Abstract

The 5-hydroxytryptamine (5-HT)2 agonist (+/- )-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and antagonist ketanserin were evaluated for acute and chronic effects on the 5-HT2 receptor-mediated head-twitch response (HTR) in mice. A single dose of DOI resulted in tolerance to the DOI-induced HTR at 24 hr but supersensitivity at 48 hr. This apparent supersensitivity persisted up to 144 hr after the first DOI injection. Chronic once daily DOI administration significantly reduced the HTR frequency (days 2-6), which then returned slowly to control levels by treatment day 13. A 48-hr withdrawal from this chronic regimen produced a similar supersensitivity to that observed after a single DOI injection upon a 48-hr challenge. This effect also persisted up to 144 hr after cessation of chronic treatment. Acute pretreatment with a single injection of ketanserin significantly reduced the DOI-induced HTR frequency when tested 24 and 48 hr, but not 120 hr, after injection of the antagonist. After withdrawal from chronic ketanserin treatment, the DOI-induced HTR was significantly reduced at 24 hr but significantly increased at 48 hr. This enhanced effect subsided when mice were tested with DOI 72 hr after cessation of chronic antagonist treatment. These data suggest that the serotonergic system adapts to chronic exposure of either agonists or antagonists in a fashion distinctly different from that exhibited by other monoamine neurotransmitter systems.