Retinal Neurotransmitter Systems in Myopia: Understanding the Role of Dopamine and Related Pathways

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January 2, 2025

By Nicole Xiao Liu, MOptom, PhD Candidate, Brien Holden Vision Institute

Dopamine, a crucial neurotransmitter in the central nervous system, plays a fundamental role in the retina’s response to visual input and subsequent eye growth regulation. This relationship has been extensively documented through both pharmacological studies and physiological investigations, establishing a robust scientific foundation for understanding dopamine’s influence on visual processing and ocular development.¹ 

How Dopamine Affects Animals
The protective effects of dopaminergic agents against experimental myopia have been demonstrated across a diverse range of species,² including but not limited to chicks,³ rhesus monkeys,⁴ and guinea pigs.⁵ These studies have consistently shown that dopamine can help prevent excessive eye growth and the development of myopia.

Inconsistencies, however, have been reported. For instance, in a C57BL/6 mouse model of form-deprivation myopia (FDM), retinal dopamine levels, dopamine-related measures, and the retinal dopaminergic system were not altered.⁶ Furthermore, treatments that suppress dopamine release have sometimes resulted in FDM inhibition,^7,8 the opposite of what would be expected if dopamine is protective against myopia. These seemingly contradictory findings strongly suggest the existence of both dopamine-dependent and independent pathways in myopia development, highlighting the complexity of the underlying mechanisms.

Factors to Consider
A critical aspect that requires further investigation is the intricate web of interactions between dopamine, melatonin, and melanopsin-containing photoreceptors within the retinal environment. These relationships form a sophisticated regulatory network that influences various aspects of visual processing and ocular development.

Dopamine is released in a dose-dependent manner associated with increased light intensity.^9,10 It shows a distinct diurnal rhythm, with higher levels during the day and lower levels at night — the opposite of melatonin’s diurnal variations. Dopamine and melatonin interact closely with each other, forming a reciprocal regulatory network that regulates retinal circadian physiology.¹¹ Melatonin release is mediated by a subset of axons of the intrinsically photosensitive retinal ganglion cells (ipRGCs, or melanopsin-containing RGCs). ipRGCs can detect light both directly through melanopsin photopigment and indirectly through inputs from rods and cones.^12,13 Furthermore, ipRGCs form synaptic connections with dopaminergic amacrine cells, allowing them to modulate their activity through complex signaling pathways.^14,15

Looking at the Research
Research utilizing genetically modified mouse models has provided valuable insights into these complex interactions. Unlike melatonin-deficient C57BL/6 mice, melatonin-proficient CBA/CaJ mice showed reduced retinal dopamine levels during FDM; and the changes in retinal dopamine levels were abolished when melatonin receptors were blocked. These findings led researchers to propose that melatonin serves as a critical mediator in the dopaminergic pathways associated with experimental myopia models.¹⁶

In another study, mice lacking melanopsin (Opn4-/-) and intrinsic light responses of ipRGCs displayed notable alterations in their refractive development trajectory, exhibiting increased myopia at younger ages followed by hyperopia in later stages. These mice also demonstrated increased susceptibility to FDM, correlating with decreased dopaminergic activity in the retina. Importantly, systematic treatment with the dopamine precursor, L-3,4-dihydroxyphenylalanine (L-DOPA), reduced FDM by half in this mouse model.¹⁷ A recent study introduced another layer of complexity by revealing that mice with selective ipRGC ablation developed steeper corneas and shorter axial lengths, resulting in a myopic shift; while less myopic shift in response to form deprivation was found in ipRGC-ablated and melanopsin deficient C57BL/6 mice, accompanied by less axial elongation.¹⁸ While these studies present some apparent discrepancies that require further investigation, they collectively emphasize the significant involvement of melanopsin pathways, either dopamine-dependent or independent, in experimental myopia models.

In conclusion, these findings collectively suggest that the interaction between dopamine, melatonin, melanopsin, and ipRGCs and ocular growth regulation represents a complex system that demands continued scientific investigation. Understanding these relationships can provide new opportunities for myopia prevention and treatment. Future therapeutic approaches might focus on several promising avenues, including the enhancement of melanopsin signaling pathways, optimization of retinal dopamine levels, or targeted interventions aimed at modulating the interactions between these various systems.

 

Nicole Liu is a current PhD candidate at UNSW School of Optometry and Vision Science and Brien Holden Vision Institute, under the supervision of Professor Padmaja Sankaridurg and Associate Professor Thomas John Naduvilath. Dr. Liu received her Bachelor of Clinical Medicine (Optometry and Ophthalmology) from Tianjin Medical University in China before obtaining her Master of Optometry degree in 2012 at UNSW. After working as a clinical research optometrist for a few years, she decided to pursue a PhD degree in optometry. She has been awarded the inaugural Dr. David Wilson Memorial Scholarship for her PhD. She was also awarded the ARVO Travel Grant and the ISCLR Student Abstract Grant in 2022 for her research on myopia and circadian rhythm.

 

References

1. Zhou X, Pardue MT, Iuvone PM, Qu J. Dopamine signaling and myopia development: What are the key challenges. Progress in Retinal and Eye Research. 2017/11/01/ 2017;61:60-71. doi:https://doi.org/10.1016/j.preteyeres.2017.06.003
2. Troilo D, Smith EL, 3rd, Nickla DL, et al. IMI – Report on Experimental Models of Emmetropization and Myopia. Invest Ophthalmol Vis Sci. Feb 28 2019;60(3):M31-M88. doi:10.1167/iovs.18-25967
3. Nickla DL, Totonelly K, Dhillon B. Dopaminergic agonists that result in ocular growth inhibition also elicit transient increases in choroidal thickness in chicks. Exp Eye Res. Nov 2010;91(5):715-20. doi:10.1016/j.exer.2010.08.021
4. Iuvone PM, Tigges M, Stone RA, Lambert S, Laties AM. Effects of apomorphine, a dopamine receptor agonist, on ocular refraction and axial elongation in a primate model of myopia. Invest Ophthalmol Vis Sci. Apr 1991;32(5):1674-7. 
5. Mao J, Liu S, Qin W, Li F, Wu X, Tan Q. Levodopa inhibits the development of form-deprivation myopia in guinea pigs. Optom Vis Sci. Jan 2010;87(1):53-60. doi:10.1097/OPX.0b013e3181c12b3d
6. Wu XH, Li YY, Zhang PP, et al. Unaltered retinal dopamine levels in a C57BL/6 mouse model of form-deprivation myopia. Invest Ophthalmol Vis Sci. Jan 20 2015;56(2):967-77. doi:10.1167/iovs.13-13362
7. Schaeffel F, Bartmann M, Hagel G, Zrenner E. Studies on the role of the retinal dopamine/melatonin system in experimental refractive errors in chickens. Vision Res. May 1995;35(9):1247-64. doi:10.1016/0042-6989(94)00221-7
8. Ohngemach S, Hagel G, Schaeffel F. Concentrations of biogenic amines in fundal layers in chickens with normal visual experience, deprivation, and after reserpine application. Vis Neurosci. May-Jun 1997;14(3):493-505. doi:10.1017/s0952523800012153
9. Brainard GC, Morgan WW. Light-induced stimulation of retinal dopamine: a dose-response relationship. Brain research. Oct 20 1987;424(1):199-203. doi:10.1016/0006-8993(87)91211-x
10. Cohen Y, Peleg E, Belkin M, Polat U, Solomon AS. Ambient illuminance, retinal dopamine release and refractive development in chicks. Exp Eye Res. Oct 2012;103:33-40. doi:10.1016/j.exer.2012.08.004
11. Stone RA, Pardue MT, Iuvone PM, Khurana TS. Pharmacology of myopia and potential role for intrinsic retinal circadian rhythms. Experimental Eye Research. 2013/09/01/ 2013;114:35-47. doi:https://doi.org/10.1016/j.exer.2013.01.001
12. Gooley JJ, Lu J, Fischer D, Saper CB. A broad role for melanopsin in nonvisual photoreception. J Neurosci. Aug 6 2003;23(18):7093-106. doi:10.1523/JNEUROSCI.23-18-07093.2003
13. Hattar S, Liao HW, Takao M, Berson DM, Yau KW. Melanopsin-containing retinal ganglion cells: architecture, projections, and intrinsic photosensitivity. Science. Feb 8 2002;295(5557):1065-70. doi:10.1126/science.1069609
14. Zhang DQ, Wong KY, Sollars PJ, Berson DM, Pickard GE, McMahon DG. Intraretinal signaling by ganglion cell photoreceptors to dopaminergic amacrine neurons. Proc Natl Acad Sci U S A. Sep 16 2008;105(37):14181-6. doi:10.1073/pnas.0803893105
15. Prigge CL, Yeh PT, Liou NF, et al. M1 ipRGCs Influence Visual Function through Retrograde Signaling in the Retina. The Journal of neuroscience : the official journal of the Society for Neuroscience. Jul 06 2016;36(27):7184-97. doi:10.1523/jneurosci.3500-15.2016
16. Qian KW, Li YY, Wu XH, et al. Altered Retinal Dopamine Levels in a Melatonin-proficient Mouse Model of Form-deprivation Myopia. Neurosci Bull. Sep 2022;38(9):992-1006. doi:10.1007/s12264-022-00842-9
17. Chakraborty R, Landis EG, Mazade R, et al. Melanopsin modulates refractive development and myopia. Experimental Eye Research. 2022/01/01/ 2022;214:108866. doi:https://doi.org/10.1016/j.exer.2021.108866
18. Liu AL, Liu YF, Wang G, et al. The role of ipRGCs in ocular growth and myopia development. Sci Adv. Jun 10 2022;8(23):eabm9027. doi:10.1126/sciadv.abm9027