The possible involvement of 5-HT2A or 5-HT2C receptors in the elevation of serum corticosterone in rats by quipazine (2-(1-piperazinyl)quinoline maleate) and MK-212 (6-chloro-(1-piperazinyl)pyrazine), direct-acting 5-HT receptor agonists, was investigated by the use of two newly available receptor antagonists, SB 200646A (N-(1-methyl-5-indolyl)-N'-(3-pyridyl)urea) and MDL 100,907 (R-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]- 4-piperidinemethanol). MDL 100,907 blocked the increase in serum corticosterone elicited by quipazine and MK-212 with ED50 values of 0.0028 and 0.0027 mg/kg, s.c., respectively. In contrast, SB 200646A only partially antagonized the serum corticosterone concentration increases by quipazine and MK-212 even at the highest dose tested, 40 mg/kg, i.p. Because published data show the affinities of MDL 100,907 and SB 200646A for 5-HT2C receptors to be nearly identical, whereas the affinity of MDL 100,907 for 5-HT2A receptors is 17500-fold higher than that of SB 200646A, our findings suggest that 5-HT2A receptors rather than 5-HT2C receptors mediate the serum corticosterone increases by both quipazine and MK-212.