PURPOSE. To investigate the production of the voltage changes evoked in the retinal pigment epithelium (RPE) by light and alcohol and the interaction of these agents. METHODS. The eye movement potential in humans was intermittently recorded to standard horizontal excursions for long periods during which either retinal illumination was altered or ethyl alcohol was administered by the oral, intragastric, or intravenous route. In other experiments, both light and alcohol were administered. RESULTS. Alcohol and light produced near identical corneofundal voltage changes (positive and then negative) over more than 40 minutes. Differences in timing between alcohol and light increases are explicable by the delays in alcohol absorption. Weak background light suppressed the effect of light steps, and low levels of background alcohol suppressed the response to subsequent doses. Backgrounds of one agent did not affect the voltage changes caused by the other. Minimal alcohol effects were seen after administration of 1 g orally or 270 mg intravenously-that is, doses that produced undetectable changes in breath alcohol. The semisaturating oral dose was approximately 20 mg/kg. CONCLUSIONS. Alcohol and light act through separate pathways to form a final common pathway inside the RPE cell that is responsible for triggering the timing of the slow oscillatory changes of EOG voltage. The sensitivity and duration with which alcohol affects the RPE are comparable with the effect of melatonin or dopamine, although only the former interacts with light similarly to alcohol. Transient modulation of the acetylcholine (Ach) neuronal receptor occurs at similar sensitivity, but all other known actions of alcohol require higher concentrations than this RPE action. (Invest Ophthalmol Vis Sci. 2000;41:2722-2729 S ince the original descriptions of the electro-oculogram (EOG) in humans, 1-4 intraretinal microelectrode recordings 5-10 have elucidated the underlying mechanisms. Light adaptation of the retina changes the quantity of an unknown substance or substances, probably produced by photoreceptors, that diffuses to the apical processes of the retinal pigment epithelium (RPE) where it binds to membrane-bound chemical receptors. These then liberate an intracellular second messenger that ultimately depolarizes the basolateral surface of the RPE cells, causing a light-induced increase in the corneofundal potential (hereafter termed light rise), by increasing the chloride conductance. 11 The external and internal transmitters are unknown, as is the relationship between the transmitter concentration and the stereotyped voltage changes. Thus, the time course of the concentration changes of the external or the internal transmitter may determine the timing of the light rise and the subsequent oscillations. The EOG remains a useful clinical test, 12-18 because it offers an overview of the functioning of photoreceptors, subretinal space, and RPE, but because light is used to provoke the voltage changes, retinal and RPE dysfunction cannot be separated. Therefore, other agents, such as bicarbonate ions, acetazolamide, and hyperosmotic solutions, which act directly on the RPE, have been investigated. 18 -22 All have been found to cause a slow decrease in corneofundal potential. Previous experiments METHODS Subjects Three students aged 20 to 25 years and the authors (seventh decade) gave informed consent, and the experimental protocols complied with the Helsinki declaration. Recording Techniques Five-millimeter chloride-coated silver disc electrodes were placed on each temple, near the lateral canthi, and a similar earth electrode was placed on the forehead. The recording was bitemporal (i.e., the voltages were generated by both eyes). Standard 30°horizontal eye movements were made at two per From the Applie
