(+/-) 1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane [(+/-)-DOI], a phenylisopropylamine hallucinogen, is a 5-HT2-receptor agonist. The drug induced a dose-dependent increase in ear-scratch response (ESR) in mice, and the R(-)-isomer was more than 6 times as potent as its S(+)-enantiomer. The induced behavior was potently inhibited by selective 5-HT2-receptor antagonists such as ketanserin and spiperone. The (+/-)-DOI-induced ESR is also inhibited by stimulation of 5-HT1-receptors and the inhibition seems to be through a 5-HT1B-receptor mechanism. Thus, taken together, the present investigation indicates that ESR is due to selective stimulation of 5-HT2-receptors and that simultaneous costimulation of 5-HT1B-receptors inhibits the induced behavior. The study further suggests that the inability of the indolealkylamine hallucinogens to induce ESR is due to simultaneous excitation of 5-HT1B-receptors which are inhibitory to induction of ESR. Moreover, the data suggest possible inhibitory control mechanisms through 5-HT1-receptor subtypes to provide a damping mechanism to reduce excessive 5-HT2-receptor excitation due to exogenous drug stimulation or pathological conditions.