In the present study, the effects of 5-HT and two 5-HT1c/5-HT2 receptor agonists, (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and alpha-methyl-serotonin (alpha-Me-5-HT) on phosphoinositide hydrolysis were compared, to determine whether DOI and alpha-Me-5-HT were full agonists. Consistent with the results obtained from previous studies, both (+/-)-DOI and alpha-Me-5-HT stimulated turnover of phosphoinositide in a concentration-dependent manner. However, the response obtained with these 5-HT1c/5-HT2 receptor agonists was only 30-40% of that of 5-HT. The stimulation of hydrolysis of phosphoinositide, produced by both 5-HT2 receptor agonists, was potently antagonized by ritanserin (a 5-HT1c/5-HT2 receptor antagonist) and alpha-phenyl-1-(2-phenylethyl)-4-piperine methanol [(+)-MDL 11,939, a 5-HT2 receptor antagonist] but not by granisetron (BRL a 5-HT3 receptor antagonist), suggesting that the action of DOI and alpha-Me-5-HT was primarily mediated by 5-HT2 receptors. When the effect of increasing the concentration of 5-HT on turnover of phosphoinositide was measured in the presence of a 1 microM concentration of the 5-HT3 receptor antagonist granisetron, the response obtained was similar to the response produced by the 5-HT2 receptor agonists, DOI and alpha-Me-5-HT. These results confirm the previous finding that 5-HT stimulates hydrolysis of phosphoinositide by interacting with 5-HT1c/5-HT2 and 5-HT3 receptors. Moreover, they suggest that DOI and alpha-Me-5-HT are full agonists at the 5-HT2 receptor, coupled to hydrolysis of phosphoinositide in the cortex of the rat.