The 5-HT1A receptor agonist 8-OH-DPAT lowers intraocular pressure in normotensive NZW rabbits

The aims of this study were first to investigate the effect of topical instillation of the 5-HT1A receptor agonist 8-OH-DPAT on intraocular pressure (IOP) in normotensive rabbits and second to establish whether the drug reaches the aqueous humour of treated and contralateral eyes at concentrations sufficient to activate ciliary epithelial 5-HT1A receptors. Following topical unilateral instillation of (+/-). (+) or (-)8-OH-DPAT, the IOP of rabbits was measured using an applanation tonometer. For the penetration study, [H-3]8-OH-DPAT was instilled into one eye of each rabbit. Animals were killed after 30 min and the radioactive content of treated and contralateral ocular tissues was assessed. Administration of (+/-)8-OH-DPAT caused dose-dependent decreases in IOP in treated eyes of rabbits during the light and dark. The full 5-HT1A agonist (+)8-OH-DPAT was shown to be a more effective hypotensive agent than the partial agonist (-)8-OH-DPAT. The effect of (+/-)8-OH-DPAT on IOP was blocked by pretreatment with pindolol, a mixed 5-HT1A antagonist/beta-blocker, but not by the specific beta-blocker betaxolol. After instillation of [H-3]8-OH-DPAT, peak levels of radioactivity were found in the cornea, followed by similar amounts in the iris-ciliary body and aqueous. There was negligible radioactivity present in tissues of the contralateral eye. This study demonstrates that topical administration of the 5-HT1A agonist 8-OH-DPAT dose-dependently decreases IOP in normotensive rabbits during the light and dark. The action of 8-OH-DPAT is presumably local to the anterior uvea as IOP was reduced only in treated eyes and [H-3]8-OH-DPAT failed to reach the contralateral eye after unilateral instillation. Moreover, since 5-HT1A receptors are located in the rabbit ciliary epithelium and the effect of 8-OH-DPAT is blocked by a recognized 5-HT1A antagonist, the mechanisms of action of 8-OH-DPAT may well involve a decreased secretion of aqueous humour. (C) 1999 Academic Press.