Adaptive changes in serotonin neurons of the raphe nuclei in 5-HT4 receptor knock-out mouse

Decreased serotonin (5‐HT) transmission is thought to underlie several mental diseases, including depression and feeding disorders. However, whether deficits in genes encoding G protein‐coupled receptors may down‐regulate the activity of 5‐HT neurons is unknown currently. Based on recent evidence that stress‐induced anorexia may involve 5‐HT4receptors (5‐HT4R), we measured various aspects of 5‐HT function in 5‐HT4R knock‐out (KO) mice. When compared to dorsal raphe nucleus (DRN) 5‐HT neurons from wild‐type mice, those from 5‐HT4R KO mice exhibited reduced spontaneous electrical activity. This reduced activity was associated with diminished tissue levels of 5‐HT and its main metabolite, 5‐hydroxyindole acetic acid (5‐HIAA). Cumulative, systemic doses of the 5‐HT uptake blocker citalopram, that reduced 5‐HT cell firing by 30% in wild‐type animals, completely inhibited 5‐HT neuron firing in the KO mice. This effect was reversed by administration of the 5‐HT1A receptor (5‐HT1AR) antagonist, WAY100635, in mice of both genotypes. Other changes in DRN of the KO mice included increases in the levels of 5‐HT plasma membrane transporter sites and mRNA, as well as a decrease in the density of 5‐HT1AR sites without any change in 5‐HT1A mRNA content. With the exception of increased 5‐HT turnover index in the hypothalamus and nucleus accumbens and a decreased density of 5‐HT1AR sites in the dorsal hippocampus (CA1) and septum, no major changes were detected in 5‐HT territories of projection, suggesting region‐specific adaptive changes. The mechanisms whereby 5‐HT4R mediate a tonic positive influence on the firing activity of DRN 5‐HT neurons and 5‐HT content remain to be determined.