ISSN 0006-2979, Biochemistry (Moscow), 2026, Vol. 91, No. 8, pp. 1307-1318 © Pleiades Publishing, Ltd., 2026.
ISSN 0006-2979, Biochemistry (Moscow), 2026. © Pleiades Publishing, Ltd., 2026.
1307
REVIEW
Dopaminergic System of the Eye
and Its Role in Glaucoma Pathogenesis
Natalya B. Chesnokova
1,a
*, Tatyana A. Pavlenko
1
, Olga V. Beznos
1
,
Sergey Y. Petrov
1
, and Natalia N. Shikareva
1
1
Helmholtz National Medical Research Center of Eye Diseases,
Ministry of Health of the Russian Federation, 105062 Moscow, Russia
a
e-mail: nchesnokova2012@yandex.ru
Received March 10, 2026
Revised April 10, 2026
Accepted April 11, 2026
Abstract— Glaucoma is a multifaceted disease characterized by optic nerve damage and retinal ganglion
cell (RGC) degeneration, leading to optic neuropathy and vision loss. Neurodegenerative processes in the
retina underlie glaucoma pathogenesis. Elevated intraocular pressure (IOP) is a contributing factor in the
development and progression of most types of glaucoma, making IOP reduction the standard treatment
approach, while existing neuroprotective therapies remain largely ineffective. Dopaminergic system (DS)
of the eye and its role in ocular pathology are insufficiently studied, yet available data suggest that DS
is one of the most significant regulatory systems in the eye. It is widely represented in ocular structures
and participates in regulation of visual function, circadian rhythms, blood circulation, and aqueous humor
dynamics, as well as in eye development. Both IOP elevation and retinal ganglion cell neurodegeneration
in glaucoma are critically influenced by an imbalance in the DS components. In the vertebrate retina, do-
pamine serves as the primary neurotransmitter and neuromodulator. It is also a precursor to sympathetic
nervous system mediators – epinephrine and norepinephrine – expanding its role in physiological processes,
including IOP regulation. This review presents recent and foundational studies on the presence of dopamine
and its receptors in various ocular structures, their significance in normal eye function, mechanisms of
involvement in neurodegenerative processes in glaucoma, and in IOP regulation. Based on analysis of the
DS role in glaucoma pathogenesis, the prospects for developing antiglaucoma drugs for neuroprotection,
IOP reduction, and combined mechanisms of action are discussed. Additionally, potential use of the analysis
of DS components in the tear fluid as a non-invasive test for early diagnosis, prognosis, and therapeutic
justification is considered.
DOI: 10.1134/S0006297926600730
Keywords: glaucoma, dopamine, dopamine receptors, retina, aqueous humor, neurodegeneration, intraocular
pressure
* To whom correspondence should be addressed.
INTRODUCTION
Despite advancements in diagnosis and treatment,
glaucoma remains a significant global issue and the
leading cause of irreversible blindness. By 2040, the
number of glaucoma patients is projected to reach
approximately 111.8 million [1-3].
Glaucoma is a group of diseases with varying eti-
ologies and pathogenesis involving chronic progres-
sive optic neuropathy characterized by retinal gangli-
on cell (RGC) degeneration and optic nerve damage.
RGC are specialized neurons located in the innermost
layer of retina, being the only retinal cells that gener-
ate nerve impulses. These cells integrate signals from
bipolar and amacrine cells and transmit them via
their axons forming the optic nerve, to correspond-
ing brain regions.
A characteristic, though not obligatory, feature of
glaucoma is sustained elevated intraocular pressure
(IOP). Current glaucoma treatments primarily aim
CHESNOKOVA et al.1308
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to reduce IOP, the only proven method to slow dis-
ease progression. However, these treatments do not
prevent RGC loss or promote optic nerve regener-
ation, which can occur even at normal IOP levels.
Pathogenic mechanisms of neurodegenerative pro-
cesses in the retina leading to optic neuropathy in
glaucoma share similarities with neurodegenerative
diseases of the central nervous system (CNS), such as
Alzheimer’s and Parkinson’s diseases. These mecha-
nisms include mitochondrial dysfunction, oxidative
stress, formation of misfolded protein aggregates, and
neuroinflammation [4].
In modern glaucoma treatment, neuroprotective
therapy plays a crucial role [5], though it faces vari-
ous challenges, including complex and multifactorial
nature of neurodegenerative processes complicating
selection of therapeutic targets for a concrete patient.
Therefore, finding new, effective, and pathogeneti-
cally justified neuroprotective methods is an urgent
problem.
Dopaminergic system (DS) plays a significant role
in neurodegeneration, and its components are widely
present in ocular tissues, participating in both retinal
neurodegeneration and IOP regulation. This makes
the DS a promising target for developing of glaucoma
treatment.
This review presents information on the pres-
ence of DS components in various ocular structures,
their role in the development of neurodegenerative
processes in the retina, and their involvement in IOP
elevation in glaucoma.
GENERAL INFORMATION
ABOUT THE DOPAMINERGIC SYSTEM
Dopamine is synthesized in cytosol of dopami-
nergic cells from L-tyrosine, which is converted by
tyrosine hydroxylase into 3,4-dihydroxyphenylalanine
(L-DOPA). L-DOPA is next converted into dopamine by
aromatic amino acid decarboxylase (DOPA-decarbox-
ylase) (Fig. 1).
Dopamine synthesized in neurons accumulates in
dopaminergic vesicles (synaptic vesicles). Upon neu-
Fig. 1. Dopamine metabolism. Designations: COMT, catechol-O-methyltransferase; MAO, monoamine oxidase; AR, aldehyde
reductase; ADH, aldehyde dehydrogenase; PNMT, phenylethanolamine-N-methyltransferase; DOPA, 3,4-dihydroxyphenylala-
nine; DOPAc, 3,4-dihydroxyphenylacetic acid; DOPAL, 3,4-dihydroxyphenylacetaldehyde.
DOPAMINERGIC SYSTEM OF THE EYE AND GLAUCOMA 1309
BIOCHEMISTRY (MOSCOW) Vol. 91 No. 8 2026
ronal excitation, dopamine is released into synaptic
cleft. Some dopamine participates in nerve impulse
transmission by acting on cellular dopamine receptors
(D-receptors) on the postsynaptic membrane, while
some is reabsorbed into the presynaptic neuron via
reuptake mechanisms. Cytosolic dopamine is convert-
ed by monoamine oxidase into 3,4-dihydroxypheny-
lacetaldehyde (DOPAL), a highly toxic molecule that is
further converted by aldehyde dehydrogenase into the
non-toxic metabolite 3,4-dihydroxyphenylacetic acid
(DOPAc) [6]. At the slightly alkaline pH characteristic
of cytosol, dopamine is relatively unstable and can
undergo auto-oxidation. Accumulation of dopamine in
the cytosol due to impaired catabolism can promote
its spontaneous oxidation, leading to formation of re-
active oxygen species and accumulation of toxic dopa-
mine quinones. In neurodegenerative diseases (such
as Alzheimer’s and Parkinson’s diseases), accumu-
lation of homovanillic acid and 3-methoxytyramine
correlates with the disease progression [7]. Produc-
tion of reactive oxygen species can occur in any cell
type, whereas formation of toxic dopamine quinones
is unique to dopaminergic neurons. These metabolites
can accumulate over long periods, contributing to de-
generation of this neuron population [8].
Dopamine receptors belong to the family of
transmembrane G-protein-coupled receptors. There
are at least five different subtypes of dopamine re-
ceptors: D1-D5. D1 and D5 receptors share significant
homology and are coupled to the GS protein, which
activates adenylate cyclase; thus, they are typically
considered together as D1-like receptors. The remain-
ing receptors are similar to D2 and are coupled to the
Gi protein, which inhibits adenylate cyclase, and are
collectively referred to as D2-like receptors.
Main secondary messenger in the dopamine re-
ceptor signaling cascade is cyclic adenosine mono-
phosphate (cAMP). The effect of dopamine depends
on the receptor subtype with which it interacts. The
D1-like receptors can have both excitatory (if associ-
ated with the opening of sodium channels) and in-
hibitory (if associated with the opening of potassium
channels) effects. The D1-like and D2-like receptors
differ in their response to binding with various ag-
onists and antagonists, effectors, and tissue distribu-
tion. The D1-like receptors are found only on post-
synaptic membranes of the dopaminergic neurons,
whereas the receptors D2 and D3 are also present on
the presynaptic membranes[9]. The D4 receptors are
typical of the retina[10]. Complex dopamine signaling
system is not limited to these pathways; it includes a
wide range of proteins, such as arrestin [11] and the
family of G-protein-associated kinases [12]. Thus, the
cellular effects of dopamine depend on the receptors
of target cells, secondary messenger reactions, ion
channels, and protein expression profiles [10].
In addition to the primary mechanism of action
through the cAMP-mediated signaling pathways, do-
pamine receptors could have other signaling mech-
anisms, both G-protein-dependent and independent,
through interactions with ion channels or specific
proteins of the DRIP (dopamine receptor interacting
proteins) family, which are involved in their desen-
sitization (reduction of receptor sensitivity to ago-
nists) [13]. For example, the dopamine receptors can
activate the MAPK/ERK and Akt/GSK-3 cascades via
β-arrestins, which modulate synaptic plasticity and
gene transcription regulation [10, 14]. In the retinal
photoreceptors, a unique mechanism associated with
expression of the so-called visual arrestins Arr1 and
Arr4 has been discovered[15]. It has been found that
for internalization of the D4 receptors after binding
to dopamine, simultaneous presence of β-arrestin
(β-Arr1 or β-Arr2) and visual arrestin (Arr1 or Arr4)
is required. Neither of these arrestins alone can en-
sure receptor internalization. This mechanism is
probably related to the adaptation of photoreceptors
to light stimulation and is necessary for fine-tuning
expression of the D4 receptors in the retina depend-
ing on the time of day.
Regulation of calcium ion influx plays an import-
ant role in modulating synaptic transmission mediat-
ed by dopamine and is implemented through a large
number of calcium channels. Studies of D2 receptors
on neuron membranes have shown important role
of the neuronal calcium sensor 1 (NCS-1) in their
function, which regulates phosphorylation, internal-
ization, and signaling profile of the D2 receptor [16].
It has been established that inhibition of D2 internal-
ization occurs via binding of NCS-1 to the intracellu-
lar region of the receptor [17]. This interaction sta-
bilizes the receptor on the membrane, preventing its
internalization. Influence on the interaction of NCS1
with the dopamine D2 receptor opens new therapeu-
tic approaches, alternative to classical receptor block-
ade. Considering the important role of D2 receptors
in the development of neurodegenerative processes
and IOP increase in glaucoma, this pathway could be
promising for glaucoma therapy.
Dopamine is precursor of the main mediators of
the sympathetic nervous system – norepinephrine and
epinephrine. Dopamine is converted to norepineph-
rine by dopamine-β-hydroxylase, which is next meth-
ylated by phenylethanolamine-N-methyltransferase to
form epinephrine. At high concentrations, dopamine
could also directly stimulate α- and β-adrenergic re-
ceptors [18]. The effect on adrenergic receptors is as-
sociated mainly not with their direct stimulation, but
with ability of dopamine to release norepinephrine
from granular presynaptic depots, i.e., to exert an
indirect adrenergic effect [19]. Thus, dopamine plays
an important role in the functioning of adrenergic
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system, which regulates IOP by influencing formation
and outflow of the intraocular fluid.
PRESENCE OF DS COMPONENTS
IN VARIOUS OCULAR STRUCTURES
AND THEIR MAIN FUNCTIONS IN THE EYE
Dopamine acts as the primary neurotransmitter
and neuromodulator in the vertebrate retina. The
most important and well-studied functions of DS in
the eye include light adaptation, maintenance of cir-
cadian rhythms, participation in primary visual in-
formation processing, regulation of local blood flow
and angiogenesis, control IOP, and ensuring proper
eye development. It is well known that dopamine
is the main mediator of retinal adaptation to light,
cone contraction, and melanin granule movement in
the pigment epithelial cells. It reduces the conduc-
tance of the gap junctions between horizontal cells,
potentiates activity of ionotropic glutamate receptors
on the horizontal and bipolar cells, and modifies the
center-surround balance of the receptive fields of
RGC [20].
There is a substantial evidence that the retinal
DS is an early and vulnerable target of neurodegen-
eration in various retinopathies and CNS diseases
[21-24]. In glaucoma, vision loss occurs due to the
damage to RGC, which generate nerve impulses, and
their axons, which transmit these impulses to corre-
sponding brain regions. Ganglion cells do not receive
direct signals from photoreceptors but integrate in-
formation processed by the intermediate retinal neu-
rons, primarily bipolar cells that transmit signals
from photoreceptors, and amacrine cells that mod-
ulate these signals through the lateral interactions
with bipolar cells (Fig. 2).
Dopamine is primarily synthesized in dopaminer-
gic amacrine and partially interplexiform cells of the
retina and is released after membrane depolarization
depending on calcium channels activation. Amacrine
cells are located in the inner plexiform layer, where
bipolar and RGC form synapses. There are at least
33 different subtypes of amacrine cells, of which do-
paminergic cells amount about 1%. These cells form
synapses with other retinal neurons, but dopamine
synthesized in them mainly acts in a paracrine fash-
ion via diffusion [25].
Dopaminergic neurons appear at early stages of
development, begin functioning before the animal
develops vision, and gradually die off in aging ani-
mals [26].
Dopamine receptors are found in all retinal cells,
as well as in anterior eye segment tissues responsible
for IOP regulation. The retinal dopaminergic chain
begins with a small population of amacrine cells ex-
pressing tyrosine hydroxylase, which receive activat-
ing signals from RGC and ON-bipolar cells. Dopamine
release by these cells depends on illumination, peak-
ing at maximum light exposure [27]. Photoreceptors
express the dopamine D4 receptor, which regulates
calcium channel activity; cone-associated bipolar cells
express the D1 receptor, enhancing light and contrast
sensitivity; horizontal and AII-type amacrine cells ex-
press D1; and RGC express D1 and D2. Functions of
the D2 receptor are not yet fully understood, but it is
known to act as an autoreceptor regulating dopamine
release [28].
It is well known that the ocular DS plays a signif-
icant role in regulating circadian rhythms and light
perception in the eye. Light stimulation causes do-
pamine release, facilitating transition from scotopic
to photopic visual information transmission, where
rods and cones predominate, respectively. This effect
Fig. 2. Structure of the eye and retina.
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is achieved via modulation of cellular, synaptic, and
gap junction signal transmission between the retinal
cells, altering sensitivity and activity of the receptive
fields of bipolar and ganglion cells, and regulating re-
lease and reuptake of neurotransmitters, particular-
ly gamma-aminobutyric acid (GABA) and glutamate.
All retinal dopaminergic receptors influence various
aspects of circadian rhythm regulation.
One of the most studied mechanisms by which
changes in dopamine concentration affect informa-
tion processing in the retina is modulation of electri-
cal coupling between the neurons via gap junctions.
As in CNS, electrical signal transmission through the
gap junctions provides direct and rapid communica-
tion between the neurons in retina, where all five
types of neurons form such contacts. Gap junctions
consist of connexin proteins that form channels al-
lowing passage of ions and small molecules. These
junctions form the basis of very fast electrical syn-
apses, enabling a large number of cells to quickly
produce a coordinated response, which is import-
ant for rapid primary visual information processing.
By modulating permeability of the gap junctions be-
tween the same types of neurons, dopamine can en-
hance or weaken the signal summation in a group
of neurons performing the same function. By mod-
ulating connections between the different types of
cells, dopamine can enhance or weaken cross-con-
nections between the different retinal regions [29].
By affecting gap junctions between photoreceptors,
it also helps maintain contrast sensitivity (ability to
distinguish changes in light intensity) [30]. In the
patients with Parkinson’s disease, who have a dopa-
mine deficiency, contrast sensitivity is reduced [31].
Permeability of the gap junctions is regulated by both
external illumination and circadian rhythms [32].
There is evidence that light and circadian rhythms
differentially enhance dopamine release, with light
being a more potent factor for dopamine release
than circadian rhythms. There is evidence for the ex-
istence of two complementary dopaminergic systems
in the retina. One system is associated with circadi-
an changes in the retinal activity and acts through
the dopamine D4 receptors controlling rod/cone gap
junction coupling, while the other, responsible for
non-circadian light/dark adaptive regulation of hor-
izontal cell interaction, is mediated by the D1 recep-
tors [27].
Functioning of the retinal pigment epithelium
also follows circadian rhythms due to DS. Retinal pig-
ment epithelium realizes daily phagocytosis of shed
outer segments of rods and cones. This is a cyclic
process activated 1-2 h after the onset of light. The
increase in phagocytic activity of the retinal pigment
epithelium occurs due to increase of dopamine con-
centration and activation of D2 receptors [33].
Circadian rhythms of dopamine synthesis and
release are closely linked to circadian rhythms of
melatonin production, whose synthesis, in contrast
to dopamine, increases at night. The feedback mech-
anism between the melatonin and dopamine content
in the retina is a crucial mechanism for maintain-
ing circadian rhythms in the retina. The dopamine
D2/D4 receptor, present on photoreceptors, mediates
suppression of melatonin synthesis [34, 35]. Degener-
ative processes in the retina during glaucoma lead to
disruption of local retinal circadian rhythms, which,
in turn, affects circadian rhythms of various physio-
logical processes not only in the eye but also through-
out the body [36, 37].
Involvement of dopamine in regulating retinal
angiogenesis during the postnatal period has been
demonstrated in experimental studies. Dopamine,
produced in excess by RGC during this period, lim-
its blood vessel growth, while dopamine deficiency
enhances angiogenesis. These data suggest that dopa-
mine could be a potential target for correcting vascu-
lar disorders in various eye diseases [38]. It has been
found that the dopamine agonist levodopa suppresses
pathological neovascularization of the retina in the
age-related macular degeneration [39, 40].
Dopamine is a key neurotransmitter in the sig-
naling cascade controlling eye refraction develop-
ment, but the exact role and site of action of the D1
dopamine receptors involved in myopia pathogenesis
remain unclear [41].
ROLE OF OCULAR DOPAMINERGIC
SYSTEM IN THE PATHOGENESIS
OF GLAUCOMA
Retina is the only structure in the body that can
be considered, both in origin and neuronal content,
as a remote part of central nervous system (CNS).
Degenerative processes in retina, including glauco-
ma, are largely similar to the neurodegeneration in
the CNS. A complex of interrelated factors causes
neuronal death: oxidative stress, mitochondrial dys-
function, endoplasmic reticulum stress, excitotoxic-
ity, and formation of misfolded protein aggregates.
Dopaminergic signaling pathways are involved in
these processes, and their imbalance plays an im-
portant role in the development of neurodegenerative
diseases of the retina, including glaucoma. Addition-
ally, DS is involved in the regulation of IOP and its
elevation in glaucoma. Although the role of DS in the
development of the glaucomatous process remains
insufficiently studied, current data indicate promise
of studying DS for the development of new methods
for prognosis, diagnosis, and treatment of various
forms of glaucoma.
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RGC and photoreceptors have high metabolic de-
mands and contain more mitochondria than other
cells in the body. RGC are more susceptible to mi-
tochondrial dysfunction than photoreceptors, as the
latter mainly rely on the aerobic glycolysis occurring
in the cytoplasm, while ganglion cells depend on ox-
idative phosphorylation in mitochondria. Mitochon-
drial dysfunction leads to accumulation of reactive
oxygen species, which, in turn, causes increased oxi-
dative stress and subsequent damage to mitochondri-
al structure and function. This vicious cycle makes
RGC highly susceptible to mitochondrial dysfunction
and oxidative stress. Elevated IOP, impaired microcir-
culation of blood and aqueous humor, and age-related
changes contribute to the development of oxidative
stress [42].
RGC continuously generate action potentials at
a certain frequency, and visual signals are super-
imposed on this background activity. Increased ex-
citability is closely associated with the RGC damage
in glaucoma [43]. Dopamine and its receptors are
involved in modulating excitability of ganglion cells.
In the rat model of glaucoma with chronic IOP ele-
vation, excessive activation of D2 dopamine receptors
in the ganglion cells was observed. Intravitreal ad-
ministration of the D2 antagonist sulpiride reduced
hyper-excitability and RGC damage. Administration of
the D1 antagonist had no such effect, while admin-
istration of the D1 agonist reduced RGC excitability.
Hence the authors suggest that selective inhibition of
D2R or activation of D1R may become an effective
strategy for neuroprotection in glaucoma [44].
Accumulation of glutamate in the vitreous body
and optic nerve in glaucoma also contributes to the
development of glutamate excitotoxicity, inducing
RGC loss [45]. Dopamine reduces the amplitude of
calcium response induced by the N-methyl-D-aspar-
tate (NMDA) receptor activation and decreases mito-
chondrial depolarization caused by glutamate. Thus,
dopamine improves neuronal survival under toxic
glutamate exposure [46].
Experimental studies in mice have revealed a
subtype of dopaminergic amacrine cells that rapidly
respond to optic nerve damage by reducing neuro-
nal activity, dopamine release, and D1 dopamine re-
ceptor expression in the RGC. Activation of dopami-
nergic amacrine cells or enhancement of dopamine
release using levodopa enhanced the RGC survival
and accelerated axon regeneration after injury. This
study highlighted crucial role of dopamine and the
D1 receptor in optic nerve regeneration, opening
prospects for using dopamine level restoration in
the optic nerve area for glaucoma treatment [47].
However, excessive accumulation of dopamine in the
cytosol or within synaptic vesicles due to impaired
catabolism could lead to its spontaneous oxidation,
resulting in formation of reactive oxygen species and
dopamine quinones, which are highly reactive elec-
trophilic molecules and could cause cytotoxic effects,
contributing to neuronal degeneration [8]. Dopamine
oxidation products promote mitochondrial dysfunc-
tion, impaired protein degradation, and aggregation
of α-synuclein into neurotoxic oligomers, which are
significant factors in the development of neurodegen-
erative processes [48]. Oxidized dopamine in the cy-
tosol could interact with α-synuclein oligomers, lead-
ing to formation of the particularly toxic compounds
that could cause synaptic dysfunction and cell death
through various mechanisms [49].
In the glaucomatous retina, in addition to α-sy-
nuclein oligomers, other misfolded proteins are pres-
ent, which is also characteristic of neurodegenera-
tive diseases of the CNS. Deposits of β-amyloid (Aβ)
in glaucoma are present in all retinal layers, where
they contribute to phosphorylation and accumulation
of another misfolded protein, p-tau, in the form of
amorphous deposits [50]. The abnormal tau protein
AT8, a marker of cell damage in various neurological
diseases, is present in the ocular tissues of humans
with glaucoma with uncompensated IOP [51]. Mean-
while, there is evidence that dopamine in its non-ox-
idized form prevents pathological phosphorylation of
tau protein[52]. Impaired dopamine catabolism could
also lead to excessive accumulation of the highly tox-
ic DOPAL, which promotes Aβ oligomerization [53].
In glaucoma, DS imbalance is not only a cause of
neurodegenerative processes in the retina but also
plays a role in IOP increasing.
INVOLVEMENT OF DS
IN IOP ELEVATION IN GLAUCOMA
Elevated IOP is a key factor in progression of
most forms of glaucoma. IOP is regulated by the bal-
ance between the rate of aqueous humor production
and its outflow. Aqueous humor is secreted in the
posterior eye chamber by the non-pigmented ciliary
epithelial cells, and drained from the anterior cham-
ber angle through the Schlemm’s canal and trabecu-
lar meshwork (Fig. 3).
Dopamine and dopamine receptors are present
in the anterior segment of the eye in humans and
animals. Dopamine is found in aqueous humor and
tear fluid at concentrations significantly higher than
in blood plasma [54, 55]. In the tear fluid of the pa-
tients with primary open-angle glaucoma, the dopa-
mine content is reduced [56].
Dopamine receptors are present in the tissues
responsible for aqueous humor production and out-
flow – ciliary epithelium, uveoscleral tissue, and tra-
becular meshwork [57, 58].
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Fig. 3. Schematic of aqueous humor circulation (shown by blue arrows).
The role of DS in IOP regulation is not yet fully
understood, but studies on the effects of various dopa-
mine receptor agonists and antagonists on IOP confirm
its involvement. Dopamine could affect IOP both di-
rectly and through the adrenergic system, as mediators
of this system– epinephrine and norepinephrine– are
synthesized from dopamine. Additionally, dopamine
could directly interact with adrenergic receptors[59].
Adrenergic receptors of different types have opposite
effects on aqueous humor secretion: β2-adrenergic
receptors stimulate secretion, while α2-adrenergic re-
ceptors suppress it. Aqueous humor outflow increases
under the action of α2- and α1-adrenergic agonists.
Drugs acting on adrenergic receptors are widely used
to reduce IOP in high-pressure glaucoma[60].
Increase in dopamine concentration in the ante-
rior eye segment leads to decrease in IOP. Instillation
of dopamine solutions in the eyes of intact rabbits
and mice resulted in a significant IOP decrease by
4-5 mm Hg [61, 62]. In the model of chronic ocular
hypertension in rabbits induced by subconjunctival
injections of betamethasone suspension, the effect of
instillations of different methyldopa concentrations on
IOP was studied. Methyldopa is a drug based on the
methylated derivative of the intermediate product of
dopamine biosynthesis, L-DOPA. Instillations of meth-
yldopa dose-dependently reduced the IOP. For compar-
ison, the widely used hypotensive drug Timolol 0.5%
reduced IOP by 30%, while effect of 2% methyldopa
was 24.25%, which is comparable and makes methyldo-
pa a promising addition to glaucoma treatments [63].
Dopamine receptors have different effects onIOP.
Stimulation of the D2- and D3-like receptors reduc-
es the norepinephrine release and suppresses aque-
ous humor production, leading to the IOP decrease.
Incontrast, the agonists of D1-like receptors stimulate
aqueous humor production, thus increasing IOP [64].
Various agonists of the D3 receptor could reduce IOP,
and this effect disappears in the D
3
R
−/−
knockout mice.
Apparently, the D3 receptors are the most important
receptors of the dopaminergic IOP regulation [65].
Itwas shown in the study of the D1 and D2 dopamine
receptor agonists effect in the patients with open-an-
gle glaucoma that all selective D1 receptor agonists
induce a significant IOP increase only in the eyes with
hydrodynamic disorders. These hypertensive effects
were not eliminated either by the use of dopaminer-
gic antagonists or by the treatment with the widely
used antiglaucoma drugs. The only substance capable
of suppressing the increase in IOP caused by the D1
receptor agonists was the D1-selective antagonist SCH-
23390. This suggests that the IOP increase in glaucoma
may be a result of the D1 receptor stimulation [66].
Dopamine receptors interact with other re-
ceptors, forming new heteromeric complexes with
unique functions and pharmacological properties. In
the cultures of non-pigmented ciliary epithelial cells
and in the basement membrane of the non-pigmented
ciliary epithelium of glaucoma patients, heterodimers
formed by the D3 and melatonin receptors MT1 or
MT2 were found. These heterodimers mediate antag-
onistic action of dopamine and melatonin in the eye.
The expression of heterodimers negatively correlated
with ocular hypertension, making them a promising
target for further research [58]. The study these het-
erodimers influence on circadian rhythms in the eye,
including diurnal IOP fluctuations under normal con-
ditions and in glaucoma, is of special interest.
To estimate the risk of developing glaucoma, a
test with instillation of the D1 receptor agonist ibo-
pamine (3,4-diisobutyryl ester of N-methyldopamine)
into the eye is used. In the individuals with impaired
aqueous humor outflow predisposed to glaucoma,
ibopamine instillations increase IOP due to enhanced
aqueous humor secretion. The study showed that in
the individuals having at least one parent with pri-
mary open-angle glaucoma, ibopamine instillation in-
creased IOP, indicating impaired function of ocular
drainage system and, consequently, predisposition to
ocular hypertension and glaucoma [67].
Glaucoma and neurodegenerative diseases of the
CNS share common mechanisms of neurodegenera-
tion. These are chronic neurodegenerative diseases
associated with aging, having similar cell damage
CHESNOKOVA et al.1314
BIOCHEMISTRY (MOSCOW) Vol. 91 No. 8 2026
mechanisms. The dopaminergic system is involved
in pathogenesis of these diseases, and neurodegener-
ative diseases of the CNS are accompanied by mor-
phological and biochemical changes in the eye that
can be detected earlier than other clinical manifes-
tations of CNS damage [28, 68, 69]. For example, in
neurodegenerative diseases of the CNS, composition
of tear fluid changes [70, 71]. It has been shown that
in the patients with Parkinson’s disease, concentra-
tion of L-DOPA, an intermediate product of dopamine
biosynthesis, is 60% higher in the tear fluid of the
ipsilateral eye compared to the healthy individuals.
In the mice with parkinsonism, IOP increase was ob-
served, and changes in dopamine metabolism in the
tear fluid were detected earlier than onset of motor
disorders [72]. Dopamine and its metabolites could
enter the tear fluid from the nerve terminals in the
conjunctiva, lacrimal glands, and cornea, and changes
in their content in tears could indicate the state of DS
in both the eye and the CNS. The data on the risk of
developing glaucoma in neurodegenerative processes
and the risk of neurodegeneration in the CNS are con-
tradictory, likely because observations were made in
the patients with pronounced clinical manifestation
of the disease receiving hypotensive therapy [73, 74].
CONCLUSION
Dysfunction of dopaminergic system plays a
key role in the development of neurodegenerative
processes in both CNS and the eye, and molecular
mechanisms of their pathogenesis share common fea-
tures. Moreover, in neurodegenerative brain diseases,
changes occur in the ocular structures that could be
detected even before clinical manifestations of neuro-
degeneration in the CNS.
Neurodegenerative processes in the retina are
the cause of vision loss in many eye diseases and
are difficult to treat. Glaucomatous optic neuropathy
arises from the pathological changes in the RGC and
optic nerve. The elevated IOP is an important factor
in the progression of almost all types of glaucoma;
however, the most common and proven method of
glaucoma treatment – IOP reduction – does not re-
store visual functions impaired due to apoptosis of
retinal neurons. Therefore, the use of effective neuro-
protective therapy is critical in glaucoma treatment.
It is known that DS is involved in all mechanisms
of neurodegeneration. The dopaminergic system is
widely represented in ocular structures, and its most
important and studied functions include regulation of
circadian rhythms, light adaptation, participation in
primary visual information processing, IOP control,
regulation of local blood flow and angiogenesis, and
ensuring proper eye development.
It has been experimentally proved that in glau-
coma, changes in the DS functioning in the eye lead
to oxidative stress, formation of misfolded proteins,
and other events leading to neurodegenerative chang-
es in the retina, as well as disruption of circadian
rhythms, light perception, and IOP increase. All this
makes the DS a promising target in glaucoma treat-
ment. Agonists and antagonists of dopamine recep-
tors could influence all these processes. Pharmaco-
logical influence on the ocular DS is promising for
neuroprotective therapy in glaucoma and could allow
combining neuroprotective action with hypotensive
effects.
For glaucoma treatment, it is important to devel-
op drugs not only for systemic but also for topical
use and methods for targeted delivery to the retina.
Assessment of the content of DS components in the
tear fluid may be a simple non-invasive method for
early diagnosis, prognosis, and justification of person-
alized glaucoma therapy. Thus, studying of the ocular
DS opens new perspectives for the treatment of glau-
coma and other eye diseases associated with neuro-
degenerative processes in the retina, but considering
complexity of the dopaminergic signaling cascades,
this area of research requires advanced study.
Abbreviations
cAMP cyclic adenosine monophosphate
CNS central nervous system
D1-D5 dopamine receptor subtypes 1-5
DOPA 3,4-dihydroxyphenylalanine
DOPAC 3,4-dihydroxyphenylacetic acid
DOPAL 3,4-dihydroxyphenylacetaldehyde
DS dopaminergic system
IOP intraocular pressure
L-DOPA levodopa
RGC retinal ganglion cells
Contributions
N. B. Chesnokova, T. A. Pavlenko, and O. V. Beznos –
writing the article text; S. Yu. Petrov – scientific edit-
ing; T. A. Pavlenko and N. N. Shikareva– illustrations;
O. V. Beznos – article formatting.
Funding
This work was supported by ongoing institutional
funding. No additional grants to carry out or direct
this particular research were obtained.
Ethics approval and consent to participate
This work does not contain any studies involving hu-
man and animal subjects.
Conflict of interest
The authors of this work declare that they have no
conflicts of interest.
DOPAMINERGIC SYSTEM OF THE EYE AND GLAUCOMA 1315
BIOCHEMISTRY (MOSCOW) Vol. 91 No. 8 2026
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