Abstract
Serotonin (5-HT) is important in some nicotine actions in the CNS. Among all the 5-HT receptors (5-HTRs), the 5-HT2CR has emerged as a promising drug target for smoking cessation. The 5-HT2CRs 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-HT2CR 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-HT2CR-immunoreactive (IR) area while decreasing the number of 5-HT2CR-IR neurons in the LHb. On the other hand, chronic nicotine increased both the 5-HT2CR-IR area and 5-HT2CR-IR LHb neurons in the LHb. Western blot analysis confirmed these findings and further revealed an increase of 5-HT2CR 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-HT2CR function mainly in the LHb and this may be relevant in nicotine addiction and its treatment.
Highlights
Intravenous administration of Ro 60-0175 (5–640 μg/kg, iv), a selective 5-HT2C R agonist, one hour after acute nicotine hydrogen tartrate salt treatment (2 mg/kg; i.p. equivalent to 0.7 mg/kg nicotine free base) induced a significant increase of lateral habenula (LHb) neuronal firing rate in 42% of recorded neurons and reached peak effect at 320 μg/kg
The main finding of this study is that non-contingent passive exposure both acutely and chronically low/medium dose of nicotine hadexposure a prominent
We observed a complex pattern of 5-HT2CR signal changes both as receptor exposure to nicotine
Summary
A large body of evidence shows that the 5-HT2C R is central in drug addiction, including nicotine dependence and relapse (see [2,3,4]). Activation of 5-HT2C Rs decreased nicotineinduced locomotion, nicotine self-administration and reinstatement of nicotine-seeking, and the discriminative stimulus properties of nicotine [5,6,7,8,9,10,11]. 5-HT2C R activation has a large inhibitory influence on different appetitive and consummatory behaviors dampening for example food and cocaine reinforcing effects [12,13]. Promising preclinical and clinical trial results on 5-HT2C R agonism as a new smoking cessation treatment, have arisen from lorcaserin [14,15], approved first by the US Food and
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