Ethanol deprivation and central 5-HT deficiency differentially affect the mRNA editing of the 5-HT(2C) receptor in the mouse brain

BACKGROUND: Serotonin (5-HT) 5-HT(2C) receptor mRNA editing (at five sites, A–E), implicated in neuropsychiatric disorders, including clinical depression, remains unexplored during alcohol abstinence—often accompanied by depressive symptoms. METHODS: We used deep sequencing to investigate 5-HT(2C) receptor editing in mice during early ethanol deprivation following prolonged alcohol exposure and mice lacking tryptophan hydroxylase (TPH)2, a key enzyme in central 5-HT production. We also examined Tph2 expression in ethanol-deprived animals using quantitative real-time PCR (qPCR). RESULTS: Cessation from chronic 10% ethanol exposure in a two-bottle choice paradigm enhanced immobility time and decreased latency in the forced swim test (FST), indicating a depression-like phenotype. In the hippocampus, ethanol-deprived “high ethanol-drinking” mice displayed reduced Tph2 expression, elevated 5-HT(2C) receptor editing efficiency, and decreased frequency of the D mRNA variant, encoding the less-edited INV protein isoform. Tph2(–/–) mice showed attenuated receptor editing in the hippocampus and elevated frequency of non-edited None and D variants. In the prefrontal cortex, Tph2 deficiency increased receptor mRNA editing at site D and reduced the frequency of AB transcript, predicting a reduction in the corresponding partially edited VNI isoform. CONCLUSIONS: Our findings reveal differential effects of 5-HT depletion and ethanol cessation on 5-HT(2C) receptor editing. Central 5-HT depletion attenuated editing in the prefrontal cortex and the hippocampus, whereas ethanol deprivation, coinciding with reduced Tph2 expression in the hippocampus, enhanced receptor editing efficiency specifically in this brain region. This study highlights the interplay between 5-HT synthesis, ethanol cessation, and 5-HT(2C) receptor editing, providing potential mechanism underlying increased ethanol consumption and deprivation. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s43440-023-00545-6.