Effects of indirect light and propranolol on melatonin levels in normal human subjects
Introduction
The pineal gland produces and secretes melatonin (Arendt, 1988, Reiter, 1993) in a circadian rhythm with maximal levels at night. In humans, daytime levels are barely detectable (<5 pg/ml), but nocturnal peaks range between 20 and 140 pg/ml (Lewy and Markey, 1978). Although there are marked inter-individual differences in levels, there is high individual consistency (Coetzee et al., 1989).
Light is the primary environmental influence on melatonin secretion. Both daylight and bright artificial light suppress nighttime melatonin serum levels (Lewy et al., 1980). The nocturnal suppression by light is a useful non-drug intervention in studying melatonin secretion. As with plasma melatonin levels, melatonin suppression after nighttime exposure to 500 lx light also varies considerably among normal subjects, ranging from 0 to 80% in studies controlled for age, sex, baseline melatonin level, and season of testing (Lewy et al., 1980, Nurnberger et al., 1988, Bojkowski et al., 1987, McIntyre et al., 1989b). Inter-individual differences in melatonin suppression may reflect genetic differences (Wetterberg et al., 1983). However, proximity to the source of illumination, pupil response and gaze behavior all affect melatonin suppression (Dawson and Campbell, 1990, Gaddy et al., 1993).
To study the neuropharmacological mechanisms by which light causes melatonin suppression, we developed a protocol for administering indirect lighting and measured melatonin levels in healthy, normal human subjects. In contrast to prior studies, we chose to use indirect lighting to reduce behavioral variation because a subject's gaze wanders in a 2-h period of light exposure. Indirect lighting was also safer since staring intensely at a bright light source can cause retinal degeneration and headaches (Dureau et al., 1996). We compared melatonin levels obtained under our conditions at several different light intensities with previous studies that found intensity-dependent suppression of nocturnal melatonin in normal subjects (Brainard et al., 1988, McIntyre et al., 1989a).
Because the indirect lighting protocol required the subject to sit up in a chair and our control condition was lying supine in the dark, we also examined the effects of body position, supine vs. sitting, on plasma melatonin levels. Moving from a supine to a standing position changes melatonin levels, perhaps due to changes in plasma volume that accompany changes in position (Deacon and Arendt, 1994).
We did not monitor the state of wakefulness of supine subjects in the dark because Morris et al. (1990)found no difference in the urinary excretion of 6-hydroxymelatonin sulfate, the primary melatonin metabolite, between normal sleep and continuous wakefulness in subjects in bed rest `constant routines' under dim light.
We used the indirect lighting protocol to examine the interaction between light and propranolol on plasma melatonin levels in normal human subjects. The β-adrenergic receptors are an important element in the neurochemical pathway mediating effects of environmental light on pinealocytes. Light resets the circadian pacemaker in the suprachiasmatic nucleus (SCN) by way of the retinohypothalamic tract from the retina to the SCN (Moore and Klein, 1974, Sadun et al., 1984). Impulses from the SCN reach the pineal by a multisynaptic pathway incorporating the superior cervical ganglion, innervating the pineal primarily via β-adrenergic receptors on pinealocytes (Moore, 1978, Roseboom and Klein, 1995). Propranolol and atenolol, β-receptor antagonists, block the nocturnal rise in melatonin plasma levels and melatonin's urinary metabolites in humans (Moore et al., 1979, Beck-Friis et al., 1983, Cowen et al., 1983, Cowen et al., 1985, Arendt et al., 1985a, Arendt et al., 1985b, Demitrack et al., 1990).
We hypothesized that changes in melatonin levels in response to β-blockers would predict individual response to light. We used two doses of propranolol, 10 mg and 40 mg, to identify an optimal dose for suppression of melatonin in the indirect lighting protocol.
Section snippets
Subject selection and study protocol
Normal subjects were recruited by campus advertisement. Both males and females were studied, with age range from 18 to 65 years old. Subjects had no major psychiatric disorder by clinical interview using the Structured Clinical Interview for DSM-III-R (SCID I and II; Spitzer and Williams, 1986) for DSM-III-R diagnosis. They were screened by physical examination, EKG, a complete blood count with differential, a biochemistry profile, a pregnancy test on premenopausal women, and an HIV titer.
Experiment 1: light exposure
Fig. 1 shows mean melatonin plasma levels through the night for a group of 21 subjects in both dark and light, n=13–20 at any time and condition. For subjects in the dark, plasma melatonin levels increased steadily from the first measurement to a peak at 02.20 h. In a mixed model ANOVA with repeated measures (Winer, 1971) looking at time and treatment and their interaction, there was a significant effect of treatment (F1,391=90.94, P<0.0001) and time (F11,391=2.36, P<0.05). The figure indicated
Discussion
This study showed that an indirect light protocol could effectively test melatonin suppression in normal subjects. The levels of melatonin in dark as well as 28% suppression of melatonin secretion by 500 lx light obtained by our indirect-lighting protocol in a large sample of normal volunteers were consistent with those of prior studies in the dark (Coetzee et al., 1989) or utilizing direct lighting (Lewy et al., 1985Bojkowski et al., 1987Nurnberger et al., 1988McIntyre et al., 1989b). Lewy et
Acknowledgements
This work was supported by funds from the National Institute of Mental Health (PHS R01 MH 43325). We also acknowledge the support of the Department of Veterans Affairs, the General Clinical Research Center at Indiana University Hospital (M012rr00750), and a grant from the Indiana State Division of Mental Health.
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