The purpose of this study was to define the ocular actions of 8-OH-DPAT(DPA
T); a 5-HT1A receptor agonist, The intraocular pressure responses to topica
lly applied DPAT were dose related (25, 125, 250 mu g) and bilateral in nor
mal rabbits but of relatively short duration, Ocular hypotension induced by
topical, unilateral DPAT (125 mu g) in normal eyes did not occur in sympat
hetically 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 hypoten
sive 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, i
n the treated (ipsilateral) eye. Following central administration of DPAT (
3 mu g) into the lateral ventricle, intraocular pressure was lowered bilate
rally at 10 min and the effect lasted for 2 hr. In in vitro experiments, DP
AT (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-ci
liary 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%, r
espectively. These findings indicate that: (1) based upon bilateral activit
y by the topical route, DPAT-induced ocular hypotension could result, in pa
rt, 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 act
ivity of DPAT on 5-HT1A and/or alpha(2C) receptors was confirmed by antagon
ism of the ocular hypotensive response by spiroxatrine, (3) although there
is no apparent prejunctional effect of DPAT on sympathetic nerves of iris-c
iliary bodies, the accumulation. of basal and isoproterenol-stimulated cAMP
levels were depressed by DPAT, and (4) as a result of inhibition by rauwol
scine, the ocular hypotensive effect of DPAT in the contralateral eye could
involve an action on alpha(2) adrenoreceptors in the central nervous syste
m. (C) 1999 Academic Press.