TEMPORAL DIFFERENTIAL ADAPTATION OF HEAD-TWITCH AND EAR-SCRATCH RESPONSES FOLLOWING ADMINISTRATION OF CHALLENGE DOSES OF DOI

Previously, we reported that administration of the 5-HT2A/C receptor a gonist, DOI -)-1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane], can sim ultaneously produce the head-twitch response (HTR) and the ear-scratch response (ESR) in mice. Our recent studies have indicated that the HT R is a 5-HT2A receptor-mediated phenomenon, whereas the ESR is probabl y a 5-HT2C receptor-mediated event. The HTR and ESR exhibit subsensiti vity to a challenge dose of DOI (2.5 mg/kg) administered 24 h after it s acute or termination of its chronic (2.5 mg/kg, once daily for 13 da ys) administration. When the dose interval for the challenge dose of D OI was increased to 48 h, both the acute- and chronically treated mice exhibited a simultaneous supersensitive HTR response and a subsensiti ve 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 o f repeated DOI injections at 2-h intervals for 8 h. Thus, in the prese nt study, initial administration of DOI produced a dose- and time-depe ndent increase in the mean frequencies of both HTR and ESR. Significan t 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. However, larger challenge doses of DOI (1 and 2.5 mg/kg) produced supersensitivity in the mean HTR score (+46% and +40%, respectively, p < 0.05) and subsensitivity i n the mean ESR frequency (-92% and -67%, respectively, p < 0.05) relat ive to their first injection control values. All administered doses of DOI (0.25, 0.5, or 1 mg/kg) eventually significantly reduced their fi rst injection (control) HTR scores when injected repeatedly at 2-h int ervals. Significant HTR reductions were attained quicker for the large r DOI doses. It appears that a mouse needs to receive either cumulativ ely or in a single injection about 1 mg/kg dose of DOI prior to exhibi ting a significant reduction in the HTR score in response to further a dministration of DOI. As with their initial first injection ESR scores , repeated administration of lower doses of DOI (0.25 and 0.5 mg/kg) d id not produce a significant effect. However, the 1 mg/kg challenge do se of DOI, 2 h following its first injection, nearly completely attenu ated its first injection control ESR score. Further repeated injection s of DOI at 2-h intervals did not cause additional alteration in the m ean ESR score. The present results indicate that adaptation mechanisms for the DOI-induced HTR and ESR are different, and this difference is probably a reflection of the adaptation mechanisms of the 5-HT2A- and 5-HT2C-receptor function.