Lateral Habenula 5-HT_2C Receptor Function Is Altered by Acute and Chronic Nicotine Exposures

Serotonin (5-HT) is important in some nicotine actions in the CNS. Among all the 5-HT receptors (5-HTRs), the 5-HT_2CR has emerged as a promising drug target for smoking cessation. The 5-HT_2CRs within the lateral habenula (LHb) may be crucial for nicotine addiction. Here we showed that after acute nicotine tartrate (2 mg/kg, i.p.) exposure, the 5-HT_2CR agonist Ro 60-0175 (5-640 µg/kg, i.v.) increased the electrical activity of 42% of the LHb recorded neurons in vivo in rats. Conversely, after chronic nicotine treatment (6 mg/kg/day, i.p., for 14 days), Ro 60-0175 was incapable of affecting the LHb neuronal discharge. Moreover, acute nicotine exposure increased the 5-HT_2CR-immunoreactive (IR) area while decreasing the number of 5-HT_2CR-IR neurons in the LHb. On the other hand, chronic nicotine increased both the 5-HT_2CR-IR area and 5-HT_2CR-IR LHb neurons in the LHb. Western blot analysis confirmed these findings and further revealed an increase of 5-HT_2CR expression in the medial prefrontal cortex after chronic nicotine exposure not detected by the immunohistochemistry. Altogether, these data show that acute and chronic nicotine exposure differentially affect the central 5-HT_2CR function mainly in the LHb and this may be relevant in nicotine addiction and its treatment.