The level of protection from the development of FDM increases with increasing light intensity. Daily exposure to 40,000 lux almost completely prevents the onset of FDM and, once myopia is established, halts further progression.

Animal models have demonstrated a link between dysregulation of the retinal dopamine system and the excessive ocular growth associated with the development of myopia. Here we show that intravitreal or topical application of levodopa, which is widely used in the treatment of neurological disorders involving dysregulation of the dopaminergic system, inhibits the development of experimental myopia in chickens. Levodopa slows ocular growth in a dose dependent manner in chicks with a similar potency to atropine, a common inhibitor of ocular growth in humans. Topical levodopa remains effective over chronic treatment periods, with its effectiveness enhanced by coadministration with carbidopa to prevent its premature metabolism. No changes in normal ocular development (biometry and refraction), retinal health (histology), or intraocular pressure were observed in response to chronic treatment (4 weeks). With a focus on possible clinical use in humans, translation of these avian safety findings to a mammalian model (mouse) illustrate that chronic levodopa treatment (9 months) does not induce any observable changes in visual function (electroretinogram recordings), ocular development, and retinal health, suggesting that levodopa may have potential as a therapeutic intervention for human myopia.

Animal models have demonstrated a link between dysregulation of the retinal dopamine system and the development of myopia (short-sightedness). We have previously demonstrated that topical application of levodopa in chicks can inhibit the development of form-deprivation myopia (fDM) in a dose-dependent manner. Here, we examine whether this same protection is observed in lens-induced myopia (LiM), and whether levodopa's protection against fDM and LiM occurs through a dopamine D1-or D2-like receptor mechanism. To do this, levodopa was first administered daily as an intravitreal injection or topical eye drop, at one of four ascending doses, to chicks developing LiM. Levodopa's mechanism of action was then examined by co-administration of levodopa injections with D1-like (SCH-23390) or D2-like (spiperone) dopamine antagonists in chicks developing FDM or LIM. For both experiments, levodopa's effectiveness was examined by measuring axial length and refraction after 4 days of treatment. Levodopa inhibited the development of LIM in a dose-dependent manner similar to its inhibition of fDM when administered via intravitreal injections or topical eye drops. in both fDM and LiM, levodopa injections remained protective against myopia when co-administered with ScH-23390, but not spiperone, indicating that levodopa elicits its protection through a dopamine D2-like receptor mechanism in both paradigms. Abbreviations DOPAC 3,4-Dihydroxyphenylacetic acid FDM Form-deprivation myopia LC-MS-MS High performance liquid chromatography-tandem mass spectrometry LIM Lens induced myopia PBS Phosphate buffered saline Myopia, commonly known as short-sightedness, is a refractive disorder arising from a mismatch between the axial length and optical power of the eye. This is generally due to excessive elongation of the eye during development and into early adulthood. In urban East and Southeast Asia the prevalence of myopia in young adults has risen from 20-30% to 80-85% in the last five decades (For review see 1). The prevalence of high myopia (≤ − 6 diopters (D)) has increased disproportionately to that of myopia in the last five decades, rising from 1-5% to 10-20% (For review see 1). Although the refractive error associated with this condition can easily be corrected, such corrections do not address the sight-threatening pathologies associated with myopia, and especially high myopia, which include retinal detachment, myopic macular degeneration, staphyloma, glaucoma, and cataracts 2-6. Furthermore, the odds of such pathologies significantly increase with the severity of myopia 7. Through work in animal models, changes in retinal dopamine release have been heavily implicated in the development of myopia (for review see 8-10). Specifically, in chicks, rhesus monkeys, guinea pigs, tree shrews and in some cases mice, retinal levels of dopamine, and its primary metabolite 3,4-dihydroxyphenylacetic acid (DOPAC), have been shown to be significantly down-regulated during the development of form-deprivation myopia (FDM) 11-16. Consistent with a role fo...

PURPOSE. Animal models have demonstrated a link between decreases in retinal dopamine levels and the development of form-deprivation myopia (FDM). However, the consistency of dopamine's role in the other major form of experimental myopia, that of lens-induced myopia (LIM), is less clear, raising the question as to what extent dopamine plays a role in human myopia. Therefore, to better define the role of dopamine in both forms of experimental myopia, we examined how consistent the protection afforded by dopamine and the dopamine agonist 6-amino-5,6,7,8-tetrahydronaphthalene-2,3-diol hydrobromide (ADTN) is between FDM and LIM. METHODS. Intravitreal injections of dopamine (0.002, 0.015, 0.150, 1.500 μmol) or ADTN (0.001, 0.010, 0.100, 1.000 μmol) were administered daily to chicks developing FDM or LIM. Axial length and refraction were measured following 4 days of treatment. To determine the receptor subtype by which dopamine and ADTN inhibit FDM and LIM, both compounds were coadministered with either the dopamine D2-like antagonist spiperone (0.005 μmol) or the D1-like antagonist SCH-23390 (0.005 μmol). RESULTS. Intravitreal administration of dopamine or ADTN inhibited the development of FDM (ED 50 = 0.003 μmol and ED 50 = 0.011 μmol, respectively) and LIM (ED 50 = 0.002 μmol and ED 50 = 0.010 μmol, respectively) in a dose-dependent manner, with a similar degree of protection observed in both paradigms (P = 0.471 and P = 0.969, respectively). Coadministration with spiperone, but not SCH-23390, inhibited the protective effects of dopamine and ADTN against the development of both FDM (P = 0.214 and P = 0.138, respectively) and LIM (P = 0.116 and P = 0.100, respectively). CONCLUSIONS. pharmacological targeting of the retinal dopamine system inhibits FDM and LIM in a similar dose-dependent manner through a D2-like mechanism.

Background and Purpose:The ability of the muscarinic-cholinergic antagonist atropine to inhibit myopia development in humans and animal models would suggest that cholinergic hyperactivity may underlie myopic growth. To test this, we investigated whether cholinergic agonists accelerate ocular growth rates in chickens. Furthermore, we investigated whether atropine alters ocular growth by down-stream modulation of dopamine levels, a mechanism postulated to underly its anti-myopic effects.Experimental Approach: Muscarinic (muscarine and pilocarpine), nicotinic (nicotine), and non-specific (oxotremorine and carbachol) cholinergic agonists were administered to chicks developing form-deprivation myopia (FDM) or chicks that were otherwise untreated. Vitreal levels of dopamine and its primary metabolite (3,4-dihydroxyphenylacetic acid (DOPAC))were examined using mass spectrometry in form-deprived chicks treated with atropine (360, 15 or 0.15nmoles). Further, we investigated whether dopamine antagonists block atropine's anti-myopic effects.Key Results: Unexpectedly, administration of each cholinergic agonist inhibited FDM (p<0.05) but did not affect normal ocular development (p=0.165). Atropine only affected dopamine (p<0.05) and DOPAC (p<0.05) levels at its highest dose. Dopamine antagonism did not alter atropine's anti-myopia effects (p=0.478).Conclusions and Implications: Muscarinic, nicotinic, and non-specific cholinergic agonists inhibited FDM development. This indicates that cholinergic hyperactivity does not underly myopic growth and questions whether atropine inhibits myopia via cholinergic antagonism.We also report that changes in retinal dopamine release are not required for atropine's antimyopic effects. Finally, nicotinic agonists may represent a novel and more targeted approach This article is protected by copyright. All rights reserved.for the cholinergic control of myopia as they are unlikely to suffer from the anterior segment side-effects associated with muscarinic treatment.