Early life blockade of 5-hydroxytryptamine 1A receptors normalizes sleep and depression-like behavior in adult knock-out mice lacking the serotonin transporter

Abstract

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. Copyright © 2006 Society for Neuroscience.