Understanding dopamine receptor function is critical when managing Parkinson’s disease (PD)

Dopamine receptor pathophysiology in Parkinson's disease

Parkinson's disease is a chronic neurodegenerative disorder that is characterized by progressive and debilitating motor symptoms, which are the hallmarks of the disease and a major focus of current therapeutic intervention.^1-4 Although Parkinson's disease is typically diagnosed when motor symptoms are present, the disease process usually begins before these symptoms occur.⁴ People living with Parkinson's disease also experience nonmotor symptoms.⁵

In Parkinson's disease, dopamine is the most disrupted neurotransmitter and acts through multiple pathways in the human brain.^6,7 Let's look more into a few of these pathways in healthy conditions. One major pathway is the nigrostriatal pathway, which is involved with motor control.⁷ Other key pathways are the mesolimbic and mesocortical pathways, in which different areas containing dopamine neurons play a role in reward and cognition, respectively.^7,8 Within the pathways there are 5 different receptor subtypes through which dopamine signaling can occur.⁹ D2, D3, and D4 dopamine receptors are referred to as D2-like receptors.^2,10-12 These receptor subtypes are the primary targets of currently approved dopamine agonists.² The other two dopamine receptors, D1 and D5, are referred to as D1-like receptors.^2,10-12 Within the nigrostriatal pathway in Parkinson's disease dopamine-producing neurons degenerate in the substantia nigra, leading to a loss of dopamine signaling and the emergence of motor symptoms.^3,13-14 Treatment focuses on offsetting the effects of these degenerating neurons by restoring dopamine signaling to improve some of the motor symptoms.^2,3,7 Now let's review some of the current treatment options.

Levodopa, which is a dopamine precursor that gets converted into dopamine, is the current oral standard-of-care for Parkinson's disease.^10,15 It leads to the activation of all dopamine receptors along the dopamine pathways.^2,10,15 Over time, neuronal degeneration, neuronal death, and pulsatile stimulation of receptors can lead to unpredictable symptom control with increased dyskinesia.^6,15-18 Other currently approved therapies include dopamine agonists, which target the D2 receptor subfamily, primarily at the D2 and D3 receptors.^2,15 However, D2/D3 agonists activate receptors that are located throughout many parts of the brain including areas outside of the nigrostriatal pathway that may not be degenerated.^2,15 This wide activation of D2/D3 receptors is primarily associated with potential burdensome nonmotor side effects, such as hallucinations, impulse control disorders, orthostatic hypotension, and excessive daytime sleepiness.^2,15 These symptoms may contribute to the emotional and physical burden of Parkinson's disease.¹⁹ Given that current treatment options may activate off-target dopamine receptors along a wide array of dopamine pathways, a more selective approach could be evaluated.^2,10,12,15 For instance, selectively targeting D1/D5 receptors through agonists is a potential approach in the treatment of Parkinson's disease.^20,21 A targeted approach to dopamine signaling may be achieved by selective D1/D5 dopamine receptor agonism.^20,21 This selective D1/D5 agonism may avoid D2/D3/D4 receptor agonism.^20,21 Selective targeting of D1-like receptors may provide a potential new approach to the treatment of Parkinson's disease.^20,21

References:

1. Tolosa E, Garrido A, Scholz SW, Poewe W. Challenges in the diagnosis of Parkinson's disease. Lancet Neurol. 2021;20(5):385-397. doi:10.1016/S1474- 4422(21)00030-2
2. Isaacson SH, Hauser RA, Pahwa R, Gray D, Duvvuri S. Dopamine agonists in Parkinson's disease: Impact of D1-like or D2-like dopamine receptor subtype selectivity and avenues for future treatment. Clin Park Relat Disord. 2023;9:100212. doi:10.1016/j.prdoa.2023.100212
3. Hussein A, Guevara CA, Valle PD, Gupta S, Benson DL, Huntley GW. Non-motor symptoms of Parkinson's disease: the neurobiology of early psychiatric and cognitive dysfunction. The Neuroscientist. 2023;29(1):97-116. doi:10.1177/10738584211011979
4. DeMaagd G, Philip A. Parkinson's disease and its management: part 1: disease entity, risk factors, pathophysiology, clinical presentation, and diagnosis. P T. 2015;40(8):504-532.
5. Fernandes M, Pierantozzi M, Stefani A, et al. Frequency of non-motor symptoms in Parkinson's patients with motor fluctuations. Front Neurol. 2021;12:678373. doi:10.3389/fneur.2021.678373
6. Kouli A, Torsney KM, Kuan WL. Parkinson's disease: etiology, neuropathology, and pathogenesis. In: Parkinson's Disease: Pathogenesis and Clinical Aspects. Stoker TB, Greenland JC, eds. Codon Publications; 2018. Accessed January 28, 2025. http://www.ncbi.nlm.nih.gov/books/NBK536722/
7. Choi J, Horner KA. Dopamine agonists. In: StatPearls. StatPearls Publishing; 2024. Accessed January 28, 2025. http://www.ncbi.nlm.nih.gov/books/NBK551686/
8. Ledonne A, Mercuri NB. Current concepts on the physiopathological relevance of dopaminergic receptors. Front Cell Neurosci. 2017;11:27. doi:10.3389/fncel.2017.00027
9. Bhatia A, Lenchner JR, Saadabadi A. Biochemistry, dopamine receptors. In: StatPearls. StatPearls Publishing; 2024. Accessed January 28, 2025. http://www.ncbi.nlm.nih.gov/books/NBK538242/
10. Mishra A, Singh S, Shukla S. Physiological and functional basis of dopamine receptors and their role in neurogenesis: possible implication for Parkinson's disease. J Exp Neurosci. 2018;12:1179069518779829. doi:10.1177/1179069518779829
11. Reynolds LM, Flores C. Mesocorticolimbic dopamine pathways across adolescence: diversity in development. Front Neural Circuits. 2021;15:735625. doi:10.3389/fncir.2021.735625
12. Ayano G. Dopamine: receptors, functions, synthesis, pathways, locations and mental disorders: review of literatures. J Ment Disord Treat. 2016;2(2):1-4. doi:10.4172/2471- 271X.1000120
13. Ouerdane Y, Hassaballah MY, Nagah A, et al. Exosomes in Parkinson: revisiting their pathologic role and potential applications. Pharmaceuticals. 2022;15(1):76. doi:10.3390/ph15010076
14. McGregor MM, Nelson AB. Circuit mechanisms of Parkinson's disease. Neuron. 2019;101(6):1042-1056. doi:10.1016/j.neuron.2019.03.004
15. Zahoor I, Shafi A, Haq E. Pharmacological treatment of Parkinson's disease. In: Parkinson's Disease: Pathogenesis and Clinical Aspects. Stoker TB, Greenland JC, eds. Codon Publications; 2018. Accessed January 28, 2025. http://www.ncbi.nlm.nih.gov/books/NBK536726/
16. Erekat NS. Apoptosis and its role in Parkinson's disease. In: Parkinson's Disease: Pathogenesis and Clinical Aspects. Stoker TB, Greenland JC, eds. Codon Publications; 2018. Accessed February 21, 2025. http://www.ncbi.nlm.nih.gov/books/NBK536726/
17. Nyholm D. The rationale for continuous dopaminergic stimulation in advanced Parkinson's disease. Parkinsonism Relat Disord. 2007;13(suppl):S13-S17. doi:10.1016/j.parkreldis.2007.06.005
18. DeMaagd G, Philip A. Part 2: Introduction to the Pharmacotherapy of Parkinson’s Disease, With a Focus on the Use of Dopaminergic Agents. Pharm Ther. 2015;40(9):590-600. 
19. Greenland JC, Barker RA. The differential diagnosis of Parkinson’s disease. In: Parkinson’s Disease: Pathogenesis and Clinical Aspects. Stoker TB, Greenland JC, eds. Codon Publications; 2018. Accessed February 21, 2025. http://www.ncbi.nlm.nih.gov/books/NBK536726/
20. Riesenberg R, Werth J, Zhang Y, Duvvuri S, Gray D. PF-06649751 efficacy and safety in early Parkinson’s disease: a randomized, placebo-controlled trial. Ther Adv Neurol Disord. 2020;13:1756286420911296. doi:10.1177/1756286420911296 
21. Sohur US, Gray DL, Duvvuri S, Zhang Y, Thayer K, Feng G. Phase 1 Parkinson’s disease studies show the dopamine D1/D5 agonist PF-06649751 is safe and well tolerated. Neurol Ther. 2018;7(2):307-319. doi:10.1007/s40120-018-0114-z