We have recently observed that effects of acute fluoxetine (FLX) administration on prefrontal cortical serotonin (5HT) extracellular levels are enhanced in 5-HT2C receptor knock out mice compared to wild type controls; and that antidepressant-like behavioral responses induced by FLX are also significantly higher in these mice (Giorgetti et al., SFN 2002). Moreover, using a pharmacological approach, it has been shown that selective antagonism of this 5-HT receptor subtype also potentiates effects of different SSRIs on prefrontal cortical and hippocampal 5-HT levels in freely moving rats (Cremers et al., 2002). In order to expand these findings, we have used a pharmacological approach that is known to induce functional down-regulation of 5-HT2C receptors. Briefly, C57BL/6 mice were treated with either saline (SAL-10 ml/kg ip) or the 5-HT2C/2A receptor agonist m-CPP (5 mg/kg ip) twice a day (9 AM and 6 PM) for 14 consecutive days (this protocol of m-CPP treatment has been previously shown to induce functional...