8OH-DPAT-induced ocular hypotension: Sites and mechanisms of action

The purpose of this study was to define the ocular actions of 8-OH-DPAT(DPAT); a 5-HT1A receptor agonist, The intraocular pressure responses to topically applied DPAT were dose related (25, 125, 250 mu g) and bilateral in normal rabbits but of relatively short duration, Ocular hypotension induced by topical, unilateral DPAT (125 mu g) in normal eyes did not occur in sympathetically denervated eyes, DPAT-induced ocular hypotension was inhibited by pretreatment with spiroxatrine, a 5-HT1A and alpha(2C) receptor antagonist, but not spiperone, a 5-HT2A receptor antagonist. In contrast, the hypotensive effect produced by unilaterally applied DPAT in the contralateral eye was abolished following pretreatment with rauwolscine, an alpha(2)-receptor antagonist, but the DPAT-induced ocular hypotension was not antagonized, in the treated (ipsilateral) eye. Following central administration of DPAT (3 mu g) 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 mu M) failed to after 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 mu M) inhibition of isoproterenol (1 mu M)-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-HT1A receptors in the eye and 5-HT1A receptors and/or alpha(2C) adrenoreceptors in the central nervous system, (2) the activity of DPAT on 5-HT1A and/or alpha(2C) receptors 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 alpha(2) adrenoreceptors in the central nervous system. (C) 1999 Academic Press.