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      Failure to respond to endogenous or exogenous melatonin may cause nonphotoresponsiveness in Harlan Sprague Dawley rats

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          Abstract

          Background

          Responsiveness to changing photoperiods from summer to winter seasons is an important but variable physiological trait in most temperate-zone mammals. Variation may be due to disorders of melatonin secretion or excretion, or to differences in physiological responses to similar patterns of melatonin secretion and excretion. One potential cause of nonphotoresponsiveness is a failure to secrete or metabolize melatonin in a pattern that reflects photoperiod length.

          Methods

          This study was performed to test whether a strongly photoresponsive rat strain (F344) and strongly nonphotoresponsive rat strain (HSD) have similar circadian urinary excretion profiles of the major metabolite of melatonin, 6-sulfatoxymelatonin (aMT6s), in long-day (L:D 16:8) and short-day (L:D 8:16) photoperiods. The question of whether young male HSD rats would have reproductive responses to constant dark or to supplemental melatonin injections was also tested. Urinary 24-hour aMT6s profiles were measured under L:D 8:16 and L:D 16:8 in young male laboratory rats of a strain known to be reproductively responsive to the short-day photoperiod (F344) and another known to be nonresponsive (HSD).

          Results

          Both strains exhibited nocturnal rises and diurnal falls in aMT6s excretion during both photoperiods, and the duration of the both strains' nocturnal rise was longer in short photoperiod treatments. In other experiments, young HSD rats failed to suppress reproduction or reduce body weight in response to either constant dark or twice-daily supplemental melatonin injections.

          Conclusion

          The results suggest that HSD rats may be nonphotoresponsive because their reproductive system and regulatory system for body mass are unresponsive to melatonin.

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          Most cited references37

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          Mammalian photoperiodic system: formal properties and neuroendocrine mechanisms of photoperiodic time measurement.

          Photoperiodism is a process whereby organisms are able to use both absolute measures of day length and the direction of day length change as a basis for regulating seasonal changes in physiology and behavior. The use of day length cues allows organisms to essentially track time-of-year and to "anticipate" relatively predictable annual variations in important environmental parameters. Thus, adaptive types of seasonal biological changes can be molded through evolution to fit annual environmental cycles. Studies of the formal properties of photoperiodic mechanisms have revealed that most organisms use circadian oscillators to measure day length. Two types of paradigms, designated as the external and internal coincidence models, have been proposed to account for photoperiodic time measurement by a circadian mechanism. Both models postulate that the timing of light exposure, rather than the total amount of light, is critical to the organism's perception of day length. In mammals, a circadian oscillator(s) in the suprachiasmatic nucleus of the hypothalamus receives photic stimuli via the retinohypothalamic tract. The circadian system regulates the rhythmic secretion of the pineal hormone, melatonin. Melatonin is secreted at night, and the duration of secretion varies in inverse relation to day length; thus, photoperiod information is "encoded" in the melatonin signal. The melatonin signal is presumably "decoded" in melatonin target tissues that are involved in the regulation of a variety of seasonal responses. Variations in photoperiodic response are seen not only between species but also between breeding populations within a species and between individuals within single breeding populations. Sometimes these variations appear to be the result of differences in responsiveness to melatonin; in other cases, variations in photoperiod responsiveness may depend on differences in patterns of melatonin secretion related to circadian variation. Sites of action for melatonin in mammals are not yet well characterized, but potential targets of particular interest include the pars tuberalis of the pituitary gland and the suprachiasmatic nuclei. Both these sites exhibit uptake of radiolabeled melatonin in various species, and there is some evidence for direct action of melatonin at these sites. However, it appears that there are species differences with respect to the importance and specific functions of various melatonin target sites.
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            Mammalian melatonin receptors: molecular biology and signal transduction.

            The pineal hormone, melatonin, is an important regulator of seasonal reproduction and circadian rhythms. Its effects are mediated via high-affinity melatonin receptors, located on cells of the pituitary pars tuberalis (PT) and suprachiasmatic nucleus (SCN), respectively. Two subtypes of mammalian melatonin receptors have been cloned and characterized, the MT1 (Mel(1a)) and the MT2 (Mel(1b)) melatonin receptor subtypes. Both subtypes are members of the seven-transmembrane G protein-coupled receptor family. By using recombinant melatonin receptors it has been shown that the MT1 melatonin receptor is coupled to different G proteins that mediate adenylyl cyclase inhibition and phospholipase C beta activation. The MT2 receptor is also coupled to inhibition of adenylyl cyclase and additionally it inhibits the soluble guanylyl cyclase pathway. In mice with a targeted deletion of the MT1 receptor, the acute inhibitory effects of melatonin on SCN multiunit activity are completely abolished, while the phase-shifting responses to melatonin (given in physiological concentrations) appear normal. Furthermore, melatonin inhibits the phosphorylation of the transcription factor cyclic AMP response element binding protein, induced by the pituitary adenylate cyclase-activating polypeptide in SCN cells predominantly via the MT1 receptor. However, a functional MT2 receptor in the rodent SCN is partially able to compensate for the absence of the MT1 receptor in MT1 receptor-deficient mice. These findings indicate redundant and non-redundant roles of the receptor subtypes in regulating SCN function. In the PT, a functional MT1 receptor is essential for the rhythmic synthesis of the clock gene product mPER1. Melatonin produces a long-lasting sensitization of adenylyl cyclase and thus amplifies cyclic AMP signaling when melatonin levels decline at dawn. This action of melatonin amplifies gene expression rhythms in the PT and provides a mechanism for reinforcing rhythmicity in peripheral tissues which themselves lack the capacity for self-sustained oscillation. Mice with targeted deletion of melatonin receptor subtypes provide an excellent model to understand cellular mechanisms through which melatonin modulates circadian and photoperiodic rhythmicity.
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              The timed infusion paradigm for melatonin delivery: what has it taught us about the melatonin signal, its reception, and the photoperiodic control of seasonal responses?

              This review summarizes the evidence showing that the duration of the nocturnal secretory profile of pineal melatonin (MEL) is critical for eliciting seasonally appropriate reproductive physiological and behavioral responses in mammals. We review experiments using the timed infusion paradigm (TIP) to deliver MEL either systemically or centrally to pinealectomized hamsters and sheep. In this paradigm, MEL is infused, usually once daily, for a specific number of hours and at a predetermined time of day. This experimental strategy tests most directly those features of the MEL signal that are necessary to trigger photoperiodic responses. The data suggest that the duration of the MEL stimulation is the critical feature of the MEL signal for both inhibitory and stimulatory effects of the hormone on the photoperiodic control of reproductive development in juvenile Siberian hamsters, and for the photoperiodic control of reproductive and metabolic responses in adult Siberian and Syrian hamsters and sheep. The use of the TIP reveals the importance of the frequency of the signal presentation of MEL and suggests the importance of a period of low-to-absent circulating concentrations of the hormone. The TIP also reveals that the characteristics of the MEL signal that regulate male sexual behavior are similar to those that are critical for reproductive and metabolic responses in Syrian hamsters. We summarize the locations of possible functional MEL target sites identified by combining the TIP with traditional brain lesion techniques. Evidence from such studies suggests that the integrity of the suprachiasmatic nucleus (SCN) region in Siberian hamsters and the anterior hypothalamus in Syrian hamsters is necessary for the response to short-day MEL signals. The TIP has been used to deliver MEL to putative target sites for the hormone in the brain of juvenile and adult Siberian hamsters. The results of these preliminary experiments suggest that the regions of specific MEL binding in this species, especially the SCN, are effective sites where MEL may stimulate short-day-type responses. In contrast, results from intracranial application of MEL in sheep suggest the medial basal hypothalamus as a critical site of action. Finally, we also discuss potential applications of the TIP for identification of brain MEL target sites, understanding of other photoperiodic phenomena and responses, and resolution of the cellular/molecular basis underlying the reception and interpretation of MEL signals.(ABSTRACT TRUNCATED AT 400 WORDS)
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                Author and article information

                Journal
                J Circadian Rhythms
                Journal of Circadian Rhythms
                BioMed Central (London )
                1740-3391
                2005
                14 September 2005
                : 3
                : 12
                Affiliations
                [1 ]Department of Biology, College of William and Mary, Williamsburg, VA 23187, USA
                Article
                1740-3391-3-12
                10.1186/1740-3391-3-12
                1242245
                16162292
                2ed55ae3-eae4-4541-8798-fc2ca6908a80
                Copyright © 2005 Price et al; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 8 July 2005
                : 14 September 2005
                Categories
                Research

                Cell biology
                Cell biology

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