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Sleep and waking in mutant mice that do not express various proteins involved in serotonergic neurotransmission such as the serotonergic transporter, monoamine oxidase A, and 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2C and 5-HT7 receptors

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Serotonin and Sleep: Molecular, Functional and Clinical Aspects

Abstract

Sleep studies in knockout mice have investigated the effects on sleep and wakefulness of targeted disruption of genes controlling various proteins involved in serotonergic neurotransmission, particulary proteins that regulate serotonin (5-hydroxytryptamine, 5-HT) concentration in the extracellular space: the serotonin transporter (5-HTT) and catabolytic enzyme, monoamine oxidase A (MAOA), as well as serotonergic receptors such as the 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2C and 5-HT7 sub-types. Mutant mice that do not express the 5-HTT, 5-HT1A or 5-HT1B receptors exhibit larger amounts of rapid eye movement (REM) sleep than their wild-type counterparts. In the case of 5-HT1A-/- and 5-HT1B-/- mice, the sleep phenotype is mimicked by pharmacological blockade of 5-HT1A and 5-HT1B receptors, respectively. This indicates that no major compensatory mechanisms have developed in these mutants, and that REM sleep is under tonic inhibitory control of serotonin via these receptors, and particularly the 5-HT1A sub-type. In contrast, pharmacological blockade of the 5-HTT in wild-type mice has effects on REM sleep opposite to those of the transporter gene deletion. In the same manner, ablation of the monoamine oxidase A (MAOA) gene results in no major impairment of sleep, whereas pharmacological inhibition of MAOA induces dramatic REM sleep decrease. These opposite effects might be related to the desensitization of 5-HT1B receptors in 5-HTT-/-, and of 5-HT1A receptors in MAOA-/- mutants, but it seems essentially accounted for by the lack of clearance of serotonin from the extracellular space during early life. Indeed, protection of the brain from this serotonin overload during early life (by treatment with an inhibitor of serotonin synthesis or with a 5-HT1A-/- receptor antagonist) rescues a lasting wild-type phenotype in 5-HTT-/- mice. In contrast to the previous mutants, 5-HT7-/- mice exhibit reduced amounts of REM sleep, a profile identical to that obtained in rats after pharmacological blockade of 5-HT7 receptors. This indicates that the latter receptor type mediate a serotonergic facilitation of REM sleep. Finally, non-REM (NREM) sleep is affected after mutations involving 5-HT2 receptors. Both 5-HT2A-/- and 5-HT2C-/- mutants exhibit reduced NREM sleep amounts compared to wild-type mice, and no change of REM sleep. However, pharmacological inactivation of each receptor type induces an effect opposite to the genetic invalidation, i.e., enhancement or no change of NREM sleep, and pronounced inhibition of REM sleep. Investigations of the response to sleep deprivation, total or REM selective, and to immobilization stress indicate that mutants have lost their homeostatic sleep properties, except for 5-HT2C-/- mice that exhibit enhanced rebound of cortical slow wave activity after sleep deprivation. In all constitutive mutants examined with pharmacological tools, sleep regulations reflect adaptations at serotonergic proteins other than the one involved in the mutation. These adaptive processes might participate in the sleep phenotype in addition to the mutation itself. To dissect more precisely the role of serotonin components in sleep regulations, the data obtained from constitutive mutant mice need to be complemented using the new molecular tools such as inducible knockout and lentiviral technology. Altogether, the studies performed to date have demonstrated the complex role ofserotonin in sleep-wakefulness regulations, particularly when taking into account the developmental components. In that sense, constitutive mutants might be interesting to help define “critical” developmental periods related to vulnerability to sleep disorders that probably parallel emotional impairments.

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Authors and Affiliations

  1. Faculté de Médecine Pierre et Marie Curie, Site Pitié-Salpêtrière, IFR 70 des Neurosciences, UMR S677, Université Pierre et Marie Curie Paris 6, 91, Bd de l’Hôpital, 75013, Paris, France

    Joëlle Adrien

  2. INSERM U677, 75013, Paris, France

    Joëlle Adrien

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  1. Joëlle Adrien
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Editors and Affiliations

  1. Pharmacology and Therapeutics, School of Medicine, Clinics Hospital, Montevideo, 11300, Uruguay

    Jaime M. Monti

  2. Division of Clinical Pharmacology and Experimental Therapeutics, Department of Medicine, College of Physicians and Surgeons of Columbia University, 630 West 168th Street - Rm # BB813, New York, NY, 10032, USA

    S. R. Pandi-Perumal

  3. Green Hall, Program in Neuroscience, Princeton University, Princeton, NJ, 08540, USA

    Barry L. Jacobs

  4. Psychopharmacology Unit, Dorothy Hodgkin Building Whitson Street, Bristol, BS1 3NY, UK

    David J. Nutt

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Adrien, J. (2008). Sleep and waking in mutant mice that do not express various proteins involved in serotonergic neurotransmission such as the serotonergic transporter, monoamine oxidase A, and 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2C and 5-HT7 receptors. In: Monti, J.M., Pandi-Perumal, S.R., Jacobs, B.L., Nutt, D.J. (eds) Serotonin and Sleep: Molecular, Functional and Clinical Aspects. Birkhäuser Basel. https://doi.org/10.1007/978-3-7643-8561-3_18

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