Intraperitoneal administration of 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) produced significant decreases in the first-hour food intake on day 1 and on day 2 relative to saline-treated animals. Complete tolerance developed to DOI-induced hypophagia by day 3. However, there was no cross-tolerance to m-chlorophenyl-piperazine (m-CPP)-induced hypophagia. Similarly, complete tolerance developed to m-CPP-induced hypophagia by day 3, but again there was no cross-tolerance to DOI-induced hypophagia. These findings suggest that DOI and m-CPP-induced hypophagia are mediated by different mechanisms, most likely by selective stimulation of 5-HT2A receptors by DOI and 5-HT2C receptors by m-CPP. The functional sensitivity changes did not parallel changes in hypothalamic [3H]-mesulergine-labeled 5-HT2C receptors or [3H]-ketanserin-labeled 5-HT2A receptors following chronic m-CPP or DOI treatment, although both treatments significantly reduced 5-HT2A and 5-HT2C receptors in cortex. Thus, future studies investigating the effects of daily m-CPP and DOI administration on phosphoinositide hydrolysis or mRNA for 5-HT2C and 5-HT2A receptors in the hypothalamus might help explain the functional sensitivity changes observed in the present study.