On the role of serotonin(2A/2C) receptors in the sensitization to cocaine

Apart from showing involvement of dopamine, recent studies also indicate a role of serotonin (5-HT) in the behavioral effects of cocaine in rodents. I n the present study we investigated the role of 5-HT2A/2C receptors in the development or expression of sensitization to cocaine in rats, using ketans erin, an antagonist at these receptors. Since ketanserin also shows a high affinity for alpha(1)-adrenoceptors, prazosin, a comparative antagonist at those receptors was also examined. Male Wistar rats were treated repeatedly (for 5 days) with cocaine (10 mg/kg) in combination with either vehicle, o r ketanserin (1-3 mg/kg) or prazosin (3 mg/kg); afterwards, on day 10, they received a challenge dose of cocaine (10 mg/kg). In another experiment, th e animals were given either with vehicle or cocaine (10 mg/kg) for 5 days, and were then challenged with cocaine (10 mg/kg) in combination with vehicl e, or ketanserin (1-3 mg/kg) or prazosin (3 mg/kg) on day 10. Acute adminis tration of cocaine increased the locomotor activity in rats; that hyperacti vation was inhibited by ketanserin Q mg/kg), but not by prazosin. In animal s treated repeatedly with cocaine, the locomotor hyperactivity induced by a challenge dose of the psychostimulant was ca. 2-3 times higher than that a fter its first administration. No difference was observed in the response t o cocaine challenge in rats treated repeatedly with cocaine, ketanserin +co caine, or prazosin +cocaine. In animals treated repeatedly with the psychos timulant, the behavioral response to a challenge dose of cocaine was dose-d ependently decreased when the drug was combined with ketanserin, but not wi th prazosin. The above findings indicate a role of 5-HT2A/2C receptors (but not alpha(1)-adrenoceptors) in the acute locomotor hyperactivity, as well as in the expression ( ut not development) of cocaine sensitization. Since chronic use of cocaine by humans may lead to psychoses or craving for this drug of abuse, our findings also seem to indicate possible importance of 5- HT2A/2C receptor antagonists in the therapy of cocaine addiction.