Serotonin 5-HT2 receptor antagonist does not reverse established ethanol-induced sensitization but blocks its development and expression

Several substances that inhibit the induction or expression of behavioral sensitization have been proposed, but patients who present for treatment often have already an established sensitized drug response. Serotonergic agents, including serotonin-2 (5-HT(2)) antagonists, reverse cocaine sensitization, but there is no evidence for the same effect with ethanol, although serotonin involvement in ethanol sensitization has been well reported. To evaluate a 5-HT(2C) antagonist effect on reversing established ethanol sensitization, three experiments were performed assessing locomotor activity of mice under different treatments. First, mice received daily intraperitoneal saline (S), mianserin 10 (M1) or 20 mg/kg (M2), ethanol 2 g/kg (E), or ethanol+mianserin for 21 days. Then, each treatment was withdrawn for 3 days, and mice were randomly challenged with S, E, M1, or M2. During the next 7 days, S and E groups were subjected to daily treatment with S, E, M1, or M2. On the eighth day, all rats were tested under ethanol challenge. The saline group expressed sensitization under ethanol challenge similarly to the ethanol group. Mianserin+ethanol blocked the development of sensitization, suggesting an involvement of the 5-HT(2C) receptor subtype on ethanol-induced sensitization. Ethanol challenge to the chronic mianserin group did not express sensitization, implicating a role for mianserin in protection against stress. Mianserin did not reverse established ethanol sensitization, suggesting that cocaine- and ethanol-induced sensitization involved different mechanisms.