Acute effects of bright light and caffeine on nighttime melatonin and temperature levels in women taking and not taking oral contraceptives.

Caffeine and bright light effects on nighttime melatonin and temperature levels in women were tested during the luteal phase of the menstrual cycle (n=30) or the pseudo luteal phase for oral contraceptive users (n=32). Participants were randomly assigned to receive either bright (5000 lux) or dim room light (<88 lux) between 20:00 and 08:00 h under a modified constant routine protocol. Half the subjects in each lighting condition were administered either caffeine (100 mg) or placebo in a double-blind manner at 20:00, 23:00, 02:00 and 05:00 h. Results showed that the combination of bright light and caffeine enhanced nighttime temperature levels to a greater extent than did either caffeine or bright light alone. Both of the latter groups had higher temperature levels relative to the dim light placebo condition and the two groups did not differ. Temperature levels in the bright light caffeine condition were maintained at near peak circadian levels the entire night in the luteal and pseudo luteal phase. Melatonin levels were reduced throughout the duration of bright light exposure for all women. Caffeine reduced the onset of melatonin levels for women in the luteal phase, but it had little effect on melatonin levels for oral contraceptive users. The results for women in the luteal phase of the menstrual cycle are consistent with our previous findings in men. The results also suggest that oral contraceptives may alter the effects of caffeine on nighttime melatonin levels.

Combination of bright light and caffeine as a countermeasure for impaired alertness and performance during extended sleep deprivation.

Effects of four conditions (Dim Light-Placebo, Dim Light-Caffeine, Bright Light-Placebo and Bright Light-Caffeine) on alertness, and performance were studied during the night-time hours across 45.5 h of sleep deprivation. Caffeine (200 mg) was administered at 20.00 and 02.00 hours and bright-light exposure (> 2000 lux) was from 20.00 to 08.00 hours each night. The three treatment conditions, compared to the Dim Light-Placebo condition, enhanced night-time performance. Further, the combined treatment of caffeine and all-night bright light (Bright Light-Caffeine) enhanced performance to a larger degree than either the Dim Light-Caffeine or the Bright Light-Placebo condition. Beneficial effects of the treatments on performance were largest during the early morning hours (e.g. after 02.00 hours) when performance in the Dim Light-Placebo group was at its worst. Notably, the Bright Light-Caffeine condition was able to overcome the circadian drop in performance for most tasks measured. Both caffeine conditions improved objective alertness on the Maintenance of Wakefulness Test. Taken together, the above results suggest that the combined treatment of bright light and caffeine provides an effective intervention for enhancing alertness and performance during sleep loss.

Caffeine and light effects on nighttime melatonin and temperature levels in sleep-deprived humans.

The effects of caffeine ingestion and exposure to bright light, both separately and in combination, on salivary melatonin and tympanic temperature were assessed in humans. Four treatments during a 45.5 h sleep deprivation period were compared: Dim Light-Placebo, Dim Light-Caffeine, Bright Light-Placebo and Bright-Light Caffeine. The Dim Light-Caffeine condition (200 mg twice each night) relative to the Dim Light-Placebo condition suppressed nighttime melatonin levels and attenuated the normal decrease in temperature. Combining caffeine ingestion with bright light exposure (> or = 2000 lux) suppressed melatonin and attenuated the normal nighttime drop in temperature to a larger degree than either condition alone; i.e. effects were additive. Circadian effects were also observed in that the amplitude and phase of the temperature rhythm were altered during treatment. These findings establish that the human melatonin system is responsive to caffeine. Other evidence suggests that caffeine may influence melatonin and temperature levels through antagonism of the neuromodulator adenosine.

Nonsteroidal anti-inflammatory drugs alter body temperature and suppress melatonin in humans.

Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit prostaglandin synthesis in humans. Prostaglandins are involved in thermoregulation, melatonin synthesis, and sleep. To determine effects of NSAIDs on body temperature (BT) and melatonin synthesis (MT) in humans, and to elucidate mechanisms by which NSAIDs may alter sleep patterns, a series of experiments using the NSAIDs aspirin and ibuprofen was conducted. Seventy-five subjects were tested under several experimental protocols. BT after NSAID or placebo was assessed in both between- and within-subjects designs at night and during the day. MT levels were assessed after NSAID or placebo at night in a within-subjects design. The normal nocturnal BT decrease was attenuated and MT was suppressed after NSAID relative to after placebo administration. Lower MT levels were associated with a relative flattening of BT. Daytime BT was not affected by NSAIDs. These results are compatible with the hypothesis that some of the behavioral changes associated with NSAIDs, including changes in sleep, are due to changes in BT and MT. We speculate that NSAID effects on sleep and BT are related to prostaglandin synthesis inhibition and/or suppression of MT.

Changes in circadian rhythms and sleep quality with aging: mechanisms and interventions.

Literature is reviewed indicating that aging is characterized by changes in circadian rhythms and sleep quality. The most marked change is an attenuation of amplitude. An advance of phase, a shortening of period, and a desynchronization of rhythms are also evident. The mechanisms underlying these changes are unknown. However, age-related changes in the retina, suprachiasmatic nucleus, and pineal gland seem relevant along with behavioral changes such as a reduction in physical activity and exposure to photic stimulation. Changes in circadian rhythms are frequently associated with a reduction in nighttime sleep quality, a decrease in daytime alertness, and an attenuation in cognitive performance; reversing such changes could enhance the quality of life for a large and rapidly increasing percentage of the population. Reversal appears possible by increasing melatonin levels with either appropriately timed exposure to photic stimulation and/or appropriately timed administration of exogenous melatonin. These interventions may increase aspects of genetic expression that have changed with aging. A hypothesis concerning the potential benefits of enhanced circadian amplitude is also offered.

Nonsteroidal anti-inflammatory drugs affect normal sleep patterns in humans.

Previous studies have demonstrated that some nonsteroidal anti-inflammatory drugs (NSAIDs), specifically aspirin and indomethacin, have acute negative effects on sleep in humans and animals. Whether this finding can be replicated and extended to other NSAIDs, particularly the widely used over-the-counter drugs ibuprofen and acetaminophen, was the focus of the present investigation. Thirty-seven male and female subjects slept in the sleep laboratory on 2 consecutive nights; sleep was polygraphically recorded on the second night. Three doses of a prostaglandin-inhibiting drug (i.e., aspirin, acetaminophen, or ibuprofen) or placebo were administered, one each at 2300 h on the day prior to sleep recording, and at 0815 h and 2300 h on the day sleep was recorded. Subjects slept from 2400-0800 h both nights. Aspirin and ibuprofen disrupted sleep in comparison to placebo by increasing the number of awakenings and percentage of time spent in stage wake, and by decreasing sleep efficiency. Ibuprofen also delayed the onset of the deeper stages of sleep. Acetaminophen did not differ significantly from placebo on any measure of polygraphically recorded sleep. However, every index of objective sleep reflected slight, albeit nonsignificant, sleep disruption for each drug group relative to placebo. The mechanisms of sleep disruption after NSAID administration may relate to direct and indirect consequences of inhibiting prostaglandin synthesis, including decreases in prostaglandin D2, suppression of nighttime melatonin levels, and changes in body temperature.

Immediate effects of different light intensities on body temperature and alertness.

The effects of different light intensities on temperature and alertness were investigated. It was hypothesized that temperature and alertness would be affected by certain light intensities but only during the melatonin release period (after 2100 h). Fifteen subjects were tested under three levels of light known to suppress melatonin (500, 1000, and 5000 lx) and a level known not to affect melatonin (50 lx). Subjects were tested on four occasions from 1700 until 2300 h. Tympanic temperature and measures of alertness (EEG power and frequency and self-reports) were obtained before and after melatonin onset. There were no differences in any measure prior to the melatonin onset, increases in temperature and alertness occurred only after melatonin onset. Temperatures and self-reported alertness scores obtained under light intensities of 500, 1000, and 5000 lx were elevated relative to those obtained under 50 lx but were not significantly different from each other. The results suggest that melatonin may be involved in mediating the effects of light on temperature and alertness and that 500 lx may be near the threshold for significant melatonin suppression, temperature enhancement, and increases in alertness.

Protection against carbon tetrachloride hepatotoxicity by pretreatment with indole-3-carbinol.

The effects of administering indole-3-carbinol (I-3-C) on carbon tetrachloride (CCl4)-induced hepatotoxicity were examined. Mice received by gavage 0-150 mg I-3-C/kg body wt in methanol-extracted corn oil, followed 1 h later by 15 microliters CCl4/kg body wt in corn oil. Animals were sacrificed 24 h after receiving CCl4. Pretreatment with I-3-C reduced the degree of centrolobular necrosis, as observed histologically. Additionally, CCl4-mediated elevated serum enzymes were reduced by I-3-C. Although I-3-C induced elevated levels of cytochrome P-450 and associated mixed-function oxidase activity, the CCl4 depression of these parameters was not clearly reversed by I-3-C. However, CCl4 produced decreases in hepatic levels of glutathione (GSH), total reducing equivalents, and protein sulfhydryls, all of which were restored to control levels by I-3-C. Using mouse liver microsomes in an NADPH-fortified reaction mixture, I-3-C inhibited, in a concentration-dependent manner, CCl4-initiated lipid peroxidation, with 50% inhibition at 35-40 microM I-3-C. When mice were treated by gavage with 50 mg [14C]I-3-C/kg body wt, concentrations of radiolabel in the liver were greater than 100 microM after 1 hr. This was five times the level of radioactivity measured in blood and three times the concentration of I-3-C necessary for 50% inhibition of CCl4-mediated lipid peroxidation in vitro. The data are consistent with the hypothesis that I-3-C intervenes in CCl4-mediated hepatic necrosis by combining with reactive free radical metabolites of CCl4, thereby protecting critical cellular target sites.

Memory for pictograms, pictures, and words separately and all mixed up.

Pictograms were created in which the outline of a work denoting an object was shaped to be the same as the object itself. A number of objects were presented, some drawn as pictograms, some as outline shapes, and some as normally printed words. The experiment was designed to test if recognition memory was superior for the pictograms as compared to outline pictures or words, and if this would be true whether the subjects were asked to attend to the form or only the content of the stimuli. One group of subjects was trained to respond OLD only if the test item was the same object in the same form, and NEW only to objects never before shown in any form. Recognition accuracy (a signal detection analysis) was greatest for the pictograms, and poorest for the words in both groups. Though the subjects could disregard form, they were most accurate when probed with the same form as presented. But in all comparisons subjects were most accurate when forced to recall both the form and the content. These and other results were taken to be mildly supportive of a dual coding hypothesis, and of the utility of these new stimuli.

The metabolism of 7H-dibenzo[c,g]carbazole, an N-heterocyclic aromatic, in the isolated perfused lung.

The metabolism of a carcinogenic N-heterocyclic aromatic, 7H-dibenzo[c,g]carbazole, was investigated in an isolated perfused rabbit lung preparation in a rat liver microsomes. A major metabolite produced in both preparation is the 7-hydroxydibenzo[c,g]carbazole. A substantial percentage of this metabolite is found in the tracheabronchi, which would be consistent with the high incidence of respiratory tract tumors due to dibenzo[c,g]carbazole.