Temporal differential adaptation of head-twitch and ear-scratch responses following administration of challenge doses of DOI

Document Type

Article

Publication Title

Pharmacology, Biochemistry and Behavior

Abstract

Previously, we reported that administration of the 5-HT 2A C receptor agonist, DOI [(±)-1-(2,5-Dimethoxy-4-iodophenyl)-2aminopropane], 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. 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 in the mean ESR frequency (-92% and -67%, respectively, p < 0.05) relative to their first injection control values. All administered doses of DOI (0.25, 0.5, or 1 mg/kg) eventually significantly reduced their first injection (control) HTR scores when injected repeatedly at 2-h intervals. Significant HTR reductions were attained quicker for the larger DOI doses. It appears that a mouse needs to receive either cumulatively or in a single injection about 1 mg/kg dose of DOI prior to exhibiting a significant reduction in the HTR score in response to further administration of DOI. As with their initial first injection ESR scores, repeated administration of lower doses of DOI (0.25 and 0.5 mg/kg) did not produce a significant effect. However, the 1 mg/kg challenge dose of DOI, 2 h following its first injection, nearly completely attenuated its first injection control ESR score. Further repeated injections of DOI at 2-h intervals did not cause additional alteration in the mean 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. © 1995.

First Page

545

Last Page

550

DOI

10.1016/0091-3057(94)00340-8

Publication Date

1-1-1995

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