Cyclic AMP

Melatonin has inhibitory effects on cAMP in both systems. In the cultured hemip-ituitaries of neonatal rats, melatonin inhibits cAMP accumulation induced by GnRH or forskolin (30,31). Melatonin also decreases the basal concentration of cAMP in the cultured hemipituitaries. Dispersed pituitary cell cultures were later used to study inhibitory effects of melatonin and its derivatives on forskolin-induced cAMP accumulation (25 Figure 3). The effect of melatonin on cAMP is dose-dependent (EC50 0.15...

In Vitro Effects of MLT on Breast Cancer

In addition to animal models, the effects of MLT on breast cancer have been investigated through in vitro studies using several different human breast tumor cell lines. Examination of MLT's effects on various breast cancer cell lines shows that MLT suppresses the growth of cells which express the estrogen receptor (ER-positive cell lines), but has no effect on ER-negative cell lines (13). One of the most extensively studied cell lines is the ER-positive MCF-7 human breast cancer cell line...

References

Anderson, J.L., Vasile, R.G., Bloomingdale, K.L., and Schildkraut, J.J. SAD Varied schedule phototherapy and catecholamines. Amer. Psychiatr. Assoc., 141st Annual Meet., Program and Abs., 166, 1988. 2. Avery, D.H., Khan, A., Dager, S.R., Cohen, S., Cox, G.B., and Dunner, D.L. Morning or evening bright light treatment of winter depression The significance of hypersomnia. Biol. Psychiatry 29 117-126, 1991. 3. Avery, D.H., Dahl, K., Eder, D.N., Larsen, L.H., Vitiello, M.V., Prinz, P.N.,...

Direct Effects Of Melatonin On Tumor Linoleic Acid Uptake And Metabolism And The Signal Transducton Mechanisms Involved

In the tumor growth experiments cited above, it was not completely clear whether the inhibitory action of melatonin on tumor growth was the result or cause of the inhibition of linoleic acid uptake and its conversion to 13-HODE. To more precisely address the question of whether melatonin directly inhibits tumor fatty acid uptake and metabolism, we perfused tissue-isolated hepatoma 7288CTC in situ with melatonin. Following a 60 minute perfusion with donor whole blood from 48-hr fasted rats with...

Melatonin Aging And The Circadian System

Aging is associated with a number of changes in the morphology, physiology and biochemistry of the pineal gland resulting in a significant reduction of the nocturnal melatonin levels in rodents and humans alike (12,20,27). It has been hypothesized that the age-related disruption of this robust signal affects the integrity of circadian time structures and is a precursor of disease states (2,21). Recent studies indicate that decreased binding of melatonin to the SCN of old rats is correlated with...

Decoding The Melatonin Signal

The ovine pars tuberalis has become a valuable pharmacological model for studying the function of the melatonin receptor, not only as it is amenable to cell culture and biochemical experiment, but also as it is a photoperiodically relevant target tissue. Using primary cultures of this gland it has been possible to define the acute signal trans-duction characteristics of the melatonin receptor. Reverse transcription PCR, using degenerate primers, has been used to amplify melatonin receptor...

Reentrainment To 8hr Advanced Ld Cycle

Male SAMP8 and SAMRl (4, 12 and 24 months of age) were used in the re-entrainment experiment. All mice were transferred to individual mouse cages (32 x 20 x 13 cm) for measuring locomotor activity rhythm. These cages were kept in a box equipped with an infrared sensor (F5B, Omron, Osaka, Japan) and a fluorescent lamp. The movements of each mouse in its cage were counted by the infrared sensor, and total activity counts were collected every 6 min by a computer. For the examination of the effect...

Melatonin In Prenatal Development Hormone Or Pheromone

Briefly consider the perceptual world of the fetus. Consider the role the mother plays in sheltering the fetus from the external environment. In this context, it seems remarkable that the mother is also actively involved in transferring environmental information to the fetus. During gestation, the mother generates signals which allow the fetus to perceive the length of the light portion of the lighting cycle (day length) as well as the phase (timing) of the light-dark cycle. We refer to these...

Winter Depression And The Phase Shift Hypothesis

One of the most responsive disorders to bright light is winter depression, which was among the earliest ever treated (3.6-37).Indeed, winter depression was discovered and identified as a result of the finding that bright light could suppress nighttime melatonin production in humans (38-39).This finding implied that humans had biological rhythms that were cued to natural daylight, relatively unperturbed by ordinary-intensity indoor light, and that biological rhythm disorders could be treated by...

Introduction

Melanophores from fish scales can aggregate or disperse their pigment granules (melanosomes) within seconds as a means of background adaptation or social signalling. The scales from the teleost fish cuckoo wrasse (Labrus ossifagus L.) can be isolated and the melanophores can be used as a simple model to answer various pharmacological and physiological questions. The melanophores are sympathetically innervated, and pigment aggregation occurs when postsynaptic 2-adrenoceptors are activated by...

Effects of MLT on RAR Transactivation

Melatonin, acting through its G-protein coupled receptor, mt1, has been shown by our laboratory to modulate the estrogen response pathway, as measured by several parameters (34). For example, we have demonstrated that MLT pre-treatment of MCF-7 cells transiently transfected with an ERE-luciferase reporter gene for 5 min followed by EGF transactivates the ER in a ligand-independent manner. Recent experiments using this system have also demonstrated that MLT pre-treatment is able to blunt the...

Are Humans Photoperiodic

Humans are not generally considered to be photoperiodic. However there are seasonal variations in many human functions which may or may not be related to photoperiod. Seasonal affective disorder (SAD) is probably the most well known (9). Extended winter darkness leading to extended melatonin secretion was thought to be the cause. Certainly increasing the amount of bright light exposure was and is a successful treatment. But to date there is little evidence that this is due to a shortening of...

Effects Of Melatonin On The Growth And Linoleic Acid Metabolism Of Hepatoma 7288ctc

We initially determined the sensitivity of hepatoma 7288CTC to the oncostatic effects of pharmacological doses of melatonin (50 to 200 (g) injected S.C. into tumor-bearing rats, maintained on a 12L 12D light dark cycle, every afternoon one to two hours prior to lights off (PM). Injections with melatonin or vehicle began one week prior to tumor implantation and continued until the end of the experiment three to four weeks later. Melatonin treatment was effective in delaying the appearance and...

Roles Of Tph And Aanat In Regulating Melatonin Biosynthesis

The dramatic nocturnal increase of melatonin biosynthesis involves the induction of both TPH and AA-NAT. Similar to the situation in Xenopus retina (9), administration of the serotonin precursor, 5-hydroxytryptophan (5HTP), at night greatly increases chick retinal melatonin levels (Figure 6). Administration of tryptophan has no effect. This observation indicates that AA-NAT is not saturated with substrate in situ, and that the induction of TPH at night contributes to high rates of melatonin...

Physiological Role For The Pars Tuberalis

Physiological studies involving hypothalamic-pituitary disconnected (HPD) Soay rams have shown that photoperiodically regulated cycles in plasma prolactin can still be maintained in the absence of hypothalamic input to the pituitary (8). As melatonin receptors are not located on the pars distalis, a direct action of melatonin upon the lac-totrophs cannot explain the photoperiodic effects of melatonin on plasma prolactin levels. The possibility that the loss of hypothalamic pituitary input to...

Melatonin As A Phaseresetting Agen

In some animals, exogenous melatonin causes phase shifts and can even provide an entraining signal (see above). Early work by Arendt suggested that melatonin could intermittently have phase-advancing effects (48). Blind people appear to be even more sensitive to these effects than sighted people, perhaps because they are not affected by a competing light dark cycle (49-51). Eventually, a melatonin PRC (four days of administering 0.5mg) was described in sighted people that for the first time 1)...

Conclusions And Summary

With the advent of RIAs capable of measuring the melatonin onset (60), the DLMO has been increasingly utilized as a marker for the phase of the ECP. Measurement of melatonin not only helps assess circadian phase but also has been important in developing the use of bright light to assess light sensitivity, as well as to shift the ECP in the treatment of circadian phase disorders. Physiological doses of melatonin have been used to describe a PRC that is about 12 hours out of phase with the PRC to...

Info

RELATIONSHIPS BETWEEN MELATONIN, GLUTATHIONE PEROXIDASE, GLUTATHIONE REDUCTASE, AND CATALASE Endogenous Rhythms on Cerebral Cortex in Gallus domesticus M. T. Agapito,* I. Redondo, R. Plaza, S. Lopez-Burillo, J. M. Recio, and M. I. Pablos Dept. Biochemistry and Molecular Biology Faculty of Sciences Univ. ofValladolid 47005-Valladolid, Spain In this report, we studied the endogenous rhythms of three antioxidant enzymes glutathione peroxidase (E.C.1.11.1.9), glutathione reductase (E.C.1.6.4.2) and...

Vascular Effects Ofmelatonin

There is now compelling evidence that melatonin acts directly on blood vessel receptors in certain vascular beds, such as the brain, heart and skin. Initial autoradiographic studies using 2- 125I iodomelatonin indicated a restricted localization of vascular melatonin receptors. Specific binding was detected in cerebral and tail (caudal) arteries, but not in other arteries of the rat, including the aorta (53). Both vasoconstrictor and vasodilator effects have been reported for melatonin in...

Melatonin Biosynthesis In Chicken Retina

The retinae of many vertebrates have the capacity to synthesize melatonin (44). However, this source of melatonin does not appear to contribute substantially to circulating melatonin, which is pineal derived. Retinal melatonin appears to act locally as a paracrine neuromodulator and regulator of rhythmic retinal physiology (21,23). Retinal melatonin is synthesized primarily in photoreceptor cells (2,10,17,18,42) and its production is regulated by a local, retinal circadian clock (4,10,41)....

Effect of Photoperiod

The finding that an early night light stimulus phase delays primarily the evening marker of the SCN and pineal rhythms and a late night light stimulus phase advances primarily the morning marker of both rhythms suggests that on long days light perturbing into the late evening and early morning hours may compress the waveform of the SCN and pineal rhythms on short days, the waveform may decompress. This actually happens. The interval between the evening rise in c-fos photoinduction and the...

Proposed Autonomic Regulation Of Melatonin Syntheis By Glutaminergic Systems

Based on these observations, we concluded that rat pinealocytes are equipped with machineries for input, output and termination of the glutamate signals (Fig. 1). Since the same pinealocytes express all these glutaminergic elements, the glutamate may be used as autocrine- or paracrine-like signals in the endocrine organ upon stimulation, pinealocytes secrete L-glutamate so as to inhibit NE-stimulated melatonin synthesis. Excess amount of glutamate is rapidly taken up by the reuptake system(s)....

Sources Of Melatonin During Development

The primary source of circulating melatonin in adult mammals is the pineal gland (38). Melatonin levels are elevated at night. As reviewed in detail elsewhere in this volume, melatonin production from the pineal is regulated by the circadian clock in the suprachiasmatic nuclei. Other tissues appear capable of producing melatonin. Melatonin is produced rhythmically in the retina, but the retina does not appear to contribute significantly to circulating melatonin levels in rodents....

Melatoninand Reproduction

A major physiological role of melatonin in adult mammals is the regulation of seasonal reproduction (for reviews see 3,21,33,68 and this volume). The pineal gland is necessary for appropriate perception of seasonal changes in day length and thus for the proper timing of reproduction in species which breed seasonally. The duration of the nocturnal melatonin elevation is regulated by the photoperiod. Melatonin ultimately affects reproductive activity by modulating the activity of hypothalamic...

Sites Of Action Of Melatonin 41 Melatonin Receptors

In situ autoradiography using 2-(125I)iodomelatonin as a ligand has been used to map the distibution of putative melatonin receptors in the ovine brain and pituitary gland with the aim of identifying target sites for the action of melatonin (Figure 2). Specific, high affinity binding of melatonin has been demonstrated in many sites in the hypothalamus, limbic system and brain, with highest levels of binding in the pars tuber-alis of the pituitary gland (5,20). Using in situ hybridization with a...

Melatonin Receptors As Therapeutic Targets

Molecular and pharmacological studies suggest the presence of melatonin receptors in the human central nervous system. Melatonin receptors were localized to the human suprachiasmatic nucleus and to the molecular layer of the cerebellum by receptor autoradiography with 2- 125I -iodomelatonin (19,21). In postmortem human cerebellar membranes 2- 125I -iodomelatonin binds to a site showing pharmacological characteristics similar to those of the human mt1 melatonin receptor (24,39). Both mt1 and MT2...

Chronobiotics And Insomnia Therapy 21 Definition of Chronobiotic

A chronobiotic was first defined loosely as a drug that specifically affects some aspect(s) of biological time structure (60) and then more precisely as a chemical substance capable of therapeutically re-entraining short-term dissociated or long-term desynchronized circadian rhythms, or prophylactically preventing their disruption following environmental insult (59) (see reviews elsewhere (20,55)). MLT may be an internal zeitgeber (7,8) and as a rule of thumb, its effects on cir-cadian timing...

The Pineal NAT Rhythm

When rats were exposed to a light stimulus in the early night and then released into darkness, the next day both the SCN rhythm in c-Fos photoinduction and the pineal Figure 1. Example of the light-evoked induction of the immunoreactive c-Fos protein in the suprachiasmatic nucleus. A rat was exposed to a 30-min light pulse at 21 h in the night, then returned to darkness and killed 30 min later. Note that the photic c-Fos induction occurred predominantly in the VL-SCN. Adapted from Sumova et...

Intergeniculate Leaflet And Photoperiodic Information

The IGL receives retinal projections and sends NPY containing fibers to the SCN. Although the role of the IGL in photic entrainment has been the subject of extensive investigation, its exact function is still unknown. The IGL does not appear to be essen tial for photic entrainment since, in a number of studies, entrainment was not affected by lesion of the IGL (48,55). However, other data indicate that the IGL may play a role, micro injections of NPY into the SCN or activation of the IGL by...

Hypothalamo Pituitary Disconnection and Surgical Ablation

The hypothalamo-pituitary disconnection (HPD) Soay sheep model in which the pituitary gland is surgically separated from the hypothalamus has been used to further investigate the potential sites of action of melatonin in the regulation of seasonality (35). The surgical procedure involves visualising the stalk region of the pituitary gland via a paramedial, transnasal, transphenoidal approach, entering the median eminence above the pituitary portal vasculature, and evacuating the neural tissue...

Cloning Of Aanat

Sometime after the identification of AANAT as a novel enzyme, it became apparent that the developing cloning technology would eventually allow us to obtain large amounts of AANAT and the tools necessary to study how it is regulated. At the start of this period, techniques were primitive and inefficient certainly, molecular biology kits, reagents and commercial services were a thing of dreams. However, I was confident that sooner or later everything would fall into place and techniques required...

The Role Of Linoleic Acid In Tumor Metabolism And Growth

The Morris rat hepatoma 7288CTC is among a variety of transplantable tumors that are characterized by a unique growth requirement for linoleic acid, an essential polyunsaturated fatty acid ( 6,C18 2). Linoleic acid is the major polyunsaturated fatty acid consumed in the human diet and numerous investigations have shown that high fat diets, particularly those containing linoleic acid as the major fatty acid, increase the growth rates of transplantable tumors in murine species (10). More...

Melatonin As A Marker For Circadian Phase Position

Determination of circadian phase, normal and pathological, can be done in a number of ways. The easiest but least reliable way is to use the timing of sleep sleep offset is usually more reliable than sleep onset . Other physiological measures are more reliable but are sometimes difficult to assess, such as core body temperature and cortisol. There are also disagreements over how these data should be collected, specifically whether or not it is necessary or even desirable to use a constant...