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Effects of 5Ht1a Receptor Agonists Upon Pupil Size in Human Volunteers

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Effects of 5Ht1a Receptor Agonists Upon Pupil Size in Human Volunteers EFFECTS OF 5HT1A RECEPTOR AGONISTS UPON PUPIL SIZE IN HUMAN VOLUNTEERS M.A. Phillips, E. Szabadi and C.M. Bradshaw Division of Psychiatry, University of Nottingham, UK Central 5-hydroxytryptaminergic (5HTergic, serotonergic) neurones have been implicated in autonomic regulation, although their exact role is not fully understood [1]. Drugs interacting with 5-HT receptors have been reported to affect pupil diameter: both antagonists of 5HT2 receptors [2] and agonists of 5HT1A receptors [3] cause miosis. We examined the effects of two 5HT1A receptor agonists on pupil diameter at two luminance levels (darkness and 32 Cd m-2). The drugs used were buspirone, an anxiolytic drug with partial agonistic activity at 5HT1A receptors and lesopitron, a recently developed anxiolytic drug with full agonistic activity at 5HT1A receptors. Pupil diameter was monitored with a binocular infrared television pupillometer before and after the administration of treatment for 4 h at 20 min intervals. Two experiments were conducted. In Experiment I, fourteen 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 II, pupil diameter and oral temperature were monitored with an electronic thermometer at 40 min intervals. 20 healthy male volunteers participated in two weekly sessions, each associated with the sublingual application of 100 µl 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. 1. Ramage AG and Fozard JR 1987. Eur J Pharmac 138, 179-191 2. Fanciullacci M et al 1995. Clin Pharmac Exp Ther 57, 349-355 3. Millson DS et al. 1991. Br J Clin Pharmacol 32, 447-454 4. Cleare AJ et al 1998 Int Clin Psychopharmacol 13, 23-32 [email protected].
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