Abstract
Antipsychotic drugs haloperidol and clozapine have been reported to increase the sensitivity of retinal ganglion cells (RGCs) to flashes of light in the P23H rat model of retinitis pigmentosa. In order to better understand the effects of these antipsychotic drugs on the visual responses of P23H rat RGCs, I examined the responses of RGCs to a drifting sinusoidal grating of various contrasts. In-vitro multielectrode array recordings were made from P23H rat RGCs and healthy Sprague-Dawley (SD) rat RGCs. Retinas were stimulated with a drifting sinusoidal grating with eight values of contrast (0, 4, 6, 8.5, 13, 26, 51, and 83%). Contrast response functions based on response amplitudes were fitted with a hyperbolic ratio function and contrast thresholds were determined from the fitted curves. SD rat RGCs were divided into two categories, saturating and non-saturating cells, based on whether they showed saturation of responses at high contrast levels. Most SD rat RGCs (58%) were saturating cells. Haloperidol and clozapine decreased the responses of saturating SD rat RGCs to all grating contrasts, except for the highest contrast tested. Clozapine also decreased the responses of non-saturating SD rat RGCs to all grating contrasts, except for the highest contrast tested. Haloperidol did not however significantly affect the responses of non-saturating SD rat RGCs. Haloperidol and clozapine increased the contrast thresholds of both saturating and non-saturating cells in SD rat retinas. Most (73%) P23H rat RGCs could be categorized as either saturating or non-saturating cells. The remaining ‘uncategorized’ cells were poorly responsive to the drifting grating and were analyzed separately. Haloperidol and clozapine increased the responses of non-saturating and uncategorized P23H rat RGCs to most grating contrasts, including the highest contrast tested. Haloperidol and clozapine also increased the responses of saturating P23H rat RGCs to most grating contrasts but these increases were not statistically significant. Haloperidol and clozapine decreased the contrast thresholds of saturating cells, non-saturating cells and uncategorized cells in P23H rat retinas, although the decrease in contrast thresholds of saturating cells was not found to be statistically significant. Overall, the findings show that haloperidol and clozapine have differential effects on the contrast response functions of SD and P23H rat RGCs. In contrast to the effects observed on SD rat RGCs, both haloperidol and clozapine increased the responsiveness of P23H rat RGCs to both low and high contrast visual stimuli and decreased contrast thresholds.
Highlights
Retinitis pigmentosa (RP) is an inherited retinal degenerative disease in which there is a progressive loss of rod photoreceptors, followed by a loss of cone photoreceptors
Studies conducted in animal models of RP have shown multiple pharmacological agents that can slow down photoreceptor degeneration
Spike activity of many SD and P23H rat retinal ganglion cells (RGCs) was modulated by the full-field drifting sinusoidal grating
Summary
Retinitis pigmentosa (RP) is an inherited retinal degenerative disease in which there is a progressive loss of rod photoreceptors, followed by a loss of cone photoreceptors. Studies conducted in animal models of RP have shown multiple pharmacological agents that can slow down photoreceptor degeneration. With the loss of photoreceptors in RP and age-related macular degeneration (AMD) there is remodeling of cells of the inner retina, including horizontal cells, bipolar cells and amacrine cells [8, 9] Not surprisingly, this remodeling affects the activity of RGCs. One of the earliest documented findings is a change in the spontaneous spike activity of RGCs in the rd mouse (a model of RP with a mutation in the Pde6b gene), including the appearance of oscillatory bursts of spikes [10, 11]. The present study was undertaken to determine how haloperidol and clozapine affect the response amplitudes and contrast thresholds of RGCs in P23H and SD rat retinas to a drifting sinusoidal grating – a visual stimulus that is commonly used to measure contrast sensitivity behaviorally in rodents
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