Gregory M. Brown

Melatonin - a pleiotropic, orchestrating regulator molecule

Melatonin, the neurohormone of the pineal gland, is also produced by various other tissues and cells. It acts via G protein-coupled receptors expressed in various areas of the central nervous system and in peripheral tissues. Parallel signaling mechanisms lead to cell-specific control and recruitment of downstream factors, including various kinases, transcription factors and ion channels. Additional actions via nuclear receptors and other binding sites are likely. By virtue of high receptor density in the circadian pacemaker, melatonin is involved in the phasing of circadian rhythms and sleep promotion. Additionally, it exerts effects on peripheral oscillators, including phase coupling of parallel cellular clocks based on alternate use of core oscillator proteins. Direct central and peripheral actions concern the up- or downregulation of various proteins, among which inducible and neuronal NO synthases seem to be of particular importance for antagonizing inflammation and excitotoxicity. The methoxyindole is also synthesized in several peripheral tissues, so that the total content of tissue melatonin exceeds by far the amounts in the circulation. Emerging fields in melatonin research concern receptor polymorphism in relation to various diseases, the control of sleep, the metabolic syndrome, weight control, diabetes type 2 and insulin resistance, and mitochondrial effects. Control of electron flux, prevention of bottlenecks in the respiratory chain and electron leakage contribute to the avoidance of damage by free radicals and seem to be important in neuroprotection, inflammatory diseases and, presumably, aging. Newly discovered influences on sirtuins and downstream factors indicate that melatonin has a role in mitochondrial biogenesis.

Functional role of the prefrontal cortex in retrieval of memories: a PET study.

Retrieval of information from episodic memory involves the processes invoked by the attempt to remember (retrieval attempt) as well as processes associated with the successful retrieval of stored information (ecphory). Previous PET studies of memory have shown an activation of the prefrontal cortex in memory retrieval tasks, and we hypothesised that this activation represents retreival attempt, not ecphory. This hypothesis was directly directed using [15O]H2 PET imaging in 19 healthy subjects who performed three matched tasks which involved different levels of retrieval attempt and ecphory. The results showed that retrieval attempt was associated with activation of the prefrontal cortex, right greater than left, while ecphory involved the posterior cortical regions. These findings illuminate the functional role of the different neuroanatomical regions involved in episodic remembering.

Increased frontal and reduced parietal glucose metabolism in acute untreated schizophrenia

Frontal and parietal lobe metabolism was measured by [18F] fluorodeoxyglucose positron emission tomography in 8 never-medicated DSM-III schizophrenic patients and in 10 control subjects. Patients were in a psychotic episode at the time of this scan. Seven of eight had been ill less than 2 years and had only mild neurocognitive impairment. Frontal lobe glucose metabolism was significantly greater in schizophrenic patients than in controls. This finding differs from that of hypofrontality reported in chronic patients previously treated with neuroleptics. Relative glucose metabolism in the interior parietal lobe was significantly lower in schizophrenic patients than in controls. The frontal/parietal ratios were significantly greater in patients than in controls.

Differential modulation of GABAA receptor function by Mel1a and Mel1b receptors

Melatonin, a hormone principally produced and released by the pineal gland, has been shown to regulate a variety of biological functions including circadian rhythms, sleep-wake cycles and reproduction, presumably through activating high-affinity G-protein-coupled receptors. We report here that these subtypes can differentially modulate the function of type-A γ-aminobutyric acid (GABAA) receptor, the principal neurotransmitter receptor mediating synaptic inhibition in the CNS. This work demonstrates that melatonin, through activation of different receptor subtypes, can exert opposite effects on the same substrate, suggesting that receptor subtype is the primary molecular basis for the diversity of melatonin effects.

Stress Response Patterns of Plasma Corticosterone, Prolactin, and Growth Hormone in the Rat, Following Handling or Exposure to Novel Environment

Corticosterone, prolactin, and growth hormone responses to 5 s of handling or 3 min of novel environment were compared in rats at crest and trough of the diurnal adrenal rhythm 0, 5, 15, 30, and 60 min after stimulation. All hormones responded to stimulation, corticosterone and prolactin with a dramatic rise, and growth hormone with a precipitous fall. Resting corticosterone levels evidenced the expected diurnal variation, and prolactin but not growth hormone also showed a baseline diurnal variation of small magnitude at the times studied. Growth hormone response characteristics were unaffected by time of day or type of stimulation. Both corticosterone and prolactin response profiles differed at both times of day and following both types of stimulation. Corticosterone and prolactin levels were highly correlated and each was negatively correlated with growth hormone levels. This study confirms that hormone responses to stress are complex and depend not only on the stimulus but the context of stimulation.

Melatonin and its analogs in insomnia and depression.

Abstract:  Benzodiazepine sedative‐hypnotic drugs are widely used for the treatment of insomnia. Nevertheless, their adverse effects, such as next‐day hangover, dependence and impairment of memory, make them unsuitable for long‐term treatment. Melatonin has been used for improving sleep in patients with insomnia mainly because it does not cause hangover or show any addictive potential. However, there is a lack of consistency on its therapeutic value (partly because of its short half‐life and the small quantities of melatonin employed). Thus, attention has been focused either on the development of more potent melatonin analogs with prolonged effects or on the design of slow release melatonin preparations. The MT1 and MT2 melatonergic receptor ramelteon was effective in increasing total sleep time and sleep efficiency, as well as in reducing sleep latency, in insomnia patients. The melatonergic antidepressant agomelatine, displaying potent MT1 and MT2 melatonergic agonism and relatively weak serotonin 5HT2C receptor antagonism, was found effective in the treatment of depressed patients. However, long‐term safety studies are lacking for both melatonin agonists, particularly considering the pharmacological activity of their metabolites. In view of the higher binding affinities, longest half‐life and relative higher potencies of the different melatonin agonists, studies using 2 or 3 mg/day of melatonin are probably unsuitable to give appropriate comparison of the effects of the natural compound. Hence, clinical trials employing melatonin doses in the range of 50–100 mg/day are warranted before the relative merits of the melatonin analogs versus melatonin can be settled.

Melatonin in the retina and the Harderian gland. Ontogeny, diurnal variations and melatonin treatment.

Abstract Using highly specific antibodies, melatonin has been identified immunohistologically in the rat retina, and the Harderian gland. The first truly significant amount of retinal melatonin was already detected in the 2 day old pups. The amount of melatonin progressively increased with age reaching adult levels around the 20th day. Diurnal variations with higher night levels of melatonin have been found in the adult in both retina and Harderian gland. Intraperitoneal injection or subcutaneous implantation of melatonin in beeswax (150 μg/rat) resulted in a vast increase in melatonin content in the retina and the Harderian gland of the juvenile and adult rats. No sexual differences have been registered in any experimental group. The concept of melatonin synthesis at peripheral sites independent of pineal production, the involvement of light-dark rhythm in the regulation of pineal and extrapineal melatonin content and the possibility of uptake mechanisms or receptors for melatonin in the retina and Harderian gland are discussed.

A Randomized, Double-Blind, Placebo-Controlled Crossover Study of the Effect of Exogenous Melatonin on Delayed Sleep Phase Syndrome

Objective The effects of exogenous melatonin on sleep, daytime sleepiness, fatigue, and alertness were investigated in 22 patients with delayed sleep phase syndrome whose nocturnal sleep was restricted to the interval from 24:00 to 08:00 hours. This study was a randomized, double-blind, placebo-controlled crossover trial. Subjects received either placebo or melatonin (5 mg) daily for 4 weeks, underwent a 1-week washout period, and then were given the other treatment for an additional 4 weeks. Patients could take the melatonin between 19:00 and 21:00 hours, which allowed them to select the time they felt to be most beneficial for the phase-setting effects of the medication. Methods Two consecutive overnight polysomnographic recordings were performed on three occasions: at baseline (before treatment), after 4 weeks of melatonin treatment, and after 4 weeks of placebo treatment. Results In the 20 patients who completed the study, sleep onset latency was significantly reduced while subjects were taking melatonin as compared with both placebo and baseline. There was no evidence that melatonin altered total sleep time (as compared with baseline total sleep time), but there was a significant decrease in total sleep time while patients were taking placebo. Melatonin did not result in altered scores on subjective measures of sleepiness, fatigue, and alertness, which were administered at different times of the day. After an imposed conventional sleep period (from 24:00 to 08:00), subjects taking melatonin reported being less sleepy and fatigued than they did while taking placebo. Conclusions Melatonin ameliorated some symptoms of delayed sleep phase syndrome, as confirmed by both objective and subjective measures. No adverse effects of melatonin were noted during the 4-week treatment period.

Neuroleptic drug effects on cognitive function in schizophrenia

Neuropsychological test performance was compared in 37 neuroleptic treated DSM-III schizophrenic patients, 27 untreated schizophrenic patients, and 27 normal controls. Neuroleptic treated patients performed significantly less well than untreated patients at recalling a complex figure, at planning on a mazes test, and had poorer fine motor coordination. Controls and untreated patients performed equally well on these tests. The results were not altered in 16 neuroleptic treated patients who had been prescribed low doses of benztropine, nor 38 patients who reported prior substance abuse. Similar cognitive impairments are observed in Parkinsons disease and are associated with dopaminergic antagonist drugs in schizophrenics. Therefore, they do not comprise part of the Schizophrenic Deficit State. Two tests were better performed by controls than patients. Reaction time was slower and more variable in both treated and untreated patient groups than controls. The recall of paraphrased passages was significantly poorer in both patient groups than controls, a finding that is robust in subgroups matched for IQ. Neuroleptic treatment was associated with significantly better performance on this test.

The effects of exogenous melatonin on the total sleep time and daytime alertness of chronic insomniacs: A preliminary study

The effects of exogenous, supraphysiologic doses of melatonin on the total sleep time and daytime alertness of patients with chronic insomnia was examined in a double blind, single crossover study. Melatonin (75 mg per os) or identical placebo was administered at 10 PM daily to 13 insomniac patients for 14 consecutive days. A significant increase in the subjective assessment of total sleep time and daytime alertness was demonstrated with melatonin but not with placebo. However, 7 of the 13 patients reported that the active treatment had no significant effect on subjective feelings of well-being.