The melatonin antagonist luzindole protects retinal photoreceptors from light damage in the rat

PURPOSE: Systemic administration of melatonin can increase retinal light damage in the rat. The role of retinal melatonin receptors in modulating light-damage susceptibility was investigated by intravitreally injecting the melatonin receptor antagonist luzindole into rats. METHODS: Nine Sprague-Dawley albino rats 8 to 9 weeks of age were kept in 50 lux cyclic light for at least 7 days before receiving an intravitreal injection of 1 microl 1 mM luzindole in one eye and 1 microl vehicle in the other eye. The injection was given just before the beginning of the normal 12-hour dark phase. At the end of this dark period, animals were exposed to constant light of 2500 lux for 48 hours. Animals were returned to dim cyclic light for 7 days, and dark-adapted electroretinograms (ERGs) were then recorded from the two eyes simultaneously. The eyes were processed for retinal morphology. Photoreceptor nuclei were counted in the outer nuclear layer (ONL), and the thickness of the ONL and that of the rod outer-segment plus inner-segment layer were measured at several points along sections through the vertical meridian. Two age-matched control rats were maintained in dim cyclic light but received no injections. RESULTS: Luzindole-treated eyes had ERG b-wave thresholds of 2.7 +/- 0.5 (mean +/- SEM) log candela (cd)/m2 lower than the fellow eyes injected with vehicle (P < 0.001), and the maximum b-wave amplitude was 1.0 +/- 0.2 log microV greater in luzindole-treated eyes (P < 0.001). Thresholds of the scotopic threshold response were 0.5 +/- 0.1 log cd/m2 lower than those in vehicle-injected eyes (P < 0.05). Luzindole-treated eyes on average had twice as many photoreceptor cells remaining (P < 0.005). In some areas, several rows of photoreceptor nuclei and outer segments remained in the luzindole-treated eye, whereas the fellow control eye showed cells only occasionally and no outer segments. CONCLUSIONS: Eyes pretreated with the melatonin receptor competitive antagonist luzindole before the dark phase preceding constant light exposure were substantially protected from light damage to the retinal photoreceptors. These results implicate the intraocular melatonin-dopamine system in the regulation of light-damage susceptibility.     

Unusual responses to light and darkness of ocular melatonin in European sea bass

Regulation by light and darkness of melatonin rhythms in the plasma and eye of the European sea bass (Dicentrarchus labrax) was studied. During light-dark cycles, plasma and ocular melatonin exhibited day-night changes with higher levels at mid-dark and at mid-light, respectively. Circulating melatonin levels were low in constant light but high in constant darkness (DD); ocular melatonin levels showed the reverse pattern. Plasma melatonin exhibited circadian rhythm for 1 cycle but the rhythm was no longer apparent on day 2. There was no circadian rhythm in ocular melatonin. Acute light exposure in DD decreased plasma melatonin but increased ocular melatonin. These results suggest that circulating melatonin may be used as a signal for darkness but ocular melatonin is used as a signal for the light phase.     

Regulation mechanism of melatonin rhythm in the pineal gland by light: experimental studies by in vivo microdialysis

Light has dual effects on the pineal melatonin; one is the entrainment of the circadian rhythm and the other is suppression of the melatonin synthesis. It is not known whether the entraining and suppressing effects of light are mediated by the same pathway or not. To elucidate the mechanism of the dual effects of light, (1) the sensitivity of the retina, (2) effects of acetylcholine agonist and, (3) the arrhythmicity induced by longterm continuous light, were studied by measuring melatonin continuously from a single rat by means of in vivo microdialysis. Pineal melatonin was suppressed by light more strongly at the late dark phase than at midnight, and by green light (520nm) than by red light (660nm). Pineal melatonin measured by microdialysis was decreased rapidly by a short light exposure and the melatonin rhythm was shifted on the following days. Microinjection of cholinergic agonist, carbachol, into the suprachiasmatic nucleus neither suppressed nor entrained the pineal melatonin rhythm. Immediately after the blinding, rats showed the circadian rhythm in pineal melatonin which had been abolished under long-term continuous light. While, it took several days for the locomotor rhythm to reappear. It is concluded that, (1) suppression of the pineal melatonin by light depends on the circadian phase and on the wavelength of light, (2) the threshold for light suppression is lower than that for phase-shift, (3) the melatonin rhythm starts to phase-shift on the following day of light pulse. (4) Acetylcholine is unlikely to be involved in the photic transmission both to the circadian clock and to the pineal, (5) arrhythmicity induced by long-term continuous light seems to be due to masking for the melatonin rhythm, and to uncoupling from the clock for the locomotor rhythm.     

Panic and panic disorder in the United States

OBJECTIVES: Shift work and rapid travel across several time zones leads to desynchronization of internal circadian rhythms from the external environment and from each other with consequent problems of behaviour, physiology and performance. Field studies of travellers and shift workers are expensive and difficult to control. This investigation concerns the simulation of such rhythm disturbance in a laboratory environment. The main objectives are to assess the ability of controlled exposure to moderately bright light and darkness/sleep to delay circadian rhythms in volunteers without environmental isolation and, secondly, to evaluate the use of different indices of melatonin (MT) secretion together with self-rated alertness as marker rhythms. PATIENTS: Six normal volunteers aged 22-26 years (mean +/- SD 24.3 +/- 1.4). DESIGN: Subjects were exposed to the following periods of moderately bright light (1200 lux) on three consecutive days in early December 1991: Day (D)1: 2000-0200 h, D2: 2200-0400 h and D3: 2400-0600 h. Each period was followed by 8 hours of darkness (< 1 lux). Hourly blood, sequential 4-hourly urine (8-hourly when asleep) and hourly saliva (except when asleep) samples were taken throughout a 24-hour period on D0 (baseline), D4 (1 day post-light treatment) and D7 (4 days post-light treatment). During waking hours, subjective alertness was rated every 2 hours on a visual analogue scale. MEASUREMENTS: MT was measured in plasma and saliva, and its metabolite, 6-sulphatoxymelatonin (aMT6s), was measured in urine. MT, aMT6s and alertness scores were analysed by ANOVA and a cosinor analysis program. RESULTS: A delay shift was present in the aMT6s, plasma MT and salivary MT rhythms (degree of shift: 2.67 +/- 0.3 h (P < 0.001, n = 5); 2.35 +/- 0.29 h (P < 0.001, n = 6); and 1.97 +/- 0.32 h (P < 0.01, n = 6), mean +/- SEM, respectively) 1 day post-light treatment compared to baseline. Adaptation to the initial phase position was apparent by the 4th post-treatment day. Significant correlations were obtained between plasma MT onset (degree of shift: 3.12 +/- 0.74 h (P < 0.001, n = 6, mean +/- SEM)) and the acrophases (calculated peak times) of plasma MT (P < 0.001), salivary MT (P < 0.05) and urinary aMT6s (P < 0.01). A significant phase delay in the alertness rhythm was also evident 1 day post-treatment (3.08 +/- 0.67 h (P < 0.01, n = 6, mean +/- SEM)) with adaptation by the 2nd post-treatment day. CONCLUSIONS: This study suggests that these methods of determining MT secretion are comparable and give reliable assessments of the MT circadian phase position even after a phase-shift. Significant phase-shifts of similar magnitude can be induced in both MT and alertness rhythms using moderate intensity bright light at night.     

The therapeutic focus in significant sessions of master therapists: a comparison of cognitive-behavioral and psychodynamic-interpersonal interventions

This study was designed to test the hypothesis that bright light (BL) can have a stimulating effect on vigilance even in the absence of suppression of melatonin secretion and that this effect can be detected when measured in subjects with low vigilance levels. Seven normal subjects were exposed to bright-white light (BL group) and seven to dim-red light (DL group) on 2 consecutive days, each following a night of 4-h sleep restriction. The light treatment was administered in the late morning, between 0900 and 1330 hours. Salivary melatonin measurements indicated that BL did not suppress melatonin secretion or induce circadian phase shifts. The effects of the two treatments were compared on validated measures of daytime vigilance: immediate effects were evaluated on subjective alertness during the light treatment, whereas short-term (0.5-10.5 h) and long-term (20.5-34.5 h) carryover effects were measured on subjective alertness, daytime sleep latencies (DSL), and psychomotor performance. After two nights of sleep restriction, subjective alertness and daytime sleep latencies decreased significantly, but there was no effect of the light treatment. BL treatment did not affect global performance, but there was an effect on the strategy used by the subjects, as shown by faster reaction times and increased percentage of errors in the BL group. It was concluded that daytime BL exposure did not have a stimulating effect on our measures of vigilance even in sleep-deprived subjects but that it may increase physiological arousal and affect the subjects' behavior in some specific performance tasks.     

Non-24-hour sleep-wake syndrome in a sighted man: circadian rhythm studies and efficacy of melatonin treatment

The case of a 41-year-old sighted man with non-24-hour sleep-wake syndrome is presented. A 7-week baseline assessment confirmed that the patient expressed endogenous melatonin and sleep-wake rhythms with a period of 25.1 hours. We sought to investigate the underlying pathology and to entrain the patient to a normal sleep-wake schedule. No deficiency in melatonin synthesis was found. Furthermore, normal coupling between the melatonin and sleep propensity rhythms was documented using an "ultrashort" sleep-wake protocol. Environmental light exposure was monitored for 41 days, and the circadian timing was calculated. Sensitivity to photic input was determined with light-induced melatonin-suppression tests. Three intensities (500, 1,000, and 2,500 lux) were examined during three separate trials. The 2,500-lux trial resulted in 78% suppression, but the lesser intensity exposures were without substantial effect. Thus, the patient appeared to be subsensitive to bright light. A 4-week trial of daily melatonin administration (0.5 mg at 2100 hours) stabilized the endogenous melatonin and sleep rhythms to a period of 24.1 hours, albeit at a somewhat delayed phase. A 14-month follow-up interview revealed that the patient continued to take melatonin daily, and his sleep-wake schedule was stable to a near 24-hour schedule.     

Disruption of sleep recovery after 36 hours of exposure to moderately bright light

Eight young adults were exposed to either 36 hours of moderate bright light (BL; 1,000-2,000 lux) or a light/dark cycle (L/D < 50 lux) during constant routine. Sleep was recorded on the two subsequent recovery sleeps (R1 and R2) and compared to baseline. After the BL exposure, the rebound of stage 4 sleep and slow wave activity (SWA) were split over R1 and R2, whereas after the L/D cycle, the stage 4 sleep debt was almost completely compensated for during R1. During R1, stage 2 sleep and wakefulness accumulated faster in the BL condition than in the L/D condition. An elevation of the temperature level was also found during R1 of the BL condition. No differences between light conditions were found in urinary levels of melatonin or cortisol secreted during R1 or R2. Homeostasic process does not appear to be affected by the BL condition. A modification in the sleep-wake balance and a change in the temporal relationship between the circadian system and the sleep-wake cycle are discussed.     

The effect of melatonin on aqueous humor flow in humans during the day

BACKGROUND: Aqueous humor flow through the anterior chamber of the eye undergoes a circadian cycle. The rate of flow during the day is twice as high as the rate of flow at night. The pineal hormone, melatonin, also undergoes a circadian cycle. Melatonin levels are high at night, whereas aqueous humor flow is low. The authors studied the effect of oral melatonin on aqueous humor flow in humans. METHODS: The effect of melatonin on aqueous humor flow was evaluated in 19 healthy human volunteers in a randomized, masked crossover study with a placebo control. The hormone or placebo was administered orally during the day when endogenous levels of melatonin are low. Aqueous flow was measured by fluorophotometry for 8 hours. RESULTS: The mean rate of flow during melatonin treatment was 2.71 +/- 0.64 microliters/minute (+/- standard deviation). The rate of flow during placebo treatment was 2.80 +/- 0.66 microliters/minute. There is no statistically significant difference between these two rates (P = 0.4). With a sample size of 19, the study has a power of 92% to detect at least a 15% difference in the rate of flow under the two conditions. Measurement of plasma concentration of melatonin in five subjects confirmed that concentrations after oral dosage reached peaks comparable with the normal endogenous nocturnal peaks. CONCLUSIONS: The authors conclude that melatonin concentrations during the day, comparable with plasma concentrations that occur spontaneously during sleep, do not suppress aqueous humor formation. The authors find no support for the idea that plasma melatonin, per se, can suppress aqueous formation or that the circadian rhythm of plasma melatonin is primarily responsible for the circadian rhythm of aqueous humor flow.     

Diurnal melatonin and cortisol secretion profiles in medicated schizophrenic patients

Although melatonin and/or cortisol secretions have been suggested as markers for both circadian and noradrenaline dysfunctions in psychiatric illnesses, especially in affective disorders, studies of melatonin and cortisol in schizophrenic patients are rare. We evaluated the circadian profiles of melatonin and cortisol secretion in schizophrenic patients and control subjects. A total of 21 medicated Taiwanese male paranoid schizophrenic inpatients (mean age, 27.3 +/- 7.2 yr) and 21 age- and sex-matched controls underwent 24-hour neuroendocrine screening. Melatonin and cortisol concentrations were measured at 2-hour intervals from 0800 h to 2200 h, and at 1-hour intervals from 2300 h to 0700 h. The standard dexamethasone suppression test was performed the next day to provide an index of hypothalamic-pituitary-adrenal axis (HPA) function. The results showed that the circadian rhythm of plasma melatonin secretion was disrupted in schizophrenics compared with controls, whereas the 24-hour profile of plasma cortisol was preserved. The melatonin to cortisol ratio was significantly higher in control subjects than in schizophrenic patients. Results of the dexamethasone suppression tests indicated that there were no functional changes in the HPA axis in schizophrenic patients. Five drug-naive schizophrenic patients studied simultaneously, but whose data were not included in the above analyses, had results consistent with those of the maintenance-medicated patients. Our findings suggest the presence of abnormal melatonin metabolism in Taiwanese schizophrenics, which may possibly be related to the pathophysiologic process itself. However, broader pathogenetic aspects of these neuroendocrine interrelations remain to be clarified.     

Subclavian venogram as a guide to lead implantation

Melatonin synthesis in retinal photoreceptors is stimulated at night by a circadian oscillator and suppressed acutely by light. To identify photoreceptor mechanisms involved in the acute suppression of melatonin synthesis, an action spectrum was measured for dark-adapted Xenopus laevis eyecups at night. Intensity-response curves at six wavelengths from 400 to 650 nm were parallel, suggesting that a single photopigment predominates in melatonin suppression. Half-saturating intensities at 400, 440, 480, and 533 nm were not significantly different from one another, at 1-2 x 10(8) quanta cm(-2) s(-1). Significantly higher intensities of 580- and 650-nm light were required for melatonin suppression. These results indicate a predominant role for the principal green-absorbing rods in acute regulation of retinal melatonin synthesis in response to light, and argue against an important role for the red-absorbing cones. Higher than expected sensitivity at short wavelengths suggests that photoreceptors sensitive to blue and/or violet light may also contribute to melatonin suppression.     

Decreased melatonin levels in postmortem cerebrospinal fluid in relation to aging, Alzheimer's disease, and apolipoprotein E-epsilon4/4 genotype

Sleep disruption, nightly restlessness, sundowning, and other circadian disturbances are frequently seen in Alzheimer's disease (AD) patients. Changes in the suprachiasmatic nucleus and pineal gland are thought to be the biological basis for these behavioral disturbances. Melatonin is the main endocrine message for circadian rhythmicity from the pineal. To determine whether melatonin production was affected in AD, melatonin levels were determined in the cerebrospinal fluid (CSF) of 85 patients with AD (mean age, 75 +/- 1.1 yr) and in 82 age-matched controls (mean age, 76 +/- 1.4 yr). Ventricular postmortem CSF was collected from clinically and neuropathologically well defined AD patients and from control subjects without primary neurological or psychiatric disease. In old control subjects (>80 yr of age), CSF melatonin levels were half of those in control subjects of 41-80 yr of age [176 +/- 58 (n = 29) and 330 +/- 66 (n = 53) pg/mL, respectively; P = 0.016]. We did not find a diurnal rhythm in CSF melatonin levels in control subjects. In AD patients the CSF melatonin levels were only one fifth (55 +/- 7 pg/mL) of those in control subjects (273 +/- 47 pg/mL; P = 0.0001). There was no difference in the CSF melatonin levels between the presenile (42 +/- 11 pg/mL; n = 21) and the senile (59 +/- 8 pg/mL; n = 64; P = 0.35) AD patients. The melatonin level in AD patients expressing apolipoprotein E-epsilon3/4 (71 +/- 11 pg/mL) was significantly higher than that in patients expressing apolipoprotein E-epsilon4/4 (32 +/- 8 pg/ml; P = 0.02). In the AD patients no significant correlation was observed between age of onset or duration of AD and CSF melatonin levels. In the present study, a dramatic decrease in the CSF melatonin levels was found in old control subjects and even more so in AD patients. Whether supplementation of melatonin may indeed improve behavioral disturbances in AD patients should be investigated.     

Melatonin in light treatment of patients with seasonal and nonseasonal depression

Melatonin as a marker of circadian rhythm and the effect of bright light on melatonin were studied in 63 depressed patients, 42 with a seasonal pattern and 21 with a nonseasonal pattern. The patients were matched for age, time of treatment and severity of depression. Before light treatment, blood was sampled for melatonin and depression was clinically rated with the Comprehensive Psychopathological Rating Scale and Hamilton Depression Rating Scale. Two hours of light treatment, 350 cd/m2, was given daily for 10 days 0600 to 0800 or 1800 to 2000. Of the 42 patients with seasonal depression, 26 were treated with morning light and, 16 with evening light. The melatonin amplitude was significantly decreased by light, and the melatonin phase position was advanced by morning light and delayed by evening light. All patients except for 3 in each group changed in the expected direction. Although the patients with seasonal pattern had a more favorable outcome than patients with nonseasonal pattern, there was no difference in therapeutic outcome related to the baseline melatonin phase position. The hypothesis that the short term clinical effects of light therapy either in the morning or evening are related to pretreatment melatonin levels or alteration of melatonin amplitude or phase position was not supported in the study. There was also no significant difference between the seasonal and nonseasonal patients related to the degree of light suppression of melatonin and the rebound effect of serum melatonin levels following bright level exposure between 2200 and 2300 before regular light treatment.     

Corneal asphericity in eye bank eyes implanted with the intrastromal corneal ring

The endogenous circadian rhythm of melatonin in humans provides information regarding the resetting response of the human circadian timing system to changes in the light-dark (LD) cycle. Alterations in the LD cycle have both acute and chronic effects on the observed melatonin rhythm. Investigations to date have firmly established that the melatonin rhythm can be reentrained following an inversion of the LD cycle. Exposure to bright light and darkness given over a series of days can rapidly induce large-magnitude phase shifts of the melatonin rhythm. Even single pulses of bright light can shift the timing of the melatonin rhythm. Recent data have demonstrated that lower light intensities than originally believed are capable of resetting the melatonin rhythm and that stimulation of photopically sensitive photoreceptors (i.e., cones) is sufficient to reset the endogenous circadian melatonin rhythm. In addition to phase resetting, exposure to light of critical timing, strength, and duration can attenuate the amplitude of the endogenous circadian rhythm of melatonin. Measurement of melatonin throughout resetting trials provides a dynamic view of the resetting response of the human circadian pacemaker to light. Future studies of the melatonin rhythm in humans may further characterize the resetting response of the human circadian timing system to light.     

Effect of seasonal changes in daylength on human neuroendocrine function

The circadian pacemaker imposes stereotypic patterns of daily variation on the activity of human neuroendocrine systems. In a number of cases, these patterns exhibit waveforms that are characterized by distinct diurnal and nocturnal periods with relatively discrete transitions between them (corresponding to a biological day, a biological dusk, a biological night, and a biological dawn). In humans, for example, diurnal periods of absence of melatonin secretion, low prolactin secretion, and falling levels of cortisol alternate with nocturnal periods of active melatonin secretion, high prolactin secretion and rising levels of cortisol. In response to light, the circadian pacemaker synchronizes the timing of the biological day and night so that their timing and duration are appropriately matched with the timing and duration of the solar day and night. As the pacemaker carries out this function, it is able to adjust the duration of the biological day and night to match seasonal variation in the duration of the solar day and night. Thus, after humans have been chronically exposed to long nights (scotoperiods), the duration of nocturnal periods of active melatonin secretion, high prolactin secretion and rising levels of cortisol is longer than it is after they have been chronically exposed to short nights. Furthermore, the sleep-related peak of growth hormone secretion is half as high after exposure to long nights as it is after exposure to short nights. These responses to seasonal changes in duration of the natural scotoperiod are suppressed in most individuals - especially men - who live in modern urban environments in which they are exposed to artificial light after dark and artificial darkness during the daytime.     

Day/night differences in the stimulation of adenylate cyclase activity by calcium/calmodulin in chick pineal cell cultures: evidence for circadian regulation of cyclic AMP

In chick pineal cell culture, stimulation of adenylate cyclase with the diterpene forskolin was greater during the subjective night than during the subjective day. This rhythm of cyclic AMP (cAMP) stimulation mimicked the rhythm of unstimulated cAMP measured previously during LD cycles from flow-through culture. Direct measurement of adenylate cyclase activity in permeabilized cells revealed an adenylate cyclase activity activated by Ca2+/calmodulin during the night but not during the day. However, this difference in adenylate cyclase activity at two times of the circadian cycle is apparent only when permeabilized cells were prewashed with buffer containing GTE When cAMP was measured from flow-through cultures maintained in continuous darkness to determine whether a circadian clock may regulate cAMP, a low-amplitude rhythm was measured. The circadian rhythm of cAMP was similar to the cAMP rhythm previously measured on LD cycles except that the rhythm in darkness had a lower amplitude. Similar to the suppression of melatonin, cAMP was suppressed by light presented during the middle of the night. LD differences in nocturnal cAMP levels were abolished with dipyridamole, an inhibitor of cyclic GMP (cGMP) phosphodiesterase. These results suggest that the rhythm of cAMP in chick pineal cells involves the stimulation of adenylate cyclase by Ca2+/calmodulin during the night and a GTP-dependent suppression of adenylate cyclase activity during the day. The photic suppression of cAMP at night involves the activation of a dipyridamole-sensitive, cGMP phosphodiesterase.     

Eating disorders in adolescents: clinical and epidemiological aspects

This study aims to analyse a circadian rhythm of insulin secretion from isolated rat pancreatic islets in vitro and its potential modulation by melatonin, the concentrations of which change in vivo inversely to that of insulin. The circadian rhythm was evaluated in a perifusion system, adapted to the specific conditions of pancreatic islets. To determine rhythmicity of insulin secretion, 30-min fractions were collected continuously for investigative periods of 44 to 112 h. Insulin secretion in 10 experiments was analysed by using the MacAnova-program for period length (tau), the chi2-periodogram for test of significance (p < 0.001), and additionally the empirical cosine adaptation for amplitude and goodness-of-fit. Thereby a circadian pattern was observed with periods (tau) between 21.8 and 26.2 h. The period duration (mean +/- SEM) was 23.59 +/- 0.503 h, the overall mean insulin release 1038 +/- 13 pmol/l and the mean amplitude 88 +/- 17 pmol/l. Adding melatonin (10 nmol/l, t = 2 h) as a hormonal Zeitgeber during analysis of circadian insulin secretion phase-response studies show phase-shifts with approximately 9 h phase advance. Thereafter the circadian period was maintained, while the amplitude was enhanced. From this it is concluded that an endogenous circadian oscillator is located within the pancreatic islets of the rat that regulates circadian insulin secretion of the insulin-producing beta cells. The pacemaker is remarkably stable, because its periodicity is not affected by factors altering insulin secretion. In agreement with inhibitory influences of melatonin (range 0.5 nmol/l to 5 micromol/l) on the insulin response in vitro, the phase-responses support the contention that pancreatic beta cells may be targets for melatonin action.     

Inconsistent suppression of nocturnal pineal melatonin synthesis and serum melatonin levels in rats exposed to pulsed DC magnetic fields

The purpose of these experiments was to determine whether the exposure of rats at night to pulsed DC magnetic fields (MF) would influence the nocturnal production and secretion of melatonin, as indicated by pineal N-acetyltransferase (NAT) activity (the rate limiting enzyme in melatonin production) and pineal and serum melatonin levels. By using a computer-driven exposure system, 15 experiments were conducted. MF exposure onset was always during the night, with the duration of exposure varying from 15 to 120 min. A variety of field strengths, ranging from 50 to 500 microT (0.5 to 5.0 G) were used with the bulk of the studies being conducted using a 100 microT (1.0 G) field. During the interval of DC MF exposure, the field was turned on and off at 1-s intervals with a rise/fall time constant of 5 ms. Because the studies were performed during the night, all procedures were carried out under weak red light (intensity of <5 microW/cm2). At the conclusion of each study, a blood sample and the pineal gland were collected for analysis of serum melatonin titers and pineal NAT and melatonin levels. The outcome of individual studies varied. Of the 23 cases in which pineal NAT activity, pineal melatonin, and serum melatonin levels were measured, the following results were obtained; in 5 cases (21.7%) pineal NAT activity was depressed, in 2 cases (8.7%) studies pineal melatonin levels were lowered, and in 10 cases (43.5%) serum melatonin concentrations were reduced. Never was there a measured rise in any of the end points that were considered in this study. The magnitudes of the reductions were not correlated with field strength (i.e., no dose-response relationships were apparent), and likewise the reductions could not be correlated with the season of the year (experiments conducted at 12-month intervals under identical exposure conditions yielded different results). Duration of exposure also seemed not to be a factor in the degree of melatonin suppression. The inconsistency of the results does not permit the conclusion that pineal melatonin production or release are routinely influenced by pulsed DC MF exposure. In the current series of studies, a suppression of serum melatonin sometimes occurred in the absence of any apparent change in the synthesis of this indoleamine within the pineal gland (no alteration in either pineal NAT activity or pineal melatonin levels). Because melatonin is a direct free radical scavenger, the drop in serum melatonin could theoretically be explained by an increased uptake of melatonin by tissues that were experiencing augmented levels of free radicals as a consequence of MF exposure. This hypothetical possibly requires additional experimental documentation.     

Morning vs evening light treatment of patients with winter depression

BACKGROUND: According to the phase-shift hypothesis for winter depression, morning light (which causes a circadian phase advance) should be more antidepressant than evening light (which causes a delay). Although no studies have shown evening light to be more antidepressant than morning light, investigations have shown either no difference or morning light to be superior. The present study assesses these light-exposure schedules in both crossover and parallel-group comparisons. METHODS: Fifty-one patients and 49 matched controls were studied for 6 weeks. After a prebaseline assessment and a light/dark and sleep/wake adaptation baseline week, subjects were exposed to bright light at either 6 to 8 AM or 7 to 9 PM for 2 weeks. After a week of withdrawal from light treatment, they were crossed over to the other light schedule. Dim-light melatonin onsets were obtained 7 times during the study to assess circadian phase position. RESULTS: Morning light phase-advanced the dim-light melatonin onset and was more antidepressant than evening light, which phase-delayed it. These findings were statistically significant for both crossover and parallel-group comparisons. Dim-light melatonin onsets were generally delayed in the patients compared with the controls. CONCLUSIONS: These results should help establish the importance of circadian (morning or evening) time of light exposure in the treatment of winter depression. We recommend that bright-light exposure be scheduled immediately on awakening in the treatment of most patients with seasonal affective disorder.     

Daily and circadian variations in 2-[125I]-iodomelatonin binding sites in the pike brain (Esox lucius)

The fish pineal organ, through its 24 h rhythmic release of melatonin, acts as a transducer of the photoperiod, influencing different physiological functions (e.g. reproduction, growth). We have investigated the binding of 2-[125I]iodomelatonin to whole brain membrane preparations from pikes (Esox lucius L., teleost) maintained for 24-48 h under different photoperiodic conditions. Specific binding was stable, reversible, saturable and sensitive to the presence of a GTP analogue. Scatchard analysis revealed one class of binding sites. Displacement experiments suggested the presence of two components with affinities in the femtomolar and nanomolar range of concentrations, respectively. The Bmax exhibited monophasic nycthemeral variations, with higher values at the light-to-dark transition (34.0 +/- 4.5 fmol/mg protein) and low values during the second half of night (10.0 +/- 1.0 fmol/mg protein). Under the same conditions, the KD exhibited biphasic variations: values were low during daytime and at the middle of the dark phase (approximately 100 pM); they were high at the beginning (approximately 225 pM) and at the end (approximately 330 pM) of the night. These variations were maintained under constant light (LL) and constant darkness (DD). Thus, the variations in the number and affinity of the melatonin binding sites were controlled by circadian oscillators, synchronized by the photoperiod. The nature of these oscillators is not known. Therefore, in fish, we suggest that the photodependent effects of melatonin result from the circadian variations of both its production by the pineal and its binding sites in the brain.     

Differences in isoproterenol-stimulated melatonin production by perifused rat pineal glands: time dependent effects and role of enantiomeric forms

The perifusion of rat pineal glands removed at different times of the light-dark cycle showed a greater beta adrenergic-stimulated production of melatonin in glands obtained at the beginning of either the light or the dark stage. The effect of isoproterenol was found dependent upon its enantiomeric forms (-, +/-, +). The relative order of potency was (-) > (+/-) > (+) enantiomer. These results show that the response of pineal beta-adrenergic receptors to isoproterenol is stereospecific and circadian stage dependent.