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

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 Sp antagonists of which ketanserin (a potent vascular Sp 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 Sp 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.

Potencies of antagonists indicate that 5‐HT1C receptors mediate 1–3(chlorophenyl)piperazine‐induced hypophagia

“…None of the antagonists caused head shakes when given alone. Calculated ID50 values are given in Table 2 and were in order: metergoline = ketanserin < altanserin < ritanserin < mianserin < pizotifen < methysergide = LY The present findings strengthen previous evidence (Kennett & Curzon, 1988a) (Bedard & Pycock, 1977;Yap & Taylor, 1983;Niemegeers et al, 1983).…”

“…We have now minimized the above problems by comparing the ratios of in vivo ID50 values of ten antagonists against mCPP-induced hypophagia and 5-HT2-mediated (Bedard & Pycock, 1977;Yap & Taylor, 1983;Niemegeers et al, 1983) head shakes with the corresponding ratios of in vitro drug affinities for various 5-HT1 receptor subtypes and 5-HT2 receptors. This provides indices of blockade of different 5-HT receptors which are independent of differences in drug absorption or metabolism and which can be compared with published in vitro affinity ratios.…”

Nootropic Candidates Inhibit Head-Twitches Induced by Mescaline in Mice.

“…It has been reported that the 5-HT agonist mescaline-induced head-twitches are inhibited by various 5-HT antagonists including the selective 5-HT2 receptor antagonists ketanserin and pirenperone and that antagonism of mescaline correlates with inhibition of [3H]spiperone binding to the rat prefrontal cortex in vitro (4). These findings indicate that the head-twitches induced by mes caline are mediated by central 5-HT2 receptors.…”

Iloperidone: Preclinical Profile and Early Clinical Evaluation

“…been identified as a particular target in an attempt to reduce EPS liability (39,49,58,83). Since iloperidone inhibits binding to 5-HTzA receptors in vitro, it was tested for inhibition of 5-HTP-induced head twitch, a 5-HT2 receptor-mediated behavior (52,53,68,71). Iloperidone inhibits head twitch (EDSo = 0.07 mg/kg i. p.), consistent with its affinity for 5-HT2 receptors, indicating that iloperidone blocks 5-HT2 receptors in vivo.…”