Differential effects of serotonin (5-HT)2 receptor-targeting ligands on locomotor responses to nicotine-repeated treatment

We verified the hypothesis that serotonin (5-HT)2 receptors control the locomotor effects of nicotine (0.4 mg kg−1) in rats by using the 5-HT2A receptor antagonist M100907, the preferential 5-HT2A receptor agonist DOI, the 5-HT2C receptor antagonist SB 242084, and the 5-HT2C receptor agonists Ro 60-0175 and WAY 163909. Repeated pairings of a test environment with nicotine for 5 days, on Day 10 significantly augmented the locomotor activity following nicotine administration. Of the investigated 5-HT2 receptor ligands, M100907 (2 mg kg−1) or DOI (1 mg kg−1) administered during the first 5 days in combination with nicotine attenuated or enhanced, respectively, the development of nicotine sensitization. Given acutely on Day 10, M100907 (2 mg kg−1), Ro 60-0175 (1 mg kg−1), and WAY 163909 (1.5 mg kg−1) decreased the expression of nicotine sensitization. In another set of experiments, where the nicotine challenge test was performed on Day 15 in animals treated repeatedly (Days: 1–5, 10) with nicotine, none of 5-HT2 receptor ligands administered during the second withdrawal period (Days: 11–14) to nicotine-treated rats altered the sensitizing effect of nicotine given on Day 15. Our data indicate that 5-HT2A receptors (but not 5-HT2C receptors) play a permissive role in the sensitizing effects of nicotine, while stimulation of 5-HT2A receptors enhances the development of nicotine sensitization and activation of 5-HT2C receptors is essential for the expression of nicotine sensitization. Repeated treatment with the 5-HT2 receptor ligands within the second nicotine withdrawal does not inhibit previously established sensitization. Synapse 64:511–519, 2010. © 2010 Wiley-Liss, Inc.