THE SILENT AND SELECTIVE 5-HT1A ANTAGONIST, WAY-100635, PRODUCES VIA AN INDIRECT MECHANISM, A 5-MT2A RECEPTOR-MEDIATED BEHAVIOR IN MICE DURING THE DAY BUT NOT AT NIGHT

The head-twitch response (HTR) in rodents is considered to be a functi onal index for the activation of 5-HT2A receptors. Intraperitoneal adm inistration of the silent and selective 5-HT1A receptor antagonist, WA Y 100635, produced the HTR in mice in a dose-dependent bell-shaped man ner. The induced behaviour followed a diurnal pattern in that WAY 1006 35 only produced a robust HTR frequency during the light period of the 24 h daily cycle. Pretreatment with the selective 5-HT2A/C receptor a ntagonist, SR 46349B, potently, and in a dose-dependent manner attenua ted the induced behaviour. It appears that WAY 100635 produces the HTR indirectly via disinhibition of endogenous serotonergic inhibitory to ne operating on the somatodenritic pulse-modulating 5-HT1A autorecepto rs. The latter antagonism seems to potentiate endogenous 5-HT release in serotonergic terminal field synapses which subsequently stimulates postsynaptic 5-HT2A receptors to produce the head-twitch behaviour.