Discovering the mechanisms underlying serotonin (5‐HT)2A and 5‐HT2C receptor regulation following nicotine withdrawal in rats

• Published in: Journal of neurochemistry 2015-08, Vol.134 (4), p.704-716
• Main Authors: Zaniewska, Magdalena, Alenina, Natalia, Wydra, Karolina, Fröhler, Sebastian, Kuśmider, Maciej, McCreary, Andrew C., Chen, Wei, Bader, Michael, Filip, Małgorzata
• Format: Article
• Language: English
• Subjects: 5‐HT2A/2C receptor autoradiography; Animals; Brain - drug effects; Brain - metabolism; deep sequencing; Drug addiction; Immobilization - psychology; Male; Neurochemistry; Nicotine; Nicotine - administration & dosage; Nicotine - adverse effects; nicotine withdrawal; rat; Rats; Rats, Wistar; real‐time PCR; Receptor, Serotonin, 5-HT2A - physiology; Receptor, Serotonin, 5-HT2C - physiology; Rodents; Serotonin; Substance Withdrawal Syndrome - metabolism; Substance Withdrawal Syndrome - psychology
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.13192

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 [3H]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 [3H]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‐HT2AR, 5‐HT2A receptor; 5‐HT2CR, 5‐HT2C receptor. 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 recepto