Ex vivo receptor occupancy measurements were performed in order to study the effects of the serotonin reuptake inhibitors fluoxetine and citalopram on serotonin 5-HT(2C) receptors. To determine the degree of 5-HT(2C) receptor occupancy, [(3)H]mesulergine binding in brain sections containing rat choroid plexus was measured at various time-points after drug injection. For comparison, [(3)H]ketanserin binding to frontal cortex 5-HT(2A) receptors was measured. Fluoxetine treatments (10 and 20 mg/kg) resulted in 5-HT(2C) receptor occupancy of up to 25 and 43%, respectively. Fluoxetine (20 mg/kg) caused a persistent effect: at the 24 h time-point, 23% of 5-HT(2C) receptors were still occupied. Citalopram treatment did not result in marked 5-HT(2C) receptor occupancy. Neither drug caused significant 5-HT(2A) receptor occupancy. In conclusion, the results demonstrate pharmacodynamic differences between fluoxetine and citalopram at the level of 5-HT(2C) receptors. These findings provide evidence that direct occupancy of 5-HT(2C) receptors may contribute to the mechanism of action of fluoxetine.