Activation of 5-HT(2C) receptors reduces the locomotor and rewarding effects of nicotine.

Rationale: Various compounds believed to selectively interact with the 5-HT(2C) receptor have been demonstrated to alter the functioning of ascending dopamine systems. We postulated that this functional interaction may extend to the behavioural effects of drugs of abuse whose rewarding properties are critically dependent upon mesolimbic DA activity.

Objectives: The present studies focussed on interactions between 5-HT(2C) receptor function and behaviours either supported or induced by nicotine.

Methods: The effect of Ro 60-0175, a 5-HT(2C) agonist, was assessed for its ability to modify 1) nicotine-induced locomotor activity in nicotine-treated rats, 2) lever pressing maintained by either food or IV administration of nicotine, and 3) the development of nicotine-induced hyperactivity. The specificity of this effect was further measured in locomotor activity studies by additional administration of the selective 5-HT(2C) antagonist SB 242,084.

Results: Ro 60-0175 (0.3-3 mg/kg SC) dose-dependently reduced nicotine-induced activity, an effect which was reversed by SB 242,084 (0.5 mg/kg IP), thus confirming receptor selectivity of the response. Responding both for food and nicotine on an FR5TO1 min schedule of reinforcement was reduced by Ro 60-0175 (0.1-1 mg/kg) with proportionally similar effects on responses for both types of reinforcer. Co-administration of Ro 60-0175 (1 mg/kg SC) and nicotine (0.4 mg/kg SC) for 10 days blocked the sensitised response that developed in subjects treated with nicotine alone.

Conclusions: The present data support an involvement for the 5-HT(2C) receptor in mediating mesolimbic DA functioning as assessed by changes in behaviours indicative of nicotine reward.