Vol. 293, Issue 3, 710-716, June 2000

Mechanisms and Sites of Ocular Action of 7-Hydroxy-2-dipropylaminotetralin: A Dopamine₃ Receptor Agonist¹

Eugenia Chu, Teh-Ching Chu and David E. Potter

Department of Pharmacology and Toxicology, Morehouse School of Medicine, Atlanta, Georgia

The purpose of this study was to investigate mechanism(s) and site(s) of action involved in 7-hydroxy-2-dipropylaminotetralin (7-OH-DPAT)-induced ocular hypotension. As measured by pneumatonometry, the topical, unilateral application of 7-OH-DPAT (75 µg), a dopamine D₃-preferring receptor agonist, decreased the intraocular pressure (IOP) bilaterally. The ocular hypotensive activity of 7-OH-DPAT was diminished in sympathetically denervated rabbits. Pretreatment with raclopride, a D₂/D₃ receptor antagonist; UH232, a D₃ receptor antagonist; or U-99194A, a D₃ receptor antagonist antagonized 7-OH-DPAT-induced ocular hypotension. However, pretreatment with spiperone, a D₂ receptor antagonist, did not affect the 7-OH-DPAT-induced ocular hypotension. In addition, topically applied 7-OH-DPAT caused a reduction of aqueous humor flow rate. To examine sites of action, immunohistochemistry of D₃ dopamine receptors was performed. Dopamine D₃ receptors were found to be present on postganglionic sympathetic nerves in the ciliary body of normal rabbits but were virtually undetectable in the same tissue of sympathectomized rabbits. In summary, the IOP-lowering effect caused by 7-OH-DPAT was due, in part, to the suppression of aqueous humor flow. Immunohistochemical identification of D₃ receptors in the ciliary body, associated with the diminution of IOP-lowering effects by D₃ receptor agonist 7-OH-DPAT in sympathetically denervated rabbits provided evidence of neuronal site of action of 7-OH-DPAT. Suppression of 7-OH-DPAT-induced ocular hypotension by D₃ receptor antagonists (U-99194A and UH232) and sympathectomy, coupled with the immunohistochemical data, suggested that the primary site of D₃ receptor-mediated action of 7-OH-DPAT is located on postganglionic sympathetic nerve endings in the ciliary body of rabbit.