previous experiments in hamsters indicate that daily injections of the short-acting benzodiazepine, triazolam, can entrain the free-running circadian activity rhythm to the period of the injections and that, after discontinuation of triazolam injections, the period of the free-running activity rhythm remains close to that of the previous injection schedule for 20-50 cycles. In this paper, we extend these findings and demonstrate that 1) long-term treatment with triazolam can induce aftereffects on the period of the circadian clock underlying the activity rhythm that can last for up to 100 days, 2) triazolam-induced changes in period can lead to a loss of effect of daily injections of triazolam which can be restored if the time of injection is altered, and 3) chronic treatment with triazolam also alters the period of the circadian clock in animals entrained to a light-dark cycle, and such changes in period alter the phase relationship between the circadian clock and the entraining light-dark cycle.

Effects of the short-acting benzodiazepine triazolam, taken at bedtime, on circadian and sleep-related hormonal profiles in normal men.

Studies in rodents have shown that triazolam, a commonly used hypnotic, may shift circadian rhythms, with the direction and magnitude of the phase-shifts being dependent on the time of drug administration. To determine whether benzodiazepine, taken at standard bedtime, modifies the amount and/or temporal organization of hormonal secretion, six normal men were studied during basal conditions and on the first and third days of treatment with 0.5 mg triazolam.

Photic threshold for stimulation of testicular growth and pituitary FSH release in male Djungarian hamsters.

While the effects of photoperiod on neuroendocrine-gonadal activity have been extensively studied in a number of species, surprisingly little information concerning the quantitative aspects of light regulating reproductive activity is available. In the present experiment, Djungarian hamsters were exposed to two 10 min pulses of light per day and the light irradiance was systematically varied to determine the threshold for photostimulation by white light. After 10 days testes weight and serum follicle-stimulating hormone (FSH) levels were determined.

Carbachol phase shifts the circadian rhythm of locomotor activity in the Djungarian hamster.

The effects of light on the circadian system may involve the neurotransmitter acetylcholine (ACh). The purpose of the present study was to determine whether carbachol, a cholinergic agonist, mimics the phase-shifting effects of light on the circadian rhythm of locomotor activity (CRLA) in the Djungarian hamster. Phase response curves (PRCs) were measured for blind animals injected intracerebroventricularly with either vehicle or carbachol at different circadian times.

Phase shifting the circadian clock with cycloheximide: response of hamsters with an intact or a split rhythm of locomotor activity.

Systemic administration of the protein synthesis inhibitor, cycloheximide, induced both phase advances and phase delays in the circadian rhythm of wheel-running activity in hamsters (Mesocricetus auratus) maintained in constant darkness or constant light. The magnitude and direction of the phase shifts were dependent on the circadian time (CT) of drug treatment. The phase response curves in constant darkness and constant light were of similar general shape, but they differed in the overall mean amplitude of the phase shifts.

Stimulated activity mediates phase shifts in the hamster circadian clock induced by dark pulses or benzodiazepines.

A number of environmental and pharmacological stimuli capable of inducing phase shifts and/or period changes in the circadian clock of mammals have now been identified. Agents that can alter circadian clocks provide a means for investigating the cellular and neural mechanisms responsible for their generation, regulation and entrainment. Two stimuli that have been used to probe the basis of circadian rhythmicity are pulses of darkness on a background of constant light and injections of short-acting benzodiazepines, such as triazolam.

SCN lesions abolish ultradian and circadian components of activity rhythms in LEW/Ztm rats.

A trimodal locomotor activity pattern has been observed in LEW/Ztm rats. Complete and partial lesions of the suprachiasmatic nucleus (SCN) were used to determine whether the same neural substrate may underlie the circadian rhythms and the ultradian modulation of wheel-running activity in these rats. Whereas sham lesions had little or no effect on the wheel-running activity pattern, complete SCN lesions resulted in a complete loss of circadian and ultradian activity components under free-running or 12:12 h light-dark cycle (12:12 LD) conditions.

Beta-methyl carboline, a benzodiazepine inverse agonist, attenuates the effect of triazolam on the circadian rhythm of locomotor activity.

The benzodiazepine triazolam, the benzodiazepine inverse agonist, beta-methyl carboline (beta-CCM) or both, were administered to adult male hamsters under conditions of constant light. When given alone, triazolam induced phase advances in the circadian activity rhythm of about 90 min, while beta-CCM when given alone, had no effect on phase of the activity rhythm. However, when triazolam and beta-CCM were given at the same time, the magnitude of the phase advances induced by triazolam were attenuated to about 30 min.

Midazolam, a short-acting benzodiazepine, resets the circadian clock of the hamster.

Treatment with the short-acting benzodiazepine, triazolam, has been found to induce changes in both behavioral and endocrine circadian rhythms in hamsters. The objective of this study was to determine if these effects of triazolam could be generalized to other short-acting benzodiazepines. Therefore, the effects of midazolam on the biological clock of the hamster were examined in detail.

Administering triazolam on a circadian 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 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.

Single injections of triazolam, a short-acting benzodiazepine, lengthen the period of the circadian activity rhythm in golden hamsters.

Single injections of the benzodiazepine, triazolam, induce phase shifts and cause a lengthening of the circadian activity rhythm in the golden hamster. The effect of triazolam on period depends on the phase of injection, but is not dependent on the direction of the phase shifts. Triazolam injections caused increases in period that were associated with phase advances as well as phase delays in the activity rhythm.

Central administration of muscimol phase-shifts the mammalian circadian clock.

The suprachiasmatic nucleus (SCN) of the hypothalamus contains a neural oscillatory system which regulates many circadian rhythms in mammals. Immunohistochemical evidence indicates that a relatively high density of GABAergic neurons exist in the suprachiasmatic region. Since intraperitoneal injections of the benzodiazepine, triazolam, have been shown to induce phase shifts in the free-running circadian rhythm of locomotor activity in the golden hamster, the extent to which microinjections of muscimol, a specific agonist for gamma-aminobutyric acid (GABA), may cause phase-shifts in hamster activity rhythms was investigated.

Use of benzodiazepines to manipulate the circadian clock regulating behavioral and endocrine rhythms.

Extensive studies have now been carried out demonstrating that the systemic administration of the short-acting benzodiazepine, triazolam, can have pronounced effects on both behavioral and endocrine circadian rhythms. For example, three daily injections of triazolam can phase-advance the circadian rhythm of pituitary luteinizing hormone release and locomotor activity by about 2-3 h in female hamsters maintained in constant light. Triazolam has also been found to facilitate the rate of reentrainment of the activity rhythm following an 8-hour advance or delay in the light-dark cycle.

Effects of stimulated physical activity on the circadian pacemaker of vertebrates.

A dogma in the field of circadian rhythms is that in order to keep accurate time, pacemakers that generate such rhythms must be relatively independent of changes in the external and internal environment. While it is true that the period of circadian oscillators is conserved within a narrow range, regardless of alterations in the external and internal environment, numerous perturbations have now been found that can change the period and/or induce a phase shift in circadian pacemakers. Many of these perturbations also alter the overall level of activity and/or metabolic state of the organism.

Inhibitor of protein synthesis phase shifts a circadian pacemaker in mammalian SCN.

The suprachiasmatic nucleus (SCN) of the hypothalamus contains a circadian pacemaker that regulates many circadian rhythms in mammals. Experimental work in microorganisms and invertebrates suggests that protein synthesis is required for the function of the circadian oscillator, and recent experiments in golden hamsters suggest an acute inhibition of protein synthesis can induce phase shifts in a mammalian circadian pacemaker. To determine whether protein synthesis in the SCN region is involved in the generation of circadian rhythms in mammals, a protein synthesis inhibitor, anisomycin, was microinjected into the SCN region, and the effect on the circadian rhythm of locomotor activity of hamsters was measured.

Transfer from long to short days reduces the frequency of pulsatile luteinizing hormone release in intact but not in castrated male golden hamsters.

In the golden hamster, prolonged exposure to short days (i.e. less than 12.

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

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.

The importance of follicle-stimulating hormone in the initiation of testicular growth in photostimulated Djungarian hamsters.

Juvenile male Djungarian hamsters (Phodopus sungorus sungorus) exhibit rapid and robust increases in both serum FSH and testicular weight within 1 week of transfer from nonstimulatory short days to stimulatory long days, while serum LH levels rise little or not at all during this same time period. Two experiments were performed to determine whether the rapid increase in serum FSH is responsible for the initial increase in testis weight. In the first study, the rapid increase in serum FSH levels, which normally occurs in response to photostimulation, was suppressed by twice daily injections of porcine follicular fluid, a substance known to contain the FSH-suppressing protein inhibin.

The circadian rhythm of LH release can be shifted by injections of a benzodiazepine in female golden hamsters.

Three daily injections of the short-acting benzodiazepine, triazolam, induced pronounced phase shifts in the onset of both the circadian surge in pituitary LH release and the circadian rhythm of locomotor activity in ovariectomized hamsters treated with estrogen. Both the magnitude and the direction of the phase shifts in these two rhythms were similar. These results indicate that a master circadian clock underlying diverse behavioral and endocrine rhythms can be reset by treatment with triazolam.

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.