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 hours. Immediately prior to lens-removal, the antagonist was injected (20 μl; dose=5 nmole). Antagonists used were methylergonovine (nonspecific; 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 hours 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 um; p<0.01 for both). Both drugs were also associated with a transient thickening of the choroid over 3 hours (41 and 32 um vs -1 um; 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 lensinduced 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.

Purpose To determine the effects of imposed anisometropic retinal defocus on accommodation, ocular growth, and refractive state changes in marmosets. Methods Marmosets were raised with extended-wear soft contact lenses for an average duration of 10 wks beginning at an average age of 76 d. Experimental animals wore either a positive or negative contact lens over one eye and a plano lens or no lens over the other. Another group wore binocular lenses of equal magnitude but opposite sign. Untreated marmosets served as controls and three wore plano lenses monocularly. Cycloplegic refractive state, corneal curvature, and vitreous chamber depth were measured before, during, and after the period of lens wear. To investigate the accommodative response, the effective refractive state was measured through each anisometropic condition at varying accommodative stimuli positions using an infrared refractometer. Results Eye growth and refractive state are significantly correlated with the sign and power of the contact lens worn. The eyes of marmosets reared with monocular negative power lenses had longer vitreous chambers and were myopic relative to contralateral control eyes (p<0.01). Monocular positive power lenses produced a significant reduction in vitreous chamber depth and hyperopia relative to the contralateral control eyes (p<0.05). In marmosets reared binocularly with lenses of opposite sign, we found larger interocular differences in vitreous chamber depths and refractive state (p<0.001). Accommodation influences the defocus experienced through the lenses, however, the mean effective refractive state was still hyperopia in the negative-lens-treated eyes and myopia in the positive-lens-treated eyes. Conclusions Imposed anisometropia effectively alters marmoset eye growth and refractive state to compensate for the imposed defocus. The response to imposed hyperopia is larger and faster than the response to imposed myopia. The pattern of accommodation under imposed anisometropia produces effective refractive states that are consistent with the changes in eye growth and refractive state observed.

In eyes wearing negative lenses, the D2 dopamine antagonist spiperone was only partly effective in preventing the ameliorative effects of brief periods of vision (Nickla et al., 2010), in contrast to reports from studies using form deprivation. The present study was done to directly compare the effects of spiperone, and the D1 antagonist SCH-23390, on the two different myopiagenic paradigms. 12-day old chickens wore monocular diffusers (form deprivation) or − 10 D lenses attached to the feathers with matching rings of Velcro. Each day for 4 days, 10 µl intravitreal injections of the dopamine D2/D4 antagonist spiperone (5 nmoles) or the D1 antagonist SCH-23390, were given under isoflurane anesthesia, and the diffusers (n=16; n=5, respectively) or lenses (n=20; n=6) were removed for 2 hours immediately after. Saline injections prior to vision were done as controls (form deprivation: n=11; lenses: n=10). Two other saline-injected groups wore the lenses (n=12) or diffusers (n=4) continuously. Axial dimensions were measured by high frequency A-scan ultrasonography at the start, and on the last day immediately prior to, and 3 hours after the injection. Refractive errors were measured at the end of the experiment using a Hartinger’s refractometer. In form-deprived eyes, spiperone, but not SCH-23390, prevented the ocular growth inhibition normally effected by the brief periods of vision (change in vitreous chamber depth, spiperone vs saline: 322 vs 211 µm; p=0.01). By contrast, neither had any effect on negative lens-wearing eyes given similar unrestricted vision (210 and 234 µm respectively, vs 264 µm). The increased elongation in the spiperone-injected form deprived eyes did not, however, result in a myopic shift, probably due to the inhibitory effect of the drug on anterior chamber growth (drug vs saline: 96 vs 160 µm; p<0.01). Finally, spiperone inhibited the vision-induced transient choroidal thickening in form deprived eyes, while SCH-23390 did not. These results indicate that the dopaminergic mechanisms mediating the protective effects of brief periods of unrestricted vision differ for form deprivation versus negative lens-wear, which may imply different growth control mechanisms between the two.

Animal models have shown that myopic defocus is a potent inhibitor of ocular growth: brief (1–2 hours) daily periods of defocus are sufficient to counter the effects of much longer periods of hyperopic defocus, or emmetropic vision. While the variables of duration and frequency have been well-documented with regard to effect, we ask whether the efficacy of the exposures might also depend on the time of day that they are given. We also ask whether there are differential effects on the rhythms in axial length or choroidal thickness. 2-week-old chickens were divided into 2 groups: (1) “2-hr lens-wear”. Chicks wore monocular +10D lenses for 2 hours per day for 5 days at one of 3 times of day: 5:30 am (n=11), 12 pm (n=8) or 7:30 pm (n=11). (2) “2-hr minus lens-removal”. Chicks wore monocular −10D lenses continually for 7 days, except for a 2-hr period when lenses were removed; the removal occurred at one of 2 times: 5:30 am (n=8) or 7:30 pm (n=8). Both paradigms exposed eyes to brief myopic defocus that differed in its magnitude, and in the visual experience for the rest of the day. High frequency A-scan ultrasonography was done at the start of the experiment; on the last day, it was done at 6-hr intervals, starting at noon, over 24-hr, to assess rhythm parameters. Refractive errors were measured using a Hartinger’s refractometer at the end. In both paradigms, myopic defocus in the evening was significantly more effective at inhibiting eye growth than in the morning (“2-hr lens-wear”: X-C: −149 vs −83 μm/5d; “2-hr lens-removal: X-C: 91 vs 245 μm/7d; post-hoc Bonferroni test, p<0.01 for both). Data for “noon” was similar to that of “evening”. In general, the refractive errors were consistent with the eye growth. In both paradigms, a 2-way ANOVA showed that “time of day” accounted for the differences between the morning versus evening groups (“2-hr lens-wear”: p=0.0161; “2-hr lens-removal”: p=0.038). In the “plus-lens” morning exposure, the rhythm in axial length could not be fit to a sinusoid. In both paradigms, the rhythm in axial length for the evening group was phase-advanced relative to noon or morning (“2-hr lens-wear: evening vs noon; 1:24 pm vs 6:42 pm; “2-hr lens-removal: evening vs morning: 12:15 pm vs 6:18 pm; p<0.05 for both). Finally, the amplitude of the rhythm as assessed by the “day vs night” maximum and minimum respectively, was larger in the “evening” than in the “morning” group (“2-hr lens-wear: 88 vs 38 μm; “2-hr lens-removal: 104 vs 48 μm; p<0.05 for both). For the choroidal rhythm, there was no effect on phase, however, the amplitude was larger in most, but not all, experimental groups. These findings have potential translational applications to myopia prevention in schoolchildren, who are exposed to extended periods of hyperopic defocus during reading sessions, due to the nearness of the page. We propose that bouts of such near-work might best be scheduled later in the day, along with frequent breaks for distance vision.