The purpose of this study was to define the ocular actions of 8-OH-DPAT(DPAT), a 5-HT(1A)receptor agonist. The intraocular pressure responses to topically applied DPAT were dose related (25, 125, 250 microgram) and bilateral in normal rabbits but of relatively short duration.
Ocular hypotension induced by topical, unilateral DPAT (125 microgram) in normal eyes did not occur in sympathetically denervated eyes. DPAT-induced
ocular hypotension was inhibited by pretreatment with
spiroxatrine, a 5-HT(1A)and alpha(2C)receptor antagonist, but not
spiperone, a 5-HT(2A)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 microgram) 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 micrometer) 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 micrometer) inhibition of
isoproterenol (1 micrometer)-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-HT(1A)receptors in the eye and 5-HT(1A)receptors and/or alpha(2C)adrenoreceptors in the central nervous system, (2) the activity of DPAT on 5-HT(1A)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.