Nocturnal Plasma Melatonin Concentrations Research Articles

Can the season of birth risk factor for schizophrenia be prevented by bright light treatment for the second trimester mother around the winter solstice?

The season of birth risk factor for schizophrenia exerts a pervasive effect on the global population, particularly at northerly latitudes. The winter infection hypothesis and the low vitamin D hypothesis are both compelling but lack conclusive clinical data. The present work develops a maternal–fetal chronobiological hypothesis for this season of birth risk factor and its prevention by maternal bright light treatment. Around the winter solstice, due to decreased sunlight, the chronobiological apparatus of the at-risk second trimester mother is characterized by a reduced amplitude circadian pacemaker, and a reduced maximum of her nocturnal plasma melatonin concentrations (MTmax) and an increased minimum of her nocturnal core body temperatures (Tmin)—both of which exert adverse effects on the fetal hippocampus and dorsal striatum. The consequences for the fetus include reduced volume and increased excitability of the hippocampus, ventral striatal dysfunction, increased presynaptic nigrostriatal dopamine transmission, and increased propensity for pathological nigrostriatal neuronal phasic firing. Thus, the maternal–fetal chronobiological hypothesis fully accounts for the fetal precursors of the major pathognomonic abnormalities in adults with schizophrenia. Bright light treatment for the second trimester mother around the winter solstice, by increasing maternal circadian amplitude, could possibly prevent the fetal hippocampal and striatal abnormalities and eliminate the season of birth risk factor for schizophrenia.

Daily Rhythms of Plasma Melatonin, but Not Plasma Leptin or Leptin mRNA, Vary between Lean, Obese and Type 2 Diabetic Men

Melatonin and leptin exhibit daily rhythms that may contribute towards changes in metabolic physiology. It remains unclear, however, whether this rhythmicity is altered in obesity or type 2 diabetes (T2DM). We tested the hypothesis that 24-hour profiles of melatonin, leptin and leptin mRNA are altered by metabolic status in laboratory conditions. Men between 45–65 years old were recruited into lean, obese-non-diabetic or obese-T2DM groups. Volunteers followed strict sleep-wake and dietary regimes for 1 week before the laboratory study. They were then maintained in controlled light-dark conditions, semi-recumbent posture and fed hourly iso-energetic drinks during wake periods. Hourly blood samples were collected for hormone analysis. Subcutaneous adipose biopsies were collected 6-hourly for gene expression analysis. Although there was no effect of subject group on the timing of dim light melatonin onset (DLMO), nocturnal plasma melatonin concentration was significantly higher in obese-non-diabetic subjects compared to weight-matched T2DM subjects (p<0.01) and lean controls (p<0.05). Two T2DM subjects failed to produce any detectable melatonin, although did exhibit plasma cortisol rhythms comparable to others in the group. Consistent with the literature, there was a significant (p<0.001) effect of subject group on absolute plasma leptin concentration and, when expressed relative to an individual’s 24-hour mean, plasma leptin showed significant (p<0.001) diurnal variation. However, there was no difference in amplitude or timing of leptin rhythms between experimental groups. There was also no significant effect of time on leptin mRNA expression. Despite an overall effect (p<0.05) of experimental group, post-hoc analysis revealed no significant pair-wise effects of group on leptin mRNA expression. Altered plasma melatonin rhythms in weight-matched T2DM and non-diabetic individuals supports a possible role of melatonin in T2DM aetiology. However, neither obesity nor T2DM changed 24-hour rhythms of plasma leptin relative to cycle mean, or expression of subcutaneous adipose leptin gene expression, compared with lean subjects.

Melatonin Effects on Plasmodium Life Cycle: New Avenues for Therapeutic Approach

Malaria remains a global health problem affecting more than 515 million people all over the world including Malaysia. It is on the rise, even within unknown regions that previous to this were free of malaria. Although malaria eradication programs carried out by vector control programs are still effective, anti-malarial drugs are also used extensively for curtailing this disease. But resistance to the use of anti-malarial drugs is also increasing on a daily basis. With an increased understanding of mechanisms that cause growth, differentiation and development of malarial parasites in rodents and humans, new avenues of therapeutic approaches for controlling the growth, synchronization and development of malarial parasites are essential. Within this context, the recent discoveries related to IP3 interconnected signalling pathways, the release of Ca2+ from intracellular stores of Plasmodium, ubiquitin protease systems as a signalling pathway, and melatonin influencing the growth and differentiation of malarial parasites by its effects on these signalling pathways have opened new therapeutic avenues for arresting the growth and differentiation of malarial parasites. Indeed, the use of melatonin antagonist, luzindole, has inhibited the melatonin's effect on these signalling pathways and thereby has effectively reduced the growth and differentiation of malarial parasites. As Plasmodium has effective sensors which detect the nocturnal plasma melatonin concentrations, suppression of plasma melatonin levels with the use of bright light during the night or by anti-melatonergic drugs and by using anti-kinase drugs will help in eradicating malaria on a global level. A number of patients have been admitted with regards to the control and management of malarial growth. Patents related to the discovery of serpentine receptors on Plasmodium, essential for modulating intra parasitic melatonin levels, procedures for effective delivery of bright light to suppress plasma melatonin levels and thereby arresting the growth and elimination of malarial parasites from the blood of the host are all cited in the paper. The purpose of the paper is to highlight the importance of melatonin acting as a cue for Plasmodium faciparum growth and to discuss the ways of curbing the effects of melatonin on Plasmodium growth and for arresting its life cycle, as a method of eliminating the parasite from the host.

Season of birth in schizophrenia: A maternal–fetal chronobiological hypothesis

Being born in the winter and spring significantly increases one’s risk for developing schizophrenia. This birth seasonality may account for as many as 10% of all cases of schizophrenia. Maternal third trimester infections or vitamin D deficiencies are hypothesized to be the most likely cause and can account for many of the important features of schizophrenia, although each hypothesis has limitations. Alternatively, around the winter solstice, reduced maternal sunlight exposure during the second trimester of pregnancy may result in a reduced amplitude maternal circadian pacemaker, reduced maternal nocturnal plasma melatonin concentrations, elevated maternal nocturnal core body and incubator temperatures, and elevated fetal core body and brain temperatures. Indeed, studies in humans have shown that the core body temperatures of human fetuses near birth may vary by >2.5 °C. Reduced melatonin concentrations and elevated temperatures have been shown to have detrimental effects on immature hippocampal neurons in animals. In addition, plasma melatonin concentrations and core body temperatures are critical determinants of the dopaminergic programming of the striatal component of the human central thermostat, which appears to be functioning by the second trimester of gestation and responsive to whatever chronobiological signals its mother correctly or incorrectly transduces from the prevailing meteorological conditions. Both hippocampal and striatal thermostat dysfunction may result in reduced striatal extracellular dopamine concentrations and a tendency towards increased phasic dopamine release—the characteristic biochemical lesion in schizophrenia. Thus, the maternal–fetal chronobiological dysfunction hypothesis could account for the birth seasonality in schizophrenia and warrants further investigation.

Melatonin effect on plasma adiponectin, leptin, insulin, glucose, triglycerides and cholesterol in normal and high fat–fed rats

Melatonin effect on body weight progression, mean levels and 24-hr pattern of circulating adiponectin, leptin, insulin, glucose, triglycerides and cholesterol were examined in rats fed a normal or a high-fat diet. In experiment 1, rats fed a normal diet were divided into two groups: receiving melatonin (25 μg/mL drinking water) or vehicle for 9 wk. In experiment 2, animals were divided into three groups: two fed with a high-fat diet (35% fat) and melatonin (25 μg/mL) or vehicle in drinking water for 11 wk, while a third group was given a normal diet (4% fat). At the end of experiments, groups of eight rats were killed at six different time intervals throughout a 24-hr period. Melatonin administration for 9 wk decreased body weight gain from the 3rd wk on without affecting food intake. A significant reduction in circulating insulin, glucose and triglyceride mean levels and disrupted daily patterns of plasma adiponectin, leptin and insulin were observed after melatonin. In high fat-fed rats, melatonin attenuated body weight increase, hyperglycemia and hyperinsulinemia, as well as the increase in mean plasma adiponectin, leptin, triglycerides and cholesterol levels. The high-fat diet disrupted normal 24-hr patterns of circulating adiponectin, insulin and cholesterol, the effects on insulin and cholesterol being counteracted by melatonin. Nocturnal plasma melatonin concentration in control and obese rats receiving melatonin for 11 wk attained values 21-24-fold greater than controls. The results indicate that melatonin counteracts some of the disrupting effects of diet-induced obesity in rats.

Melatonin secretion during postnatal development in wild and domestic female lambs

This study examines the patterns of melatonin secretion during postnatal development in wild (mouflon; n = 7) and domestic (Spanish Merino; n = 6) female lambs under their natural photoperiod conditions. The aim was to determine whether these types of sheep which differ in the timing of puberty, also differ in the establishment of daily melatonin secretory rhythms and/or in the nocturnal plasma melatonin secretion. In addition, the time when the lambs first reached nocturnal levels of melatonin similar to adults was also evaluated. For this purpose, the melatonin secretion in lambs was compared with those of their mothers. A day/night (D/N) difference in plasma melatonin concentration was noticed as early as 1 day after birth in the Merino female lambs (D: 5.9 ± 1.0 pg/ml compared to N: 22.0 ± 3.3 pg/ml; p < 0.05), and by 1 week after birth in the mouflon female lambs (D: 4.9 ± 0.3 pg/ml compared to N: 56.9 ± 15.3 pg/ml; p < 0.05). An effect of the genotype ( p < 0.05) and age ( p < 0.01) was detected on mean nocturnal plasma melatonin concentrations, which were lower in the Merino than in the mouflon lambs. Night-time plasma concentration of melatonin was also high in mouflon than in Merino mothers ( p < 0.05). No differences were detected between the wild genotype and the domestic one in the time when the lambs first reached nocturnal levels of melatonin similar to those of their mothers.

Melatonin increases stress fibers and focal adhesions in MDCK cells: participation of Rho‐associated kinase and protein kinase C

Melatonin cyclically modifies water transport measured as dome formation in MDCK cells. An optimal increase in water transport, concomitant with elevated stress fiber (SF) formation, occurs at nocturnal plasma melatonin concentrations (1 nm) after 6 hr of incubation. Blockage in melatonin-elicited dome formation was observed with protein kinase C (PKC) inhibitors. Despite, this information on the precise mechanism by which melatonin increases SF formation involved in water transport is not known. Focal adhesion contacts (FAC) are cytoskeletal structures, which participate in MDCK membrane polarization. SF organization and vinculin phosphorylation are involved in FAC assembly and both processes are mediated by PKC, an enzyme stimulated by melatonin; in these processes also involved is Rho-associated kinase (ROCK). Thus, we studied FAC formation and the ROCK/PKC pathway as the mechanism by which melatonin increases SF formation and water transport. The results showed that 1 nM melatonin and the PKC agonist phorbol-12-miristate-13-acetate increased FAC. The PKC inhibitor GF109203x, and the ROCK inhibitor Y27632, blocked increased FAC caused by melatonin. ROCK and PKC activities, vinculin phosphorylation and FAC formation were increased with melatonin. The PKC inhibitor, GF109203x, abolished both melatonin stimulated FAC in whole cells and ROCK activity, indicating that ROCK is a downstream kinase in the melatonin-stimulated PKC pathway in MDCK cultured cells that causes an increase in SF and FAC formation. Data also document that melatonin modulates water transport through modifications of the cytoskeletal structure.

Olanzapine-Induced Weight Gain and Increased Visceral Adiposity is Blocked by Melatonin Replacement Therapy in Rats

The atypical antipsychotic drug olanzapine increases body weight and visceral adiposity in schizophrenia. In rats, aging-associated increased body weight and visceral adiposity are reversed by administration of the pineal hormone melatonin. We asked if melatonin similarly would reverse olanzapine-induced increased weight and visceral adiposity in rats. Four groups (n=11/group) of female rats (240-250 g) were treated for 8 weeks with olanzapine, melatonin, olanzapine+melatonin, or vehicle alone in drinking water. Body weight and food and water consumption were determined weekly, locomotor activity at weeks 3 and 6, and nocturnal plasma melatonin concentration at week 7. At week 8, the rats were killed and visceral (perirenal, retroperitoneal, omental, and mesenteric) fat pads dissected and weighed. Olanzapine treatment reduced nocturnal plasma melatonin by 55% (p<0.001), which was restored to control levels by olanzapine+melatonin. Body weight increased 18% in rats treated with olanzapine alone, but only 10% with olanzapine+melatonin, 5% with melatonin alone, and 7% with vehicle control. Body weight and visceral fat pad weight increases in rats treated with olanzapine alone were greater than in each of the other three groups (all p<0.01), which were not significantly different. These results suggest that olanzapine-induced increases in body weight and visceral adiposity may be at least in part secondary to olanzapine-induced reduction of plasma melatonin levels, and that melatonin may be useful for the management of olanzapine-induced weight gain in humans.

Genetic variability in plasma melatonin in sheep is due to pineal weight, not to variations in enzyme activities.

This study was conducted to determine the origin of the high variability in the mean nocturnal plasma melatonin concentration (MC) in sheep. Two extreme groups of 25 lambs each [low (L) and high (H)] were obtained by calculating their genetic value on the basis of the MC of their parents. The MC of lambs was significantly higher in the H group than in the L group (L: 189.7 +/- 24.4 vs. H: 344.1 +/- 33.0 pg/ml, P < 0.001). Within each group, 13 lambs were slaughtered during the day (D) and 12 lambs during the night (N). Pineal weight was significantly higher in the H group than in the L group (L: 83.5 +/- 6.7 vs. H: 119.1 +/- 9.2 mg, P < 0.01) but did not differ between D and N. The amount of melatonin released in vitro per milligram of pineal gland, the arylalkylamine N-acetyltransferase (AANAT) activity, the AANAT protein content, and the level of AANAT mRNA differed significantly between D and N but not with genetic group. Hydroxyindole O-methyltransferase activity did not differ significantly between D and N or between genetic groups. Therefore, the genetic difference in MC between the two groups of lambs was attributed to a difference in pineal size, not in enzymatic activity of the pinealocytes.

The large variability in melatonin blood levels in ewes is under strong genetic influence.

The present study was conducted to assess the degree of genetic determination of the variability in the mean nocturnal plasma concentration of melatonin in sheep. Three hundred twelve ewes born from 18 males and with known genealogy were sampled at the summer and the winter solstices. The nocturnal plasma melatonin concentration was defined as the mean of four plasma samples taken at hourly intervals in the middle of the night (2200-0200). Identity of the father (P < 0.001) and the solstice (P < 0.05) were significant. Melatonin concentrations varied considerably among individuals [338.4 +/- 197.5 (SD) pg/ml; range 26.6-981.3 pg/ml] and between rams regarding the melatonin concentrations of their daughters (range from 202.9 to 456.3 pg/ml). Inheritance was analyzed by a statistical model that allows discrimination of genetic effects from nongenetic effects and that estimates repeatability and heritability coefficients. Both the repeatability coefficient between solstices (0.60) and heritability coefficient [0.45 +/- 0.07 (SE)] were high. These results demonstrate that the variability in plasma melatonin concentration in ewes is under strong genetic control.

Nocturnal plasma melatonin levels in patients suffering from chronic primary insomnia.

Polysomnographic sleep patterns and melatonin secretion were investigated in 10 patients (age: 41.3 +/- 9.5 years) who suffered from chronic primary insomnia and complained predominantly about difficulties in maintaining sleep and in five healthy controls (age 27.2 +/- 0.7 years). Nocturnal plasma melatonin concentrations were obtained hourly, measured by direct radioimmunoassay and statistically compared between insomniacs and controls with age as a covariate. Plasma melatonin levels in the patient group tended to begin increasing earlier in the evening and were significantly (P < or = 0.01) lower during the middle of the night (peak value 82.5 +/- 26.5 pg/ml) than in the healthy controls (peak value 116.8 +/- 13.5 pg/ml). Among the patients, the most severely reduced nocturnal plasma melatonin levels were found in those patients with a history of sleep disturbance lasting for longer than five years (N = 6; age 41.8 +/- 11.7 years; duration 15.3 +/- 5.9 years; peak value 72.1 +/- 25.0 pg/ml); whereas those chronic insomniacs affected for fewer than five years had relatively higher nocturnal levels (N = 4; age 40.6 +/- 6.5 years; duration 3.8 +/- 1.5 years; peak value 98.2 +/- 23.9 pg/ml). These results show that the circadian rhythm of melatonin secretion is disturbed in patients with chronic primary insomnia, and that the nocturnal plasma melatonin secretion is increasingly more affected the longer the patients are unable to maintain a regular sleep pattern.

Melatonin, cortisol and prolactin response to acute nocturnal light exposure in healthy volunteers

An investigation of the cortisol and prolactin responses accompanying acute melatonin suppression by light (600 lux) in humans is described. Light given from midnight to 0300h suppressed nocturnal plasma melatonin concentrations by 65%. Despite this significant suppression of melatonin, no significant effect on plasma cortisol or prolactin concentrations was observed. These data support recent studies which argue that, if there is a relationship between melatonin, the hypothalamo-pituitary, and the hypothalamo-pituitary-adrenal axis in humans, it is neither direct nor simple.

Plasma concentrations of melatonin in panic disorder

Nocturnal plasma melatonin concentrations were measured in seven patients with panic disorder and eight healthy control subjects. The five patients who had never received psychotropic medication had significantly greater melatonin concentrations from 4:00 a.m. to 7:00 a.m. than the control subjects. In addition it is possible that a phase delay occurred in these unmedicated patients. The findings are discussed in terms of previous studies showing increased melatonin in manic patients and the effect of intense stress on melatonin synthesis. The two patients who had been medication free for only 1 week showed a decreased melatonin rhythm, which is consistent with previous findings in medicated patients.

Ontogenesis of pineal thyroxine 5'-deiodinase activity and plasma melatonin concentration in the rat.

Rat pineal thyroxine 5'-deiodinase (5'-D) activity was detectable by 5 days after birth. Nyctohemeral differences became significant by 10 days of age and gradually reached adult magnitude at 1-2 months, primarily due to a progressive increase in nocturnal enzyme activity. A nyctohemeral difference in N-acetyltransferase (NAT) activity was observed by 5 days postnatally and the maturation of NAT rhythmicity was characterized by both a decrease in diurnal and an increase in nocturnal enzyme activity. The maturation of 5'-D rhythmicity was slower than that of NAT. Isoproterenol stimulated 5'-D activity in 5-day-old rats in which there was no spontaneous nyctohemeral 5'-D rhythm, suggesting that the appearance of rhythmicity in pineal 5'-D may depend on the development of pineal innervation. Melatonin was detectable in plasma by 5 days postnatally and reached adult levels at 21 days. A nyctohemeral difference in plasma melatonin concentration existed from day 5 with the highest value at midnight. The difference between noon and midnight increased approximately 10-fold to the adult amplitude by 15 days of age. There was a transient rise of both diurnal and nocturnal plasma melatonin concentration which peaked at 10 days before dropping severalfold to the adult level for both noon and midnight values by 21 days. Since the rhythms of pineal NAT activity and of plasma melatonin concentration are established before that of pineal 5'-D, it is unlikely that the rhythm of melatonin secretion is initiated by a prior maturation of the pineal 5'-D rhythm.

An alpha2 adrenoceptor antagonist, Org 3770, enhances nocturnal melatonin secretion in man

Nocturnal plasma melatonin concentration was significantly increased in ten normal volunteers following the administration of an alpha 2 adrenoceptor antagonist, Org 3770 (30 mg). This result supports the existence of an alpha 2 adrenergic influence on melatonin secretion in man and provides a possible clinical neuroendocrine marker of the action of an alpha 2 antagonist.

Evidence for a functional role of alpha-1 adrenoceptors in the regulation of melatonin secretion in man

Nocturnal plasma melatonin concentrations were reduced following administration of the α 1 adrenoceptor antagonist, prazosin (2 mg orally at 1900h), to 10 normal men. These data indicate that α 1 adrenoceptors are involved in the physiological control of melatonin secretion in man.

Human melatonin response to light at different times of the night

Normal control subjects were examined on three separate occasions with light of sufficient intensity to suppress nocturnal plasma melatonin concentrations. One hour of light was given at each of the following times: (a) 2100–2200h; (b) midnight to 0100h; (c) 0400–0500h. Melatonin synthesis was just becoming apparent at 2100h. There was significant suppression of melatonin by light when given at midnight-0100h and 0400–0500h, but not when light was given at 2100–2200h. In each case following light, melatonin synthesis was shown to resume, even after light applied in the second half of the dark period (0400–0500h). A second experiment was undertaken to examine a possible “rebound” in melatonin levels following light given at 2100–2200h. Six further control subjects were exposed to light at this time, and plasma melatonin levels were measured until 0400h. No rebound in melatonin concentrations was observed. These results are compared with other studies of melatonin response to evening light exposure.

Abnormal circadian rhythm of melatonin in diabetic autonomic neuropathy.

The circadian rhythm of melatonin secretion from the pineal body is entrained to the light-dark cycle and is controlled via sympathetic fibres originating from the superior cervical ganglia. We have therefore examined plasma melatonin profiles in diabetics with and without evidence of autonomic neuropathy and in normal matched controls. The physiological increase in nocturnal plasma melatonin concentration was not observed in diabetics neuropaths. There was no consistent pattern in the diabetics without neuropathy; only three out of the eight subjects in this group had a sustained nocturnal increase in melatonin. Normal diurnal variation of plasma cortisol was present in all groups of subjects. The present study shows that diabetic patients with evidence of autonomic neuropathy lack the normal circadian changes of plasma melatonin concentration. This provides confirmation for the control of pineal function via the sympathetic nervous system in man. The impaired melatonin profiles observed in diabetic patients without apparent autonomic neuropathy suggest that a subclinical state of sympathetic denervation may exist in this group of diabetics.

Overnight Plasma Profiles of Melatonin and Certain Adenohypophyseal Hormones in Men*

Melatonin levels exhibited a day-night rhythm with highest levels at night. Nocturnal plasma melatonin concentrations were unrelated to sleep stages, whereas secretion of GH was temporally related to slow wave sleep. Levels of corticotropin rose in the later sleep cycles. We found no relationship between endogenous nocturnal melatonin and adenohypophyseal hormone levels. The results indicate that in young men nocturnal levels of melatonin are controlled separately from those of LH, PRL, corticotropin, and GH.