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Guerra et al. J Transl Genet Genom 2022;6:304-21 https://dx.doi.org/10.20517/jtgg.2022.08 Page 306

[13]
sequentially .

Dopamine is synthesized and acts primarily in the central nervous system (CNS). Dopaminergic neurons
project to different brain regions along the mesolimbic, mesocortical, nigrostriatal, and tuberoinfundibular
pathways. Dopamine exerts its effects by binding to five G-protein-coupled receptors (D1-D5); of these, D1
receptors are the most abundant in the CNS. These receptors are divided into D1-like (D1 and D5) and
D2-like (D2, D3, and D4) receptors. D1-like receptors exert a stimulatory effect through sodium channels or
an inhibitory effect through potassium channels. At the peripheral level, dopamine does not cross the
blood–brain barrier and is synthesized independently. Dopamine is present in plasma as dopamine sulfate,
and only a small unconjugated amount can be synthesized by peripheral tissues [14,15] .

DOPAMINE AND SWALLOWING
The swallowing process requires, at least in part, dopamine activity and its binding to its receptors .
[16]
Although most dopamine receptors would theoretically be relevant to ND, the role of the dopamine
D1 receptor (DRD1) is particularly important in this condition. For example, DRD1 antagonists alter the
[17]
swallowing reflex and reduce substance P (SP) levels in peripheral organs . Specifically, in the striatum in
an animal model of Huntington’s chorea, Drd1a, SP, and dynorphin expression is downregulated, whereas
the expression of the dopamine D2 receptor (Drd2) and enkephalin is upregulated after ablation of D1
receptor-expressing cells . In this animal model, the resulting phenotype includes swallowing disturbances
[18]
and poor oromotor coordination with tongue protrusion . This role of DRD1 has also been observed in
[18]
certain single nucleotide polymorphisms (SNPs) in humans. The DRD1 rs4532 polymorphism confers a
worse prognosis of swallowing function in individuals over the age of 65 following a stroke. Other SNPs,
such as DRD2 rs1800497 and DRD3 rs6280, do not appear to be involved in ND . Moreover, interactions
[19]
between the COMT rs165599 and BDNF rs10835211 polymorphisms are linked to dysphagia with increasing
[20]
age; the effect of the SNP rs10835211 heterozygosity is dependent on the status of SNP rs165599 .

The use of dopaminergic agonists in the treatment of neurogenic dysphagia
Levodopa, rotigotine, cabergoline, apomorphine, and amantadine are dopamine agonists that have been
[8]
used generically to treat a variety of neurological conditions associated with oropharyngeal dysphagia . The
drug that provides the best outcome is controversial because of conflicting outcomes across different
studies. However, among these, levodopa is the most widely used, and it is also used to evaluate the
swallowing response during the Fiberoptic Endoscopic Evaluation of Swallowing (FEES) test [21,22] . Most
studies have focused on the effect of dopaminergic agonists in Parkinson’s disease, and several publications
show that these drugs improve dysphagia, especially in the oral phase and, to a lesser extent, in the
pharyngeal phase [23-25] . This clinical improvement is related to swallowing alterations due to nigrostriatal
dopamine deficits and to other structures such as the pedunculopontine nucleus or the medulla . In a
[23]
small group of patients, an improvement in bolus fragmentation, vallecular stasis, and laryngeal penetration
was observed, together with a shortening of the swallowing phase; these findings are associated with an
improvement in bucco-linguo-facial motility . Paradoxically, and despite most articles reporting a
[26]
beneficial effect, one clinical trial showed that levodopa could worsen dysphagia by inhibiting brainstem
reflexes . Overall, however, the results appear to support its use in PD patients despite the lack of high-
[27]
[28]
quality evidence . Although dopaminergic agonists have a modest effect on the motor symptoms of
progressive supranuclear palsy, they help some patients improve their swallowing . However, these drugs
[21]
can also be employed in acquired neurological conditions. Following a lacunar stroke involving the basal
ganglia, for example, levodopa decreases the risk of aspiration by shortening the latency of the swallowing
reflex, as shown after examining the submental electromyographic activity and the visual observation of the
[29]
laryngeal movement . This reduction, according to monocentric randomized trials in which imaging and