Melatonin, a neurohormone secreted by the pineal gland, can stimulate three subtypes of receptors, namely: mt(1), MT(2) and MT(3). We examined the ability of melatonin and the selective MT(3) receptor agonist, 5-methoxycarbonylamino-N-acetyltryptamine (5-MCA-NAT), to modify intraocular pressure in rabbits. Both compounds significantly reduced intraocular pressure, maximally by 24% and 43%, respectively, with IC(50) values of 363+/-23.0 and 423+/-30.0 ng/10 microl (1.6+/-0.1 and 1.8+/-0.1 nmol, respectively). The non-specific melatonin receptor antagonist, luzindole, abolished the depressant effect of both compounds, thus confirming the involvement of melatonin receptors. Our results show, for the first time, a functional response that may be regulated by melatonin MT(3) receptors, and provide evidence that supports a role of melatonin in the circadian changes of intraocular pressure.