title: Discovering the mechanisms underlying serotonin (5-HT)2A and 5-HT2C receptor regulation following nicotine withdrawal in rats.
abstract: We have previously demonstrated that nicotine withdrawal produces depression-like behavior and that serotonin (5-HT)2A/2C receptor ligands modulate that mood-like state. In the present study we aimed to identify the mechanisms (changes in radioligand binding, transcription or RNA-editing) related to such a behavioral outcome. Rats received vehicle or nicotine (0.4 mg/kg, s.c.) for 5 days in home cages. Brain 5-HT2A/2C receptors were analyzed on day 3 of nicotine withdrawal. Nicotine withdrawal increased [(3)H]ketanserin binding to 5-HT2A receptors in the ventral tegmental area and ventral dentate gyrus, yet decreased binding in the nucleus accumbens shell. Reduction in [(3)H]mesulergine binding to 5-HT2C receptors was seen in the ventral dentate gyrus. Profound decrease in the 5-HT2A receptor transcript level was noted in the hippocampus and ventral tegmental area. Out of five 5-HT2C receptor mRNA editing sites, deep sequencing data showed a reduction in editing at the E site and a trend toward reduction at the C site in the hippocampus. In the ventral tegmental area, a reduction for the frequency of CD 5-HT2C receptor transcript was seen. These results show that the reduction in the 5-HT2A receptor transcript level may be an auto-regulatory response to the increased receptor density in the hippocampus and ventral tegmental area during nicotine withdrawal, while decreased 5-HT2C receptor mRNA editing may explain the reduction in receptor labeling in the hippocampus. Serotonin (5-HT)2A/2C receptor ligands alleviate depression-like state in nicotine-withdrawn rats. Here, we show that the reduction in 5-HT2A receptor transcript level may be an auto-regulatory response to the increased receptor number in the hippocampus and ventral tegmental area during nicotine withdrawal, while attenuated 5-HT2C receptor mRNA editing in the hippocampus might explain reduced inverse agonist binding to 5-HT2C receptor and suggest a shift toward a population of more active receptors. 5-HT, serotonin; 5-HT2A R, 5-HT2A receptor; 5-HT2C R, 5-HT2C receptor.
authors.affiliation: Laboratory of Drug Addiction Pharmacology, Department of Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland.|Molecular Biology of Peptide Hormones, Department of Cardiovascular Research, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
authors.forename: Magdalena
authors.identifier: http://orcid.org/0000-0001-9716-6661
authors.initials: M
authors.lastname: Zaniewska
authors.affiliation: Molecular Biology of Peptide Hormones, Department of Cardiovascular Research, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
authors.forename: Natalia
authors.initials: N
authors.lastname: Alenina
authors.affiliation: Laboratory of Drug Addiction Pharmacology, Department of Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland.
authors.forename: Karolina
authors.initials: K
authors.lastname: Wydra
authors.affiliation: Laboratory for New Sequencing Technology, Berlin Institute for Medical Systems Biology, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Fröhler
authors.affiliation: Laboratory of Biochemical Pharmacology, Department of Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Kuśmider
authors.affiliation: Brains-On-Line, Groningen, The Netherlands.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: McCreary
authors.affiliation: Laboratory for New Sequencing Technology, Berlin Institute for Medical Systems Biology, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: Molecular Biology of Peptide Hormones, Department of Cardiovascular Research, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Bader
authors.affiliation: Laboratory of Drug Addiction Pharmacology, Department of Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Filip
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D007103:Immobilization / Q000523:psychology; D008297:Male; D009538:Nicotine / Q000008:administration & dosage / Q000009:adverse effects*; D051381:Rats; D017208:Rats, Wistar; D044402:Receptor, Serotonin, 5-HT2A / Q000502:physiology*; D044405:Receptor, Serotonin, 5-HT2C / Q000502:physiology*; D013375:Substance Withdrawal Syndrome / Q000378:metabolism* / Q000523:psychology
chemical_list: D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D009538:Nicotine
keywords: 5-HT2A/2C receptor autoradiography; deep sequencing; nicotine withdrawal; rat; real-time PCR