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Purpose: We developed a novel technique for accelerated drug screening and retinotoxin characterization using time-lapse optical coherence tomography (OCT) and a drug microapplication device., Methods: Using an ex vivo rabbit eyecup preparation, we studied retinotoxin effects in real-time by microperfusing small retinal areas under a transparent fluoropolymer tube. Known retinotoxic agents were applied to the retina for 5-minute periods, while changes in retinal structure, thickness, and reflectance were monitored with OCT. The OCT images of two agents with dissimilar mechanisms, cyanide and kainic acid, were compared to their structural changes seen histologically., Results: We found the actions of retinotoxic agents tested could be classified broadly into two distinct types: (1) agents that induce neuronal depolarization, such as kainic acid, causing increases in OCT reflectivity or thickness of the inner plexiform and nuclear layers, and decreased reflectivity of the outer retina; and (2) agents that disrupt mitochondrial function, such as cyanide, causing outer retinal structural changes as evidenced by a reduction in the OCT reflectivity of the photoreceptor outer segment and pigment epithelium layers., Conclusions: Retinotoxin-induced changes in retinal layer reflectivity and thickness under the microperfusion tube in OCT images closely matched the histological evidence of retinal injury. Time-lapse OCT imaging of the microperfused local retina has the potential to accelerate drug retinotoxicological screening and expand the use of OCT as an evaluation tool for preclinical animal testing., (Copyright 2015 The Association for Research in Vision and Ophthalmology, Inc.)