Insights into the mechanism by which atropine inhibits myopia: evidence against cholinergic hyperactivity and modulation of dopamine release

Abstract

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.

Studies on the interactions of retinal dopamine with choroidal thickness in the chicken

“…At this dose, atropine also blocked development of deprivation myopia completely [21]. An increase in dopamine release from the retina at the same dose of atropine was found by Thomson et al [22] but no changes were observed at lower doses (10 µg and 0.1 µg).…”

“…Dopamine was measured by mass spectrometry which interestingly showed a DOPAC to dopamine ratio in the vitreous of 150 to 300 while the ratio was about 10 in our HPLC measurements, or even lower in other studies [44,52]. Another difference was that Thomson et al [22] measured dopamine 1 h after injection while we measured after about 2 h. Tian et al [52] had stated that "The retinal DOPAC/ dopamine ratio, indicating the metabolic efficiency of dopamine, is correlated with ocular growth." Therefore, we also studied whether the DOPAC to dopamine ratios might achieve better correlations with choroidal thickness changes.…”

“…However, their atropine doses were very low (0.1 µg), a dose which had no effect on myopia development in an earlier study by Diether et al [21]. It is possible that part of the inhibitory effect was due to the intravitreal injection itself, an idea which is in line with the lack of a dose-dependent effect of atropine [22]. Dopamine was measured by mass spectrometry which interestingly showed a DOPAC to dopamine ratio in the vitreous of 150 to 300 while the ratio was about 10 in our HPLC measurements, or even lower in other studies [44,52].…”

“…Thomson et al [22] recently excluded a role of dopamine during myopia inhibition by atropine for two reasons. They found that coadministration of the dopamine D2-like receptor antagonist spiperone did not inhibit the protective effects of 0.15 nmol of atropine against deprivation myopia, and that nicotinergic agents can inhibit myopia without affecting dopamine levels.…”

Identification of miR-671-5p and Its Related Pathways as General Mechanisms of Both Form-Deprivation and Lens-Induced Myopia in Mice

“…It was proven that retinal dopamine exerts a protective effect against myopic growth via a D2-like mechanism in both models [ 15 ]. More importantly, dopamine signaling seemed to play a role in the protective effect of time outdoors, increased illuminance and low-dose atropine [ 16 , 17 , 18 , 19 ], which suggests that the shared mechanism in the retina of the two models might have general clinical implications. Although dopamine signaling plays an important role in myopia development, it cannot fully explain the onset and progression of myopia, and its upstream and downstream pathways are not fully understood [ 20 ].…”