Mescaline‐induced head‐twitches in the rat: An in vivo method to evaluate serotonin S2 antagonists

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Abstract
An intravenous dose of 20.0 mg/kg of mescaline induced a reproducible head‐twitch response in rats. Drugs with very different pharmacological activities were tested for potential inhibition of this response. Among these drugs were a large number of serotonin antagonists, including several members of the recently described selective S2 antagonists of which ketanserin (a potent vascular S2 antagonist) and pirenperone (a pure LSD antagonist) are two prototypes. The same compounds were further studied in six in vivo tests in rats; these tests presumably measure antagonism at sites responsive to serotonin, dopamine, norepinephrine, histamine, or acetylcholine. A large number of test compounds inhibited mescaline‐induced head‐twitches. Although it was often associated with it, this activity did not correlate with any of the following effects: antagonism of apomorphine, norepinephrine, compound 48/80, physostigmine, or with mydriatic activity. Antagonism of mescaline did correlate, however, with in vivo antagonism of tryptamine and 5‐hydroxytryptophan, and with inhibition of 3H‐spiperone binding to the rat prefrontal cortex in vitro. It is concluded that inhibition of mescaline‐induced head‐twitches in the rat is a valid measure of serotonin S2 antagonist activity, also for those compounds whose primary activity occurs at dopamine, norepinephrine, histamine, or acetylcholine receptors. Ketanserin, pirenperone, and several chemically related compounds are very potent mescaline antagonists.