Effects of 5-HT2A and 5-HT2C receptor antagonists on acute and chronic dyskinetic effects induced by haloperidol in rats

An important limitation of classical antipsychotic drugs such as haloperidol (HAL) is their liability to induce extrapyramidal motor symptoms acutely and tardive dyskinetic syndromes when given chronically. These effects are less likely to occur with newer antipsychotic drugs, an attribute that is often thought to result from their serotonin-2 (5-HT2) receptor antagonistic properties. In the present study, we used selected doses of the 5-HT2A antagonist M100,907, the 5-HT2C antagonist SB242,084 and the mixed 5-HT2A/C antagonist ketanserin to re-examine the respective roles of 2A vs. 2C 5-HT2 receptor sub-types in both acute and chronic motor effects induced by HEAL Acutely, SB242,084 (0.5 mg/kg) reduced HAL-induced catalepsy, while M100,907 (0.5 mg/kg) and ketanserin (1 mg/kg) were without effect. None of the drugs reduced HAL-induced Fos expression in the striatum or frontal cortex, and M100,907 actually potentiated HAL-induced Fos expression in the n. accumbens. In rats chronically treated with HAL, both ketanserin and SB242,084 attenuated vacuous chewing movements, while M100,907 had no effect. In addition, 5-HT2C but not 5-HT2A mRNA levels were altered in several brain regions after chronic HAL These results highlight the importance of 5-HT2(2C) receptors in both acute and chronic motoric side effects of HAL, and suggest that 5-HT2C antagonism could be targeted as a key property in the development of new antipsychotic medications. (C) 2011 Elsevier B.V. All rights reserved.