Date Published: June 10, 2019
Publisher: Public Library of Science
Author(s): Ralph Jensen, Alfred S. Lewin.
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.
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. This genetically heterogeneous disease affects about 1 in 4000 people worldwide . Unfortunately, no approved pharmacological treatment exists for patients with RP. However, studies conducted in animal models of RP have shown multiple pharmacological agents that can slow down photoreceptor degeneration. These neuroprotectants included nerve growth factor , fluocinolone acetonide [3, 4], 9-cis-retinyl acetate [5, 6], and N-acetylcysteine , all of which have moved into clinical trials with RP subjects (clinicaltrials.gov; clinicaltrialsregister.eu).
Spike activity of many SD and P23H rat RGCs was modulated by the full-field drifting sinusoidal grating (spatial frequency: 1 cycle/mm, temporal frequency: 2 cycles/s). However, about one-third of the recorded RGCs (n = 415) were unresponsive to this grating in both the presence and absence of an antipsychotic drug. Fig 1 shows recordings from two RGCs (from one retina) to the drifting sinusoidal grating. Both cells elicited a response to a full-field flash of light (upper traces in A and B) but only one RGC responded to the drifting sinusoidal grating (lower trace in panel A). Cells that did not show a response to the drifting sinusoidal grating in both the presence and absence of an antipsychotic drug were not included in the data analyses. As will be shown below, the responses of SD and P23H rat RGCs to the drifting grating were affected differently by the antipsychotic drugs haloperidol and clozapine. Results from SD rat RGCs will be described first.
In this study I examined the effects of the antipsychotic drugs haloperidol and clozapine on the responses of RGCs in both SD rats and P23H rats to a drifting sinusoidal grating of various contrasts. The effects of haloperidol and clozapine on the responses of the RGCs to the drifting grating are for the most part very similar. In general, the antipsychotic drugs 1) decrease response amplitudes of SD rat RGCs but increase response amplitudes of P23H rat RGCs, and 2) increase contrast thresholds of SD rat RGCs but decrease contrast thresholds in P23H rat RGCs. One striking difference between clozapine and haloperidol is that latter did not reduce the response amplitudes of non-saturating cells in SD rat retinas. Although both clozapine and haloperidol block dopamine D2 receptors, clozapine—unlike haloperidol—has a high affinity for serotonin (5-HT) receptors, particularly the 5-HT2 receptor subtype . Given that the retina expresses 5-HT2 receptors [22, 23], the clozapine-induced decrease in the response amplitudes of non-saturating SD cells may be to the binding of clozapine to these receptors. Future studies in this area should be conducted with selective receptor antagonists.T 2 receptors……