The effects of the novel anxiolytic drug lesopitron, a full and selective 5-HT1A receptor agonist, on pupil diameter and oral temperature in man: comparison with buspirone.

Abstract

We investigated the effects of two 5-HT1A receptor agonists, buspirone and lesopitron, upon pupil size in human volunteers at an ambient luminance level of 32 Cd m(-2) and in darkness. Pupil diameter was monitored with a binocular infrared television pupillometer, before and after the administration of treatments for 4 h at 20-min intervals. Two experiments were conducted. In Experiment 1, 14 healthy male volunteers participated in seven weekly sessions, each associated with the ingestion of one capsule (buspirone 5, 10 and 20 mg, lesopitron 10, 20 and 40 mg and placebo), according to a double-blind balanced, cross-over design. Both buspirone and lesopitron tended to decrease pupil diameter. In darkness, only the highest dose of buspirone (20 mg) caused a miosis that was statistically significant. However, at the luminance level of 32 Cd m(-2) buspirone 10 and 20 mg evoked statistically significant miotic effects, as did the highest dose of lesopitron (40 mg). The miotic effect was significantly greater at 32 Cd m(-2) than in darkness after each dose of buspirone and the highest dose (40 mg) of lesopitron. In Experiment 2, pupil diameter and oral temperature were monitored with an electronic thermometer at 40-min intervals. Twenty healthy male volunteers participated in two weekly sessions, each associated with the sublingual application of 100 microl hydroalcoholic solution (lesopitron 20 mg, placebo), according to a double-blind balanced cross-over design. Lesopitron caused a significant miosis both in darkness and at the luminance level of 32 Cd m(-2); the miosis was greater at 32 Cd m(-2) than in darkness. Lesopitron tended to decrease oral temperature; this effect however, was not statistically significant. The greater effectiveness on the pupil of lesopitron administered sublingually in a solution indicates the importance of first-pass metabolism in reducing the effectiveness of the drug when administered by the mouth. The miosis observed in both experiments may be due to either a sympatholytic or a parasympathomimetic effect of the drugs, or both. The light-dependence of the miosis indicates that the 5-HT1A receptor agonists can modulate the light reflex, possibly via the noradrenergic control of central cholinergic neurones in the Edinger-Westphal nucleus.