Blocking melanin-concentrating hormone MCH1 receptor affects rat sleep–wake architecture
| Autor: | J. Adriaan Bouwknecht, Thomas Steckler, Jesús Alcázar, Frank M. Dautzenberg, Abdellah Ahnaou, Wilhelmus Drinkenburg |
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| Rok vydání: | 2008 |
| Předmět: |
Male
medicine.medical_specialty Melanin-concentrating hormone Injections Subcutaneous Sleep REM CHO Cells Biology Rats Sprague-Dawley Inhibitory Concentration 50 chemistry.chemical_compound Cricetulus Cricetinae Internal medicine medicine Animals Humans Receptors Somatostatin Circadian rhythm Receptor Slow-wave sleep Pharmacology Sleep Stages Dose-Response Relationship Drug Antagonist Rats Endocrinology chemistry Calcium Sleep onset Hormone |
| Zdroj: | European Journal of Pharmacology. 579:177-188 |
| ISSN: | 0014-2999 |
| DOI: | 10.1016/j.ejphar.2007.10.017 |
| Popis: | Melanin-concentrating hormone (MCH) is a hypothalamic peptide that centrally regulates food intake, energy balance and emotion. Interestingly, MCH and melanin-concentrating hormone MCH(1) receptors are distributed in brain areas known to regulate vigilance states. Effects of subcutaneous administration of two selective melanin-concentrating hormone MCH(1) receptor antagonists, labeled A and B were examined over a broad dose range (1, 3, 10, 20, 40 mg/kg) on rat sleep-wake architecture. Both compounds have a nanomolar antagonist activity at recombinant human melanin-concentrating hormone MCH(1) receptor (IC(50)=44.1+/-6.1 nM and 26.6+/-5.4 nM, respectively) and potently inhibited the MCH-induced mobilization of [Ca(2+)] (IC(50) 29.1+/-8.1 nM and 10.5+/-4.1 nM, respectively). The selectivity of both compounds was further confirmed on a panel of receptors, transporters and channels. In vivo, both compounds dose-dependently decreased deep sleep primarily by decreasing the mean duration of episodes during the first 4 h post-administration. In parallel, REM sleep and intermediate stage sleep were decreased while active and passive waking increased. Deep sleep and REM sleep onset latencies were significantly prolonged at higher doses. No homeostatic rebound of deep sleep was observed, while a tendency for recovery of REM sleep was found during subsequent dark phase. Together, the results support a role of the melanin-concentrating hormone MCH(1) receptor in the regulation of deep slow-wave sleep-REM sleep cycle. Therapeutic application of melanin-concentrating hormone MCH(1) receptor-inhibiting agents should take into account the significant decreases in deep sleep without recovery as these may interfere with sleep dependent memory consolidation. |
| Databáze: | OpenAIRE |
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