Previously, we reported that administration of the 5-HT2A/C receptor agonist, DOI [(+/-)-1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane], can simultaneously produce the head-twitch response (HTR) and the ear-scratch response (ESR) in mice. Our recent studies have indicated that the HTR is a 5-HT2A receptor-mediated phenomenon, whereas the ESR is probably a 5-HT2C receptor-mediated event. The HTR and ESR exhibit subsensitivity to a challenge dose of DOI (2.5 mg/kg) administered 24 h after its acute or termination of its chronic (2.5 mg/kg, once daily for 13 days) administration. When the dose interval for the challenge dose of DOI was increased to 48 h, both the acute- and chronically treated mice exhibited a simultaneous supersensitive HTR response and a subsensitive ESR effect. The purpose of the present study was to investigate the dose-response effects of lower challenge doses of DOI 48 h following their respective first injections as well as determining the effects of repeated DOI injections at 2-h intervals for 8 h. Thus, in the present study, initial administration of DOI produced a dose- and time-dependent increase in the mean frequencies of both HTR and ESR. Significant HTRs were observed after administration of the lowest tested dose of DOI (0.25 mg/kg), whereas a robust frequency of ESR was only evident at 1 mg/kg or greater doses of DOI. A 48-h challenge administration of lower doses of DOI (0.25 and 0.5 mg/kg) did not significantly affect their respective first injection HTR scores.(ABSTRACT TRUNCATED AT 250 WORDS)