Dopamine is a neurotransmitter that plays a crucial role in many behavioral and physiological processes. It does so via signal transduction, meaning it binds to receptors in the central nervous system (CNS) to elicit various effects. It was first proposed in 1979 that there were at least two dopamine receptors at work in the CNS’s dopaminergic system, a hypothesis that has been adapted –and to various degrees disproved– in the years since. Researchers have identified five different types of dopamine receptors, but these are often sub-grouped based on their structural and pharmacodynamic similarities (1,2,3). Below is a list of the known receptors and their functions:
- D1: memory, attention, impulse control, regulation of renal function, and locomotion
- D2: locomotion, attention, sleep, memory, and learning
- D3: cognition, impulse control, attention, and sleep
- D4: cognition, impulse control, attention, and sleep
- D5: decision-making, cognition, attention, and renin secretion
The reason we primarily discuss D1 and D2 receptors is that the above five are grouped together based on their structural similarities and pharmacodynamics. D1-like receptors are D1 and D5 while the remaining three fall under the D2 category.
Understanding D1 and D2 Receptors
D1 receptors are located mainly in the striatum and the cerebral cortex and are involved in movement regulation, motivation, and attention–as mentioned above (1). When D1 receptors are activated, it causes a release of the secondary messenger cAMP (cyclic adenosine monophosphate) which activates the PKA protein (protein kinase A) and leads to the phosphorylation of target proteins (4).
D2 receptors, meanwhile, are primarily located in the striatum, the substantia nigra, and the hypothalamus. They are similarly involved in movement regulation and motivation, but D2 receptor activation–as well as following the dopamine pathway described above–can inhibit certain signalling pathways.
Naturally, the distinct pathophysiology of these receptors means their clinical significance differs. Dopamine dysfunctions may be indicative of many different diseases, whether levels are low or high. Parkinson's disease, for example, is caused by decreased dopamine in the nigrostriatal pathway while schizophrenia is associated with an elevated dopaminergic activity. The D2 receptors are often overactive in schizophrenia, which can lead to disordered thinking, delusions, or even hallucinations. Treatments for Parkinsons aim to increase dopamine availability while antipsychotics aim to block the D2 receptor to achieve the opposite outcome. The latter is usually described as receptor antagonism, specifically D2 antagonism, which is naturally attained using a D2 antagonist.
What Does D2 Antagonism Do?
As mentioned, D2 antagonism describes the inhibition or complete blocking of D2 receptor activity. This disrupts the normal signalling pathways that occur when dopamine binds to the receptor, which can–in turn–cause changes in the activity of various other neurotransmitters. The goal of D2 antagonism is to affect physiological changes by preventing dopamine overactivity, which is a key driver of myriad symptoms of Parkinson’s, schizophrenia, and other conditions.
Determining the efficacy of agonists and antagonists in preventing or stimulating dopamine release is typically achieved via binding assay with a fluorescent antagonist (6). The fluorescent antagonist can bind to D1 and D2 receptors while also emitting fluorescence, which is quantified using several applications as fluorescent polarization, flow cytometry and fluorescent microscopy. This is extremely beneficial to cellular and molecular biologists, especially in clinical neuroscience and pharmacological fields, as it allows users to observe the activity and density of D1 and D2 receptors in different regions of the CNS.
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References and Further Reading
- Ayano, G. J. J. M. D. T. (2016). Dopamine: receptors, functions, synthesis, pathways, locations and mental disorders: review of literatures. J Ment Disord Treat, 2(120), 2.
- Jeffrey, J. M., Salloway, S. (1994) Dopamine Receptors in the Human Brain. Psychiatric Times,l 11 (5).
- Guzman, F.,D2 Receptors in Psychopharmacology. Psychopharmacology institute.
- Bhatia, A., Lenchner, J. R., & Saadabadi, A. (2019). Biochemistry, dopamine receptors.
- Osinga, T. E., Links, T. P., Dullaart, R. P., Pacak, K., van der Horst-Schrivers, A. N., Kerstens, M. N., & Kema, I. P. (2017). Emerging role of dopamine in neovascularization of pheochromocytoma and paraganglioma. The FASEB Journal, 31(6), 2226.
- Karra, A. S., Stippec, S., & Cobb, M. H. (2017). Assaying protein kinase activity with radiolabeled ATP. JoVE (Journal of Visualized Experiments), (123), e55504.