8OH-DPAT-Induced Ocular Hypotension: Sites and Mechanisms of Action

Abstract

The purpose of this study was to define the ocular actions of 8-OH-DPAT(DPAT), a 5-HT1Areceptor agonist. The intraocular pressure responses to topically applied DPAT were dose related (25, 125, 250 μg) and bilateral in normal rabbits but of relatively short duration. Ocular hypotension induced by topical, unilateral DPAT (125 μg) in normal eyes did not occur in sympathetically denervated eyes. DPAT-induced ocular hypotension was inhibited by pretreatment with spiroxatrine, a 5-HT1Aand α2Creceptor antagonist, but not spiperone, a 5-HT2Areceptor antagonist. In contrast, the hypotensive effect produced by unilaterally applied DPAT in the contralateral eye was abolished following pretreatment with rauwolscine, an α2-receptor antagonist, but the DPAT-induced ocular hypotension was not antagonized in the treated (ipsilateral) eye. Following central administration of DPAT (3 μg) into the lateral ventricle, intraocular pressure was lowered bilaterally at 10 min and the effect lasted for 2 hr. In in vitro experiments, DPAT (0.1, 1, 10 μm) failed to alter norepinephrine release in rabbit iris-ciliary bodies. However, DPAT depressed basal cAMP levels in rabbit iris-ciliary bodies and also caused a dose-related (1, 10, 100 μm) inhibition of isoproterenol (1 μm)-stimulated cAMP accumulation by 26%, 58% and 82%, respectively. These findings indicate that: (1) based upon bilateral activity by the topical route, DPAT-induced ocular hypotension could result, in part, through activation of 5-HT1Areceptors in the eye and 5-HT1Areceptors and/or α2Cadrenoreceptors in the central nervous system, (2) the activity of DPAT on 5-HT1Aand/or α2Creceptors was confirmed by antagonism of the ocular hypotensive response by spiroxatrine, (3) although there is no apparent prejunctional effect of DPAT on sympathetic nerves of iris-ciliary bodies, the accumulation of basal and isoproterenol-stimulated cAMP levels were depressed by DPAT, and (4) as a result of inhibition by rauwolscine, the ocular hypotensive effect of DPAT in the contralateral eye could involve an action on α2adrenoreceptors in the central nervous system.