5HT(3) RECEPTOR ANTAGONISTS DO NOT BLOCK NICOTINE-INDUCED HYPERACTIVITY IN RATS

The effects of 5-HT3 receptor antagonists (ondansetron 0.1 mg kg(-1) SC 30 min; bemesetron 0.03 mg kg(-1) SC 45 min) on nicotine-induced increases in locomotor activity were measured in male Sprague-Dawley rats. Intermittent daily injections of nicotine (0.3-1.2 mg kg(-1) SC 30 min) resulted in increased locomotor activity as measured by photocell counts. The effect of nicotine was not affected by administration of the 5-HT3 receptor antagonists at doses that are reported to block nicotine- and morphine-induced place-preference conditioning. Neither of the 5-HT3 receptor antagonists tested affected activity counts in vehicle treated animals. Nicotine-induced hyperactivity was blocked by the dopamine antagonist haloperidol (0.03 mg kg(-1) SC 2 h) and by the nicotinic antagonist mecamylamine (1 mg kg(-1) SC 1 min). The effects of a range of doses (0-1 mg kg(-1)) of the 5-HT3 receptor antagonists ondansetron, bemesetron, granisetron and tropisetron on hyperactivity induced by 0.6 mg kg(-1) nicotine were then assessed. Only tropisetron at 1 mg kg(-1) attenuated nicotine-induced hyperactivity. To demonstrate the efficacy of the present range of doses of the 5-HT3 receptor antagonists in this study, conditioned taste aversion experiments were conducted. Ondansetron (0.1 mg kg(-1)) failed to attenuate a conditioned taste aversion to saccharin induced by nicotine (0.6 mg kg(-1)), but did induce a reduction in saccharin preference in choice tests following three saccharin-ondansetron pairings. This conditioned reduction in saccharin preference was replicated with this dose of ondansetron and extended to bemesetron (0.03 mg kg(-1)) and granisetron (0.1 mg kg(-1)) in a subsequent experiment. Nicotine-induced hyperactivity and place-preference conditioning are associated with dopamine release in the nucleus accumbens. The present data appear to be inconsistent with the proposal that 5-HT3 receptor antagonists decrease the behavioural effects of increased dopamine release in the nucleus accumbens.