Interactions of Serotonin (5-HT)2 Receptor-Targeting Ligands and Nicotine: Locomotor Activity Studies in Rats

Male Wistar rats were used to verify the hypothesis that serotonin (5-HT)(2A) or 5-HT2C receptors may control the locomotor effects evoked by nicotine (0.4 mg/kg). The 5-HT2A receptor antagonist (M100,907), the 5-HT2A receptor agonist (DOI), the 5-HT2C receptor antagonist (SB 242,084), and the 5-HT2C receptor agonists (Ro 60-0175 and WAY 163,909) were used. M100,907 (0.5-2 mg/kg) did not alter, while DOI (1 mg/kg) enhanced the nicotine-induced hyperlocomotion. The effect of DOI was antagonized by M100,907 (1 mg/kg). SB 242,084 (0.25-1 mg/kg) augmented, while Ro 60-0175 (1 and 3 mg/kg) and WAY 163,909 (1.5 mg/kg) decreased the overall effect of acute nicotine; effects of Ro 60-0175 and WAY 163,909 were attenuated by SB 242,084 (0.125 mg/kg). In another set of experiments, M100,907 (2 mg/kg) on Day 10 attenuated, while DOI (0.1-1 mg/kg) enhanced the nicotine-evoked conditioned hyperlocomotion in rats repeatedly (Days 1-5) treated with nicotine in experimental chambers. SB 242,084 (0.125 or 1 mg/kg) did not change, while Ro 60-0175 (1 mg/kg) or WAY 163,909 (1.5 mg/kg) decreased the expression of nicotine-induced conditioned hyperactivity. Only DOI (0.3 and 1 mg/kg) and SB 242,084 (1 mg/kg) enhanced the basal locomotion. The present data indicate that 5-HT2A receptors are significant for the expression of nicotine-evoked conditioned hyperactivity. Conversely, 5-HT2C receptors play a pivotal role in the acute effects of nicotine. Pharmacological stimulation of 5-HT2A receptors enhances the conditioned hyperlocomotion, while activation of 5-HT2C receptors decreases both the response to acute nicotine and conditioned hyperactivity. Synapse 63:653-661, 2009. (c) 2009 Wiley-Liss, Inc.