Lusutrombopag (S-888711), an oral small-molecule thrombopoietin receptor (TPOR) agonist, has gained first approval as a drug to treat thrombocytopenia of chronic liver disease in patients undergoing elective invasive procedures in Japan. Preclinical studies were performed to evaluate its efficacy against megakaryopoiesis and thrombopoiesis. To investigate the proliferative activity and efficacy of megakaryocytic colony formation via human TPOR, lusutrombopag was applied to cultured human c-Mpl-expressing Ba/F3 (Ba/F3-hMpl) cells and human bone marrow-derived CD34-positive cells, respectively. Lusutrombopag caused a robust increase in Ba/F3-hMpl cells by activating pathways in a manner similar to that of thrombopoietin and induced colony-forming units-megakaryocyte and polyploid megakaryocytes in human CD34-positive cells. Because lusutrombopag has high species specificity for human TPOR, there was no suitable experimental animal model for drug evaluation, except for immunodeficient mouse based xenograft models. Therefore, a novel genetically modified knock-in mouse, TPOR-Ki/Shi, was developed by replacing mouse Mpl with human mouse chimera Mpl. In TPOR-Ki/Shi mice, lusutrombopag significantly increased circulating platelets in a dose-dependent manner during 21-day repeated oral administration. Histopathological study of the TPOR-Ki/Shi mice on day 22 also revealed a significant increase in megakaryocytes in the bone marrow. These results indicate that lusutrombopag acts on human TPOR to upregulate differentiation and proliferation of megakaryocytic cells, leading to platelet production. (C) 2018 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.

A single nucleotide polymorphism (SNP) within the acetyl CoA carboxylase (ACC) β gene (ACACB), rs2268388, has been shown to be associated with susceptibility to development of proteinuria in patients with type 2 diabetes. To investigate the biological roles of ACCβ in the pathogenesis of diabetic nephropathy, we examined the effects of overexpression of ACACB using podocyte-specific ACACB-transgenic mice or ACACB-overexpressing murine podocytes. Podocyte-specific ACACB-transgenic mice or littermate mice were treated with streptozotocin (STZ) to induce diabetes, and 12 weeks after induction of diabetes, we examined the expression of podocyte markers to evaluate the degree of podocyte injury in these mice. We also examined the effects of ACCβ on podocyte injury in ACACB- or LacZ-overexpressing murine podocytes. Podocyte-specific ACACB overexpression did not cause visible podocyte injury in non-diabetic mice. In STZ-induced diabetic mice, ACACB-transgenic mice showed a significant increase in urinary albumin excretion, accompanied by decreased synaptopodin expression and podocin mislocalization in podocytes, compared with wild-type mice. In cultured murine podocytes, overexpression of ACACB significantly decreased synaptopodin expression and reorganized stress fibers under high glucose conditions, but not in normal glucose conditions. The decrease of synaptopodin expression and reorganized stress fibers observed in ACACB overexpressing cells cultured under high glucose conditions was reversed by a treatment of 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside (AICAR), activator of AMP-activated protein kinase (AMPK). The excess of ACCβ might contribute to exacerbation of podocyte injury in the kidney of an animal model for diabetes mellitus, and the AMPK/ACCβ pathway may be a novel therapeutic target for the prevention of diabetes-related podocyte injury.

Background: Psoriasis is one of the most common immune-mediated chronic inflammatory skin disorders and is accompanied by erythematous scaly plaques. There is growing evidence that the IL-23/Th17 axis plays a critical role in development of the disease. It was recently shown that in addition to CD4(+). Th17 cells, various IL-17-producing cell subsets such as CD8(+) Tc17 cells, dermal gamma delta Tcells, and innate lymphoid cells are also involved in the development of psoriatic inflammation in humans.Objective: To investigate which subsets of IL-17-producing cells are involved in psoriasis-like skin inflammation in a TPA (tumor promoter 12-O-tetradecanoylphorbol-13-acetate)-induced K14.Stat3C mouse model.Method: Skin-infiltrating cells were isolated from inflamed lesions of TPA-treated K14.Stat3C transgenic mice, and analyzed for IL-17 producing cell subsets by flow cytometry.Results: We observed significantly increased numbers of IL-17-producing CD4(+) T cells, CD8(+) T cells and dermal gamma delta T cells in TPA-induced skin lesions of K14.Stat3C mice. Additionally, we found that another IL-17-producing T cell subset, alpha beta-TCR+ CD4CD8 double negative T cells (DN alpha beta T cells), was also increased in lesional skin. These IL-17-producing DN alpha beta T cells are NK1.1 negative, suggesting they are not natural killer Tcells or mucosal associated invariant Tcells. As well as other IL-17-producing cells, DN alpha beta T cells in the inflamed skin can also respond to IL-23 stimulation to produce IL-17. It is also suggested that DN alpha beta T cells may express retinoic acid-related orphan receptor gamma t and CC chemokine receptor 6.Conclusion: In TPA-induced lesional skin of K14.Stat3C mice, IL-17-producing CD4(+) Th17 cells, CD8(+) Tc17 cells, dermal gamma delta T cells and TCR- cells probably containing ILCs all participated in skin inflammation, which is similar to human clinical psoriatic features. Furthermore, we showed for the first time the possibility that an IL-17-producing DN T cell subset is also involved in psoriatic inflammation. (C) 2016 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

atopic dermatitis acetone ether water protein gene product 9.5 transient receptor potential vanilloid subfamily 3 TO THE EDITOR Itch is a common symptom in various forms of dermatitis characterized by dry skin, such as senile xerosis and atopic dermatitis (AD). It is defined as an unpleasant sensation that provokes a desire to scratch and, because itch-elicited scratching aggravates lesions of the skin, the itch is intensified (Ikoma et al., 2006Ikoma A. Steinhoff M. Ständer S. et al.The neurobiology of itch.Nat Rev Neurosci. 2006; 7: 535-547Crossref PubMed Scopus (748) Google Scholar). Therefore, reduction of itching and scratching is an effective strategy for preventing aggravation of skin lesions and improving quality of life. Histamine is the best-known pruritogen and has been regarded as a main target for antipruritic therapies, but H1 receptor (histamine H1R) antagonists are often ineffective against certain kinds of pruritus including dry skin pruritus (Wahlgren et al., 1990Wahlgren C.F. Hägermark O. Bergström R. et al.The antipruritic effect of a sedative and a non-sedative antihistamine in atopic dermatitis.Br J Dermatol. 1990; 122: 545-551Crossref PubMed Scopus (138) Google Scholar). It is suggested that mediators other than histamine also have a key role in itch; for example, physiological temperature, inflammatory mediators, and nitric oxide. These putative pruritogens are also recognized as activators of transient receptor potential (TRP) V3 (Xu et al., 2002Xu H. Ramsey I.S. Kotecha S.A. et al.TRPV3 is a calcium-permeable temperature-sensitive cation channel.Nature. 2002; 418: 181-186Crossref PubMed Scopus (703) Google Scholar; Hu et al., 2006Hu H.Z. Xiao R. Wang C. et al.Potentiation of TRPV3 channel function by unsaturated fatty acids.J Cell Physiol. 2006; 208: 201-212Crossref PubMed Scopus (127) Google Scholar; Yoshida et al., 2006Yoshida T. Inoue R. Morii T. et al.Nitric oxide activates TRP channels by cysteine S-nitrosylation.Nat Chem Biol. 2006; 2: 596-607Crossref PubMed Scopus (457) Google Scholar), which is a warm-sensitive Ca2+-permeable cation channel highly expressed in epidermal keratinocytes (Peier et al., 2002Peier A.M. Reeve A.J. Andersson D.A. et al.A heat-sensitive TRP channel expressed in keratinocytes.Science. 2002; 296: 2046-2049Crossref PubMed Scopus (726) Google Scholar). Interestingly, we indicated previously that a gain-of-function mutation in TRPV3 caused itchy dermatitis in rodents (Asakawa et al., 2006Asakawa M. Yoshioka T. Matsutani T. et al.Association of a mutation in TRPV3 with defective hair growth in rodents.J Invest Dermatol. 2006; 126: 2664-2672Crossref PubMed Scopus (159) Google Scholar; Yoshioka et al., 2009Yoshioka T. Imura K. Asakawa M. et al.Impact of the Gly573Ser substitution in TRPV3 on the development of allergic and pruritic dermatitis in mice.J Invest Dermatol. 2009; 129: 714-722Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar). However, we could not sufficiently suggest a possibility of TRPV3 as a therapeutic target of pruritus. Hence, we focused on TRPV3 as a new therapeutic target for histamine H1R antagonist–resistant pruritus and carried out experiments using ICRTRPV3-/- mice to determine the maximum therapeutic impact of TRPV3 for a certain type of itch (Inagaki et al., 2001Inagaki N. Nagao M. Igeta K. et al.Scratching behavior in various strains of mice.Skin Pharmacol Appl Skin Physiol. 2001; 14: 87-96Crossref PubMed Scopus (95) Google Scholar). The distinguishing feature of ICRTRPV3-/- mice is the presence of wavy whiskers. Information regarding TRPV3-knockout mice is shown in Supplementary Figure S1 online. In contradiction to previous reports (Moqrich et al., 2005Moqrich A. Hwang S.W. Earley T.J. et al.Impaired thermosensation in mice lacking TRPV3, a heat and camphor sensor in the skin.Science. 2005; 307: 1468-1472Crossref PubMed Scopus (590) Google Scholar; Cheng et al., 2010Cheng X. Jin J. Hu L. et al.TRP channel regulates EGFR signaling in hair morphogenesis and skin barrier formation.Cell. 2010; 141: 331-343Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar), we did not find that mice lacking the TRPV3 gene also exhibit wavy hair coat (data not shown). This discrepancy may be due, partially, to the differences in mice strains used in the different studies. Download .pdf (.06 MB) Help with pdf files Supplementary Figure S1 Recently, Miyamoto et al., 2002Miyamoto T. Nojima H. Shinkado T. et al.Itch-associated response induced by experimental dry skin in mice.Jpn J Pharmacol. 2002; 88: 285-292Crossref PubMed Scopus (151) Google Scholar developed a murine model of dry skin pruritus, which was constructed by daily treatment of an acetone/ether (1:1) mixture and water (AEW) applied to the rostral back, and the resulting spontaneous scratching of these models were thought to be histamine-independent. By using a modification of this method, ICRTRPV3-/- mice and their age-matched littermates (ICR TRPV3+/+) were treated with AEW for 4 days to develop skin dryness and barrier disruption on their backs. Daily treatment with AEW increased transepidermal water loss and decreased stratum cutaneous hydration in both ICRTRPV3+/+ and ICRTRPV3-/- mice (Figure 1a). Hematoxylin–eosin staining revealed remarkable epidermal hyperplasia without infiltration of inflammatory cells in the dermis in both ICRTRPV3+/+ and ICRTRPV3-/- mice (Figure 1b). It has been reported that TRPV3 is required for the formation of the stratum corneum layer, which is thought to be a key factor in maintaining skin barrier functions (Cheng et al., 2010Cheng X. Jin J. Hu L. et al.TRP channel regulates EGFR signaling in hair morphogenesis and skin barrier formation.Cell. 2010; 141: 331-343Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar). Contrary to our expectations, there was no difference in the manner of the development of dry skin caused by AEW treatment between mice with and without TRPV3 in this study. This may be because the mouse strain used in each study was different or the effects of AEW treatment were too strong to detect the effects of TRPV3 on the development of dry skin. To examine the impact of TRPV3 deletion on the development of spontaneous scratching behavior, we conducted behavioral tests. Repeated treatment with AEW resulted in a significant increase in spontaneous scratching directed toward the AEW-treated area, which was suppressed by subcutaneous injections of naltrexone, a μ-opioid receptor antagonist (Figure 2b). Given that μ-opioid receptor antagonists reduce experimentally induced itch in humans (Heyer et al., 1997Heyer G. Dotzer M. Diepgen T.L. et al.Opiate and H1 antagonist effects on histamine induced pruritus and alloknesis.Pain. 1997; 73: 239-243Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar), spontaneous scratching behavior observed in the AEW-treated mice might reflect similar itch sensation in humans. In the AEW-treated ICRTRPV3-/- mice, there was no increase in the types of scratching behaviors compared with those without AEW-treatment (Figure 2c). To rule out the possibility of a sedative effect, we also measured the spontaneous motor activity and could not find any locomotor effects evoked by TRPV3 deletion in these mice (Figure 2a). These results indicated that TRPV3 has a pivotal role in the development of itch in mice with dry skin. It is well known that increased nerve density is involved in producing pruritus. In AD patients, increased sprouting of epidermal C-fibers is seen, inducing hypersensitivity to itching, which aggravates the disease (Paus et al., 2006Paus R. Schmelz M. Bíró T. et al.Frontiers in pruritus research: scratching the brain for more effective itch therapy.J Clin Invest. 2006; 116: 1174-1186Crossref PubMed Scopus (317) Google Scholar). In the present study, we also found that the density of the invasive nerve fibers in the skin was increased in AEW-treated mice, as observed by immunohistochemical examination of the sensory neurons using anti-protein gene product 9.5 (PGP9.5) antibody (Figure 3). PGP9.5-positive neurites in the dermis were more prominent in the AEW-treated skin of wild-type mice compared with that of ICRTRPV3-/- mice, and some fibers expanded into the epidermal layer. These results suggested that TRPV3 affected nerve sprouting in dry skin. Previous studies indicate that TRPV3 affects the production of epidermal nerve growth factor (Gopinath et al., 2005Gopinath P. Wan E. Holdcroft A. et al.Increased capsaicin receptor TRPV1 in skin nerve fibres and related vanilloid receptors TRPV3 and TRPV4 in keratinocytes in human breast pain.BMC Womens Health. 2005; 5: 4-9Crossref PubMed Scopus (137) Google Scholar; Yoshioka et al., 2009Yoshioka T. Imura K. Asakawa M. et al.Impact of the Gly573Ser substitution in TRPV3 on the development of allergic and pruritic dermatitis in mice.J Invest Dermatol. 2009; 129: 714-722Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar), which suggests that TRPV3 causes pruritus in lesional skin through nerve fiber expansion. In AD patients with pruritus, higher expressions of TRPV3 messenger RNA are observed compared with those without pruritus (data not shown). This suggests that TPPV3 is involved in human and murine pruritus in a similar manner. Although we could not carry out pharmacological studies using TRPV3 antagonists to elucidate the therapeutic role of TRPV3 for a certain type of pruritus, we believe that this is the first report referring to their role by genetic studies using ICRTRPV3-/- mice. TRPV3 may have an important role in dry skin itch, and TRPV3 antagonists could be a therapeutic option in managing AD and dry skin patients with histamine H1R antagonist–resistant pruritus. We thank Shunji Shinohara for comments on the manuscript. Supplementary material is linked to the online version of the paper at http://www.nature.com/jid

We reported that the Gly573Ser substitution in transient receptor potential vanilloid 3 (TRPV3) led to increased ion channel activity in keratinocytes and caused spontaneous hairlessness in DS-Nh mice. DS-Nh mice also develop allergic and pruritic dermatitis. As the hairless and dermatitis phenotypes were both inherited in an autosomal dominant fashion and could not be segregated from each other, we speculated that TRPV3(Gly573Ser) might be responsible for the dermatitis. Here, we constructed TRPV3(Gly573Ser) transgenic mice, with a putative promoter sequence in the 5' region of TRPV3, to investigate the involvement of TRPV3 in the development of specific types of dermatitis. These transgenic mice spontaneously developed dermatitis, whereas wild-type mice did not display this phenotype when maintained under the same conditions. Histological and serological analyses were carried out to better understand the clinical features of TRPV3(Gly573Ser) transgenic mice. A physiological study revealed that TRPV3(Gly573Ser) induced a higher nerve growth factor response to heat. Finally, C57BL-Nh mice were used to investigate the penetrance of the TRPV3(Gly573Ser) gene for dermatitis. Interestingly, C57BL-Nh mice developed spontaneous scratching behavior, separately from the development of dermatitis. We propose that TRPV3(Gly573Ser) is a cause of pruritus and/or dermatitis associated with scratching, and suggest that TRPV3 may represent a therapeutic target in pruritic dermatitis.

DS-Nh mice and WBN/Kob-Ht rats are spontaneous hairless mutant rodent strains. These animals develop spontaneous dermatitis under normal conditions. The non-hair Nh and Ht phenotypes are inherited in an autosomal dominant fashion, and the Nh mutation possesses a high potency for penetration. We previously reported that genes involved in dermatitis and hairlessness did not segregate from each other. Here, we carried out genetic analysis to identify the genes responsible for these hairless mutations. An amino-acid substitution at the same position in one gene was detected in DS-Nh mice and WBN/Kob-Ht rats: Gly573 to Ser (Nh mutation) or Gly573 to Cys (Ht mutation), located in the transient receptor potential (TRP) cation channel subfamily V member 3 (TRPV3) gene. Mutated TRPV3 was expressed in skin keratinocytes of DS-Nh mice. Histopathological analyses revealed that mast cells in skin lesions were increased in both rodents compared to their age-matched parent strains, and that this may partially be due to hairlessness and dermatitis. We concluded that TRPV3 was the gene responsible for Nh and Ht mutations, and that mutation in TRPV3 possibly correlated with increased mast cell numbers.

To investigate the effects of ascorbic acid deficiency on the pathogenesis of hypertension and/or its complications, we established a rat strain with both genetic hypertension and a defect of ascorbic acid biosynthesis. The od gene (L-gulono-gamma-lactone oxidase gene) of the ODS (Osteogenic Disorder Shionogi) rat, which is a rat mutant unable to synthesize ascorbic acid, was introduced into spontaneously hypertensive rats (SHR), and a novel congenic strain, SHR-od, was established. SHR-od showed scurvy when fed an ascorbic acid-free diet. Systolic blood pressure of male SHR-od began to increase at 9 weeks of age and reached 190-200 mmHg at 20 weeks of age. In 25-week-old SHR-od, ascorbic acid deficiency when fed an ascorbic acid-free diet for 6 weeks caused a remarkable reduction of blood pressure to lower than 110 mmHg. The wall to lumen ratio of the testicular artery in ascorbic acid-deficient SHR-od was lower than that of the control rats. When rats were fed a diet supplemented with ascorbic acid (300 mg/kg), ascorbic acid concentration in SHR-od was lower in the serum and liver than that in ODS rats. These results indicate that ascorbic acid could be closely related to the development of hypertension in SHR-od. We believe that SHR-od will be a useful model for experimental studies on hypertension and its complications, since all of them suffer from hypertension spontaneously and the level of ascorbic acid deficiency in these rats could be controlled at will both in concentration and duration.

We analyzed effects of aging on behavioral rhythms in the mouse showing senescence acceleration, SAMP8 strains. The free-running rhythms had longer free-running periods (τ) in SAMP8 than in the control strain (SAMR1). Drinking of melatonin promoted the adaptation to advanced LD in SAMR1 but not in SAMP8, although both strains exhibited melatonin MT1 and MT2 receptors. The present results suggest that melatonin promotes the adaptation to advanced LD cycles in normal aging mice.

BACKGROUND AND PURPOSE:A new strain of mouse, named FLS (fatty liver Shionogi), which develops spontaneous fatty liver without obesity, was established by inbreeding. Morphologic, physiologic, and genetic characterization of the strain was done.METHODS:Characteristics of male FLS mice were compared with those of the sister strain, dd Shionogi (DS), which does not develop spontaneous fatty liver. A genetic cross experiment was performed by mating FLS with C3H/He/Shi mice.RESULTS:The hepatocytes of neonatal FLS mice contained fine lipid droplets throughout the lobules, and large lipid droplets appeared as mice aged. Liver triglyceride concentrations of FLS mice were fivefold higher than those of DS mice, but serum lipid concentrations and the lipoprotein profile did not indicate abnormalities. Higher plasma aspartate transaminase and alanine transaminase activities in FLS, compared with DS mice, suggested hepatocellular lesions. The genetic cross experiment suggested that the fatty liver formation is a complex polygenic trait.CONCLUSION:The FLS mice develop a progressive hepatic steatosis without obesity and diabetes. The FLS mouse might be a good model for investigating hepatic disorders accompanied by fatty liver unrelated to alcoholism or obesity.

Melatonin is synthesized from serotonin by the enzymes serotonin N-acetyltransferase (SNAT) and hydroxyindole-O-methyltransferase (HIOMT). We have previously reported that C57BL/6 mice do not have SNAT activity because of a mutation in an autosomal gene which is responsible for the absence of normal SNAT activity. In the present study, we have tried to map the loci of Nat-2 (the locus controlling SNAT activity) on chromosomes using a set of the BxH recombinant inbred strains which were derived from an initial cross between C3H/He with SNAT and C57BL/6 without the enzyme. Based on strain distribution patterns (SDPs), a close linkage on chromosome 11 was found between Nat-2, Es-3 (esterase-3), Glk (the locus controlling galactokinase activity) and Myla (myosin alkali light chains expressed in cardiac atrial muscle). The linkage between Nat-2 and Es-3 was confirmed by a conventional linkage test and the recombination frequency between these loci was estimated to be 16.1 ± 3.6% (mean ± S.E.M.).

Circadian rhythms of pineal melatonin release were measured in free-moving pigeons, Japanese quails, and chickens under light-dark cycles followed by constant dim light. Although melatonin levels differed among individual birds, circadian rhythms of melatonin were observed in all of them. Using this technique, we could examine phase shifts of melatonin rhythms and suppression of melatonin release by photic stimulation in pigeons. We could also examine effects of norepinephrine infusion on melatonin release. These results indicate that microdialysis is useful for the study of pineal melatonin rhythms in birds.

Although pinealectomy or blinding resulted in loss of the clarity of the free-running rhythm of locomotor activity and body temperature and reduced the peak level of circulating melatonin rhythms to approximately a half in intact pigeons, neither pinealectomy nor blinding abolished any of these rhythms. However, when pinealectomy and blinding were combined, the rhythms of locomotor activity and body temperature disappeared in prolonged constant dim light, and melatonin concentration was reduced to the minimum level of detection. In order to examine the role of melatonin in the pigeon's circadian system, it was administered either daily or continuously to PX + EX-pigeons in LLdim. Daily administration of melatonin restored circadian rhythms of locomotor activity which entrained to melatonin injections, but continuous administration did not induce any remarkable change of locomotor activity. These results suggest that melatonin synthesized in the pineal body and the eye contributes to circulating melatonin and its rhythmicity is important for the control of circadian rhythms of locomotor activity and body temperature in the pigeon.

Pineal melatonin content at several times during the day and night was measured in 36 inbred strains of mice (Mus musculus) kept under LD 12:12 cycles. The results have indicated that only five inbred strains have pineal melatonin content, with higher levels during the night and lower levels during the day; the other 31 strains do not contain detectable melatonin in their pineal gland at any of times examined. The former group includes two commonly used strains (C3H/He and CBA/Ms) and three wild‐derived strains (Mol‐A, Mol‐Nis, MOM). C3H and CBA mice showed a similar pattern of pineal melatonin rhythm with a peak at 2 hours before lights on. The peak levels were about 150 pg/gland in both strains. The rhythmic patterns of melatonin content in Mol‐A, Mol‐Nis, and MOM were slightly different from those in CBA and C3H. In the wild‐derived strains, the peak of melatonin content did not occur at 2 hours before lights on but tended to occur at midnight. The peak levels were 67–91 pg/gland at the highest point in these strains.

A new computer-based system for collection and analysis of circadian body temperature and locomotor activity rhythms is described. This system makes possible the simultaneous measurements of body temperature and locomotor activity rhythms from 16 animals kept in separate cages. Several programs were developed for measurement and analysis of the data. This system is available not only in the study of circadian rhythms but also in other biological studies where long-term recordings of rest-activity cycles and body temperature are required.

The phase response curves (PRCs) generated by pentobarbital injections (30 mg/kg) were obtained in SK and C57BL mice. Pentobarbital injections induced both advance and delay phase-shifts in the circadian rhythm of locomotor activity in SK mice but no phase-shifts were observed at any circadian time (CT) for pentobarbital injections in C57BL mice. The observation that a higher dose of pentobarbital (80 mg/kg) does not induce phase-shifting in C57BL mice has indicated that the differences in phase-shifting effects of pentobarbital are not quantitative but qualitative. These strains may be useful for studying the neurochemical regulation of the mammalian circadian rhythm.

Locomotor activity and feeding activity were measured together with circulating levels of melatonin in pigeons which were exposed to constant bright light (LLbright, 2000 lux) following light-dark (LD) cycles. Although all the pigeons showed daily rhythms of locomotor activity, feeding activity, and melatonin levels under LD cycles, they lost all the rhythms in prolonged LLbright. Acute exposure to bright light (2000 lux) during darkness reduced plasma melatonin levels. The half-time for the suppression in melatonin levels was about 30 min after short-term light exposure. These results support the hypothesis that melatonin may control the circadian rhythms of locomotor activity and feeding activity in the pigeon.