Dopamine is a major neurotransmitter in central nervous system and retina. Recently, dopamine D3 preferring receptor agonists have been proposed for the treatment of neuropsychiatric disorders such as schizophrenia and Parkinson's disease. Although the potential of D2 receptor agonists as intraocular pressure (IOP)-lowering agents has been investigated, the therapeutic value has not been determined. Research in this laboratory has revealed that topically administered 7-OH-DPAT, a D3 preferring receptor agonist, lowered IOP bilaterally in rabbits. To understand the ocular action of D3 agonists, the mechanism(s) of IOP-lowering effects will be examined. Long-term objectives: 1) to ascertain the sites of action whereby aqueous humor inflow/outflow are regulated by D3 agonists, 2) to elucidate the cellular mechanisms for the ocular hypotension induced by D3 agonists and 3) to determine the mechanisms of neuroprotection provided by D3 agonists. Hypotheses: D3 preferring receptor agonists: 1) lower IOP by modifying aqueous inflow/outflow through interaction with cellular function of sympathetic neurons and 2) antagonize the glutamate-induced toxicity of retinal ganglion cells.
Specific aims : 1) characterize the effects on norepinephrine release from sympathetic nerve endings of ciliary body, 2) determine sites of action of D3 agonists by evaluating effects on norepinephrine release from sympathetic nerve endings of ciliary body, 3) determine which signal transduction mechanisms are suppressed by D3 agonists in sympathetic retinal ganglion cells. Tonometry, fluorophotometry, two-stage constant pressure perfusion, immunohistochemistry, radioimmunoassay, image analysis and patch-clamp will be utilized to accomplish the specific aims. The goal of this project is to provide evidence for the sites and mechanisms of potential antiglaucoma agents (D3 agonists) and to define, more specifically, the potential role(s) of these compounds in modulating ocular hydrodynamics and neuroprotection. This research should provide significant leads to the discovery of novel therapeutic agents (D3 agonists) for the treatment of chromic, open-angle glaucoma.
