Contribution of the "knock-out" technology to understanding the role of serotonin in sleep regulations

Joëlle Adrien, C. Alexandre, B. Boutrel, D. Popa

Research output: Contribution to journalArticlepeer-review

Abstract

Genetic manipulation of the 5-HT system leads to alterations of 5-HT neurotransmission and provides new opportunities to investigate the role of 5-HT in sleep regulations. Indeed, it represents an alternative to the use of pharmacological tools and, to some extent, of localized lesions of the 5-HT system, which have been, from the 1960s until recently, the main approaches to investigate this question. The homologous recombinaison for the knock-out of genes coding for various proteins involved in 5-HT neurotransmission in the mouse, has allowed to explore further the role of the serotonin transporter (5-HTT), the momoamine oxydase A (MAO-A), or the 5-HT1A, 5-HT 1B and 5-HT2 receptors in the regulation of sleep. In 5-HT1A-/- and 5-HT1B-/- knock-outs, REM sleep (REMs) was enhanced. Pharmacological blockade of these receptors had the same effects in wild-types. Thus, both receptor types exert a tonic inhibitory influence on REMs. In addition, 5-HT1A-/- and 5-HT1B-/- mutants exhibited hypersensitivity of other serotoninergic receptor types (notably the 5-HT1A in 5-HT1B-/- mice and vice versa), which suggests that adaptive changes at 5-HT neurotransmission develop in knock-outs. In the same manner, 5-HTT-/- knock-outs exhibited increased REMs. This may be accounted for by a decrease of 5-HT1A and 5-HT1B receptor-mediated sleep regulations. In contrast, MAO-A-/- knock-outs exhibited decreased REMs, associated with an enhanced response to 5-HTT blockade. Finally, in 5-HT 2A-/- mice, we observed more wakefulness and less SWS than in wild-types. These effects could not be reproduced by 5-HT2A blockade in wild-types. To conclude, constitutive knock-outs undergo adaptive processes involving other proteins than those coded by the invalidated gene, which render the interpretation of the corresponding sleep phenotype difficult. Inducible knock-outs will probably help to overcome this difficulty. Finally, we believe that association of genetic manipulations with relevant pharmacological ones should allow further progress in the understanding of sleep mechanisms.

Original languageEnglish (US)
Pages (from-to)369-377
Number of pages9
JournalArchives Italiennes de Biologie
Volume142
Issue number4
StatePublished - Jul 2004
Externally publishedYes

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

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