Dopaminergic agonists that result in ocular growth inhibition also elicit transient increases in choroidal thickness in chicks

Abstract

The dopaminergic system has been implicated in ocular growth regulation in chicks and monkeys. In both, dopamine D2 agonists inhibit the development of myopia in response to form deprivation, and in chicks, to negative lenses as well. Because there is mounting evidence that the choroidal response to defocus plays a role in ocular growth regulation, we asked whether the effective agonists also elicit transient thickening of the choroid concomitant with the growth inhibition. Negative lenses mounted on velcro rings were worn on one eye starting at age 8-12 days. Intravitreal injections (20 μl; dose = 10 nmole) of the agonist (dissolved in saline) or saline, were given through the superior temporal sclera using a 30G needle. Eyes were injected daily at noon, for 4 days, and the lenses immediately replaced. Agonists used were apomorphine (non-specific; n = 17), quinpirole (D2; n = 10), SKF-38393 (D1; n = 9), and saline controls (n = 22). For the antagonists, the same protocol was used, but on each day, the lenses were removed for 2 h. Immediately prior to lens-removal, the antagonist was injected (20 μl; dose = 5 nmole). Antagonists used were methylergonovine (non-specific; n = 12), spiperone (D2; n = 20), SCH-23390 (D1; n = 6) and saline controls (n = 27). Comparisons to saline (continuous lens wear) controls were from the agonist experiment. Axial dimensions were measured using high frequency A-scan ultrasonography at the start of lens wear, and on day 4 prior to the injections, and then again 3 h later. Refractive errors were measured using a Hartinger's refractometer at the end of the experiment. Apomorphine and quinpirole inhibited the refractive response to the hyperopic defocus induced by the negative lenses (drug vs saline controls: -1.3 and 1.2 D vs -5.6 D; p < 0.005 for both). This effect was axial: both drugs prevented the excessive ocular elongation (change in axial length: 233 and 205 μm vs 417 μm; p < 0.01 for both). Both drugs were also associated with a transient thickening of the choroid over 3 h (41 and 32 μm vs -1 μm; p < 0.01; p = 0.059 respectively) that did not summate: choroids thinned significantly over the 4 day period in all lens-wearing eyes. Two daily hours of unrestricted vision during negative lens wear normally prevents the development of myopia. Spiperone and SCH-23390 inhibited the ameliorating effects of periods of vision on lens-induced refractive error (-2.9 and -2.8 D vs 0.6 D; p < 0.0001), however, the effects on neither axial length nor choroidal thickness were significant. These data support a role for both D1 and D2 receptors in the ocular growth responses.

Figure 1

Effect of three dopamine agonists on the ocular responses to negative lenses, and saline controls. “Fellow” is data for contralateral eyes in all graphs. ”Saline” refers to saline injected lens-wearing eyes. A. Effect on refractive error (ANOVA, p=0.0001). Both apomorphine (“apomor”; non specific) and quinpirole (“quinpir”, D2) inhibited the development of refractive myopia (p<0.005 for both comparisons with saline). SKF-38393 (SKF, D1) had no effect. B. Effect on axial length (ANOVA, p<0.005). Both apomorphine and quinpirole inhibited the excessive axial elongation in response to the negative lenses (p<0.01 for both). SKF had no effect. C. Effect on choroidal thickness (ANOVA, p<0.005). Both apomorphine and quinpirole increased choroid thickness over the 3 hours after the injection (p<0.01; p=0.05 respectively). SKF had no effect. Part of this graph was reproduced with permission from: Nickla & Wallman, 2010 © Elsevier. D. Change in choroidal thickness over the 4 days of the experiment. Choroids of all lens-wearing eyes showed significant thinning, as expected. Error bars are standard errors of the mean in all graphs. Asterisks denote significant differences with saline controls in all graphs.

Figure 2

Effect of two dopamine antagonists on the daily 2 hours of vision-evoked ocular responses in eye wearing negative lenses. “Sal/vis” refers to saline-injected eyes that received the same 2 hours of daily vision as the drug groups; statistical comparisons are between drug groups and this group. “Sal/lens” refers to saline-injected eyes wearing lenses continually; these are the same data as are in Figure 1 (“saline”). A. Effect on refractive error (ANOVA, p<0.0001). Spiperone (“spiper”) and SCH-23390 (“SCH”) inhibited the vision-induced protection from myopia development (p<0.005). B. Effect on axial length (ANOVA, p=0.01). While spiperone tended to result in an increase in ocular elongation compared to saline controls, the effect was not significant. C. Effect on choroidal thickness (ANOVA, p<0.0001). Neither antagonist showed a significant difference from the saline-injected controls.