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The Journal of Neuroscience, May 17, 2006, 26(20):5554-5564; doi:10.1523/JNEUROSCI.5156-05.2006

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Behavioral/Systems/Cognitive
Early Life Blockade of 5-Hydroxytryptamine 1A Receptors Normalizes Sleep and Depression-Like Behavior in Adult Knock-Out Mice Lacking the Serotonin Transporter

Chloé Alexandre,¹ Daniela Popa,¹ Véronique Fabre,¹ Saoussen Bouali,¹ Patrice Venault,² Klaus-Peter Lesch,³ Michel Hamon,¹ and Joëlle Adrien¹

¹Unité Mixte de Recherche (UMR) 677, Institut National de la Santé et de la Recherche Médicale/Université Pierre et Marie Curie, ²UMR 7593, Centre National de la Recherche Scientifique, Institut Fédératif de Recherche 70 des Neurosciences, Faculté de Médecine Pierre et Marie Curie–Site Pitié-Salpêtrière, 75634 Paris Cedex 13, France, and ³Department of Psychiatry, University of Würzburg, 97080 Würzburg, Germany

Correspondence should be addressed to Joëlle Adrien, Unité Mixte de Recherche 677, Institut National de la Santé et de la Recherche Médicale/Université Pierre et Marie Curie, Faculté de Médecine Pierre et Marie Curie, Site Pitié-Salpêtrière, 91 Boulevard de l’Hôpital, 75634 Paris Cedex 13, France. Email: adrien{at}ext.jussieu.fr

In serotonin transporter knock-out (5-HTT–/–) mice, extracellular serotonin (5-HT) levels are markedly elevated in the brain, and rapid eye movement sleep (REMS) is enhanced compared with wild-type mice. We hypothesized that such sleep impairment at adulthood results from excessive serotonergic tone during early life. Thus, we assessed whether neonatal treatment with drugs capable of limiting the impact of 5-HT on the brain could normalize sleep patterns in 5-HTT–/– mutants. We found that treatments initiated at postnatal day 5 and continued for 2 weeks with the 5-HT synthesis inhibitor para-chlorophenylalanine, or for 4 weeks with the 5-HT_1A receptor (5-HT_1AR) antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexane carboxamide (WAY 100635), induced total or partial recovery of REMS, respectively, in 5-HTT–/– mutants. Early life treatment with WAY 100635 also reversed the depression-like behavior otherwise observed in these mutants. Possible adaptive changes in 5-HT_1AR after neonatal treatment with WAY 100635 were investigated by measuring 5-HT_1A binding sites and 5-HT_1A mRNA in various REMS- and/or depression-related brain areas, as well as 5-HT_1AR-mediated hypothermia and inhibition of neuronal firing in the dorsal raphe nucleus. None of these characteristics were modified in parallel with REMS recovery, suggesting that 5-HT_1ARs involved in wild-type phenotype rescue in 5-HTT–/– mutants are located in other brain areas or in 5-HT_1AR-unrelated circuits where they could be transiently expressed during development. The reversal of sleep alterations and depression-like behavior after early life blockade of 5-HT_1AR in 5-HTT–/– mutants might open new perspectives regarding preventive care of sleep and mood disorders resulting from serotonin transporter impairments during development.

Key words: sleep; development; serotonin transporter; knock-out mice; 5-HT_1A receptors; depression; DRN neurons

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Received Dec. 3, 2005; revised April 10, 2006; accepted April 10, 2006.

Correspondence should be addressed to Joëlle Adrien, Unité Mixte de Recherche 677, Institut National de la Santé et de la Recherche Médicale/Université Pierre et Marie Curie, Faculté de Médecine Pierre et Marie Curie, Site Pitié-Salpêtrière, 91 Boulevard de l’Hôpital, 75634 Paris Cedex 13, France. Email: adrien{at}ext.jussieu.fr

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