LACK OF CROSS-TOLERANCE FOR HYPOPHAGIA INDUCED BY DOI VERSUS M-CPP SUGGESTS SEPARATE MEDIATION BY 5-HT2A AND 5-HT2C RECEPTORS, RESPECTIVELY

Intraperitoneal administration of 1-(2,5-dimethoxy-4-iodophenyl)-2-ami nopropane (DOI) produced significant decreases in the first-hour food intake on day 1 and on day 2 relative to saline-treated animals. Compl ete tolerance developed to DOI-induced hypophagia by day 3. However, t here was no cross-tolerance to m-chlorophenylpiperazine (m-CPP)-induce d hypophagia. Similarly, complete tolerance developed to m-CPP-induced hypophagia by day 3, but again there was no cross-tolerance to DOI-in duced hypophagia. These findings suggest that DOI and m-CPP-induced hy pophagia are mediated by different mechanisms, most likely by selectiv e stimulation of 5-HT2A receptors by DOI and 5-HT2C receptors by m-CPP . The functional sensitivity changes did not parallel changes in hypot halamic [H-3]-mesulergine-labeled 5-HT2C receptors or [H-3]-ketanserin -labeled 5-HT2A receptors following chronic m-CPP or DOI treatment, al though both treatments significantly reduced 5-HT2A and 5-HT2C recepto rs in cortex. Thus, future studies investigating the effects of daily m-CPP and DOI administration on phosphoinositide hydrolysis or mRNA fo r 5-HT2C and 5-HT2A receptors in the hypothalamus might help explain t he functional sensitivity changes observed in the present study.