Abnormal response of melanin-concentrating hormone deficient mice to fasting: Hyperactivity and rapid eye movement sleep suppression

doi:10.1016/j.neuroscience.2008.08.048

Neuroscience

Volume 156, Issue 4, 28 October 2008, Pages 819-829

https://doi.org/10.1016/j.neuroscience.2008.08.048 Get rights and content

Abstract

Melanin-concentrating hormone (MCH) is a hypothalamic neuropeptide that has been implicated in energy homeostasis. Pharmacological studies with MCH and its receptor antagonists have suggested additional behavioral roles for the neuropeptide in the control of mood and vigilance states. These suggestions have been supported by a report of modified sleep in the MCH-1 receptor knockout mouse. Here we found that MCH knockout (MCH⁻^/⁻) mice slept less during both the light and dark phases under baseline conditions. In response to fasting, MCH⁻^/⁻ mice exhibited marked hyperactivity, accelerated weight loss and an exaggerated decrease in rapid eye movement (REM) sleep. Following a 6-h period of sleep deprivation, however, the sleep rebound in MCH⁻^/⁻ mice was normal. Thus MCH⁻^/⁻ mice adapt poorly to fasting, and their loss of bodyweight under this condition is associated with behavioral hyperactivity and abnormal expression of REM sleep. These results support a role for MCH in vigilance state regulation in response to changes in energy homeostasis and may relate to a recent report of initial clinical trials with a novel MCH-1 receptor antagonist. When combined with caloric restriction, the treatment of healthy, obese subjects with this compound resulted in some subjects experiencing vivid dreams and sleep disturbances.

Section snippets

Production of MCH null mice

All animal procedures were approved by the Institutional Animal Care and Use Committee of the University of Texas Southwestern Medical Center and were strictly in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals. Every effort was made to minimize the number of mice used in this study and their suffering at all times. Independent targeting of the MCH allele to produce MCH null mice has been previously described (Shimada et al., 1998). The first

MCH deficiency increases wakefulness

We characterized the sleep and wakefulness of MCH⁻^/⁻ mice from EEG/EMG records. The overall organization of vigilance states in MCH⁻^/⁻ mice during normal feeding resembled that of C57Bl6/J wild-type mice: both genotypes exhibited long, consolidated bouts of wakefulness, especially during the dark phase. Sleep episodes were similarly consolidated, particularly during the light phase. However, MCH⁻^/⁻ mice spent about 90 min more time awake compared with wild-type mice over the 24-h period (Table 1

Discussion

Indirect evidence suggested that MCH might modulate vigilance states (Kilduff and de Lecea 2001, Verret et al 2003, van den Pol et al 2004, Modirrousta et al 2005), and MCH-1 receptor antagonists decrease sleep, including REM sleep, and increase wakefulness (Ahnaou et al., 2008). Here we have demonstrated for the first time that, under baseline conditions, MCH⁻^/⁻ mice exhibit consolidated, increased wakefulness during the dark phase without any rebound in the light phase. Our data thus provide

Conclusion

In conclusion, our data reveal that the link between energy homeostasis and behavioral adaptation, including vigilance state regulation, involves MCH. Additional studies will be required if MCH-1 receptor antagonists are to be used in the treatment of obesity.

Acknowledgments

We thank D. Sierra and D. Koovakkattu for programming and data analysis, S. A. Dixon for technical support, and W. H. Koster and J. E. Krause, formerly of Neurogen Corporation, for unpublished results from preclinical and clinical studies with NGD-4715. M.Y. is an investigator of the Howard Hughes Medical Institute. J.T.W. was previously a fellow of the Medical Scientist Training program of the University of Texas Southwestern Medical Center at Dallas. This work has been supported in part by

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¹: J.T.W. and C.M.S. contributed equally to this work.

²: Present address: Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO 63110, USA.

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Behavioural neuroscienceAbnormal response of melanin-concentrating hormone deficient mice to fasting: Hyperactivity and rapid eye movement sleep suppression

Abstract

Section snippets

Production of MCH null mice

MCH deficiency increases wakefulness

Discussion

Conclusion

Acknowledgments

Eur J Pharmacol

Neuroscience

Brain Res

Behav Brain Res

Cell

Physiol Behav

Neuroscience

Regul Pept

Physiol Behav

Brain Res

Neuron

FEBS Lett

Neuron

Neuron

Sleep architecture of the melanin-concentrating hormone receptor 1-knockout mice

Eur J Neurosci

Role of leptin in the neuroendocrine response to fasting

Nature

The melanin-concentrating hormone system of the rat brain: an immuno- and hybridization histochemical characterization

J Comp Neurol

Neuropeptide-E-I antagonizes the action of melanin-concentrating hormone on stress-induced release of adrenocorticotropin in the rat

J Neuroendocrinol

Antidepressant, anxiolytic and anorectic effects of a melanin-concentrating hormone-1 receptor antagonist

Nat Med

Physiological changes in glucose differentially modulate the excitability of hypothalamic melanin-concentrating hormone and orexin neurons in situ

J Neurosci

Relation of dreaming and REM sleep: the effects of REM deprivation under two conditions

J Pers Soc Psychol

Anxiolytic- and antidepressant-like profile of ATC0065 and ATC0175: nonpeptidic and orally active melanin-concentrating hormone receptor 1 antagonists

J Pharmacol Exp Ther

The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity

Proc Natl Acad Sci U S A

Behavioural neuroscience
Abnormal response of melanin-concentrating hormone deficient mice to fasting: Hyperactivity and rapid eye movement sleep suppression