Further evidence for enigmas in adaptation mechanisms for the DOI-induced behaviors

The acute and chronic effects of the 5-hydroxytryptamine2/1C (5-HT2/1C) receptor agonist (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and the antagonist ketanserin were evaluated on the DOI-induced 5-HT2 receptor-mediated ear-scratch response (ESR) in mice. A challenge dose of DOI (2.5 mg/kg) administered 24 h following its first injection reduced the ESR frequency by 80-97%. The ESR score attained first injection value when the time lag between the first and the second injection was greater than 72 h. On the other hand, a single administration of ketanserin (1.0 mg/kg) caused no significant effect at 24 or 48 h but significantly reduced (51%, p < 0.05) the DOI-induced ESR 120 h following its injection. Chronic once-daily DOI injections reduced the ESR score by 80-97% throughout the treatment regimen. Following cessation from chronic treatment, the DOI-induced ESR frequency returned to control levels in a time-dependent manner. Repeated ketanserin administration significantly reduced the DOI-induced ESR score by 46% when tested 24 or 48 h following cessation of antagonist administration but had no effect at 78 h. Recently, we reported that 48 h following either a single DOI injection or termination from repeated DOI or ketanserin administration the DOI-induced head-twitch response (HTR) in mice exhibited supersensitivity. Thus, it appears that the DOI-induced behaviors exhibit differential adaptation mechanisms following either agonist or antagonist exposure. These studies further support our hypothesis that serotonergic drugs may have the ability to change independently the 5-HT-receptor sensitivity (signal transduction) and receptor density in the same or opposite directions.(ABSTRACT TRUNCATED AT 250 WORDS)