2024-12-27

The Variabilities of Dopamine (₯) - PART V: MeSH: D005239 & NBO:0000209 (Fear Comes in to Play)

Do you still remember the 67-year-old dopamine girl in the history of dopamine science this year? She gradually became a spokesperson for happiness in her twenties. However, behind this happiness is actually a little fear. In the early stages of research, scientists used basic tools to explore dopamine's role, focusing on its relevance to psychosis and antipsychotic drugs. Initial claims that dopamine was involved in fear conditioning were dismissed due to the inadequacies of the drugs, tools, and techniques used. However, with the development of science, it turns out that the purple "Fear" in "Inside Out" also has some relationship with the dopamine girl. Let's do some brain teasers together this time!
 
In "Dopamine at Forty," we learned that dopamine (DA) is more than just the "happy molecule" we once thought it was. Thanks to advancements in genetics, chemistry, and other technologies in the 21st century, scientists now understand dopamine and its interactions with neurons (DAN) and receptors much better.

These breakthroughs have shown us how dopamine is involved in both fear conditioning (how we learn to fear things) and fear extinction (how we stop fearing things). For example, a 40-year review of dopamine research revealed that different dopamine receptors play different roles in this process: D1 in the amygdala “promotes” neuronal plasticity; D2 “inhibits” the plasticity of neurons; D3 in the ventral striatum (nucleus accumbens and olfactory tubercle) reflects functions such as fear, anxiety, and depression.
 
Figure 1: Dopamine, worker cells DAN and dopamine receptors are involved in fear conditioning and extinction
 
Canadian scientists, including Hamati, have studied dopamine and fear for almost 66 years. So why don't we hear much about dopamine's role in fear? Early research methods were limited, and most studies focused on animals, with human studies being relatively new. However, fear, like happiness, is one of our most basic emotions. By looking at Hamati's research, we can see which brain areas are active during fear conditioning and extinction. This new information about dopamine and its receptors is helping us understand the full story of dopamine's varied roles in the brain.
 
First, we first use the U.S. National Library of Medicine Medical Subject Title (MeSH) knowledge tree to quickly grasp fear (MeSH: D005239). The knowledge structure in behavior and behavioral mechanisms is shown in Figure 2. And the fear condictioning of Neuro Behavior Ontology (NBO) (NBO:0000209) is shown in Figure 3. According to the NBO's definition of fear conditioning: 
 A type of associative learning that allows organisms to acquire affective responses, such as fear, in situations where a particular context or stimulus is predictably elicits fear via an aversive context.
In other words, fear conditioning is the process by which our brains learn to associate certain things with fear. This mechanism plays a crucial role in how we respond to potentially threatening situations, where the brain makes connections between ordinary things and scary things.
Figure 2: Fear MeSH: D005239 Knowledge Tree｜Source: MeSH and revised by A.H. 
 Figure 3: Fear Conditioning: NBO: 0000209 knowledge tree | Source: NBO and revised by A.H.

Hamati et al. discussed the role of dopamine in classical fear conditioning and extinction. The process of encoding fear roughly includes several stages: Acquisition, Consolidation, Recall, Extinction(training, recall and return) of memory. In fact, what is most fascinating about DA's role in fear is its dual nature. While it helps encode fear, it also plays a role in the extinction of these memories. The study uses the acquisition and recall of conditioned fear stimulus (CS+) in classical conditioning theory to represent the ability to learn fear; the acquisition and recall of conditioned safety stimulus(CS−) as well as extinction training and extinction recall represent the ability to inhibit learned fear. Overall, both fear conditioning and extinction altered the activity of worker DAN cells and altered DA concentration levels in multiple brain regions, see Figure 4.
Figure 4: Effects of fear conditioning and extinction stages on DA levels in the brain｜Source: adapted from Table 2 of Hamati et al.
 
  • Areas with increased DA activity levels: The amygdala is the most critical area in fear conditioning. DA increases during the acquisition and recall stages, along with terminal activity in the prefrontal cortex and most ventral midbrain periaqueductal gray matter (PAG)/ In the dorsal raphe nucleus (DRN) area, DA was increased.
  • Varies according to its location: Ventral tegmental area (VTA) in the animal literature suggests that DA is released in the medial prefrontal cortex (mPFC) during all stages of fear conditioning and extinction, but DAN activity in the medial and lateral VTA may depend on anatomy location and species. Because the number of active DANs in the substantia nigra pars compacta (SNpc) did not change after fear acquisition, the involvement of the SNpc in fear conditioning was not supported in the initial study. However, with the advancement of technology, during the fear acquisition process, the dorsolateral part of the SNpc has been suggested that regional DAN activity tends to increase, and the ventromedial region activity tends to decrease, which suggests that similar to the VTA, DA neuron activity in the SNpc varies depending on its location.
  • Uncertain region: Although the striatum, together with the amygdala, is considered a hub for coordinating fear responses and has the highest density of DA receptors relative to other brain regions, due to technical differences, the causal discussion on DA fear is still inconsistent and open for discussion.
Both D1-like and D2-like dopamine receptors help in learning and unlearning fear. D1-like receptors are important for picking up and solidifying memories, while D2-like receptors help in storing and recalling these memories. These receptors can work together in some brain areas or have their own unique roles. They work by sending signals through different brain regions like the amygdala, prefrontal cortex, hippocampus, and thalamus. See Figure 5.

Figure 5: Fear conditioning and extinction binding receptors｜Source: adapted from Hamati et al. Figure 3
  • Amygdala and Prefrontal Cortex: Both these brain areas help in fear learning and unlearning. D1-like and D2-like receptors work together here. In the amygdala, when dopamine binds to these receptors, it helps create and stabilize fear memories. When recalling these memories, the brain reactivates them. On the other hand, getting rid of fear, like during fear extinction training, creates new circuits to suppress fear. In the medial prefrontal cortex (mPFC), dopamine helps inhibit fear, influenced by different subregions and types of neurons.
  • Hippocampus: The D1-like and D2-like receptors in the CA1 part of the hippocampus help in consolidating fear memories, recalling them, and unlearning them during extinction training.
  • Thalamus: Here, D2 receptors help in fear learning, while D1 receptors help in unlearning fear.
  • Olfactory Tubercle: This area, part of the nucleus accumbens, has neurons with dopamine receptors that respond to fear conditioning cues.
In the past, we thought of dopamine mainly as the chemical behind pleasure, motivation, and setting goals. But thanks to scientific progress, we now know dopamine does much more. Think of dopamine and the cells it works with (DAN) as storytellers, recording tales of curiosity, fear, and safety. Our brain isn't just a static memory bank; it's like a constantly changing landscape, shaped by our experiences. Dopamine sends signals through receptors that help form, strengthen, and retrieve memories of fear and how to overcome it.

Dopamine isn't just hanging out; it's a key player in learning fear. When we're conditioned to fear something, DAN cells light up, record fear memories, and send signals to parts of the brain like the amygdala and prefrontal cortex, which handle fear processing. Overcoming fear, or fear extinction, is like turning on a light in a dark room, slowly making the fear disappear. During this process, the brain learns that the once-feared thing is no longer a threat. Dopamine plays a dual role here, working with DAN cells and receptors to update and overwrite fear memories. Fear becomes a useful emotion, helping us prepare for danger. In the end, there's a balance between fear and safety, and dopamine helps maintain that balance.

Reference
  • Kawahata, I., Finkelstein, D. I., & Fukunaga, K. (2024). Dopamine D1–D5 Receptors in Brain Nuclei: Implications for Health and Disease. Receptors, 3(2), 155-181.
  • Hamati, Rami, et al. "65 years of research on dopamine's role in classical fear conditioning and extinction: A systematic review." European Journal of Neuroscience 59.6 (2024): 1099-1140
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2024-12-25

The Variabilities of Dopamine (₯) - PART IV: MeSH:D011954

Dopamine is a pretty quirky character. Not only does it act as a neurotransmitter, but it also behaves differently depending on the "dopamine receptor" it binds to. Imagine these receptors as different doorways on the surface of a cell, each one changing how dopamine does its job. So, what's so special about these receptors? Well, think of them like the VIP passes that let dopamine into the cell club. You've probably heard about receptors because of the coronavirus (yep, the COVID-19 villain). The virus uses a special receptor called "ACE2" to sneak into our cells. Using this same idea, you can picture dopamine needing its own special receptors to get things done. In short, dopamine receptors are like the bouncers deciding who gets into the cell party, and without them, dopamine would just be left knocking on the door! 

Receptors on the surface of cell membranes are like the gatekeepers for cells to receive signals. These signals come from neurotransmitters, which are chemicals that help pass messages in the brain. When a neurotransmitter arrives, it interacts with G proteins in the cell membrane through special receptors on the surface, generating second messages inside the cell. These second messages kickstart various biochemical reactions in the cell, influencing downstream activities.

These receptors are called G protein-coupled receptors (GPCRs), the largest group of receptors that affect nearly all aspects of human physiology. Interestingly, about 40% of all approved drugs work by acting on GPCRs. Dopamine receptors are a type of GPCR found in neurons throughout the brain and body. When dopamine (DA) signals reach a nearby neuron, they bind to these specific receptors on the cell membrane of the neuron. This interaction helps regulate sensory and nerve signal transmission, as well as important processes related to cell balance and growth. 

Figure 1 shows how the small chemical molecule dopamine (DA) attaches to a larger dopamine receptor molecule and sends chemical signals by causing changes in the neurons that receive the signal. Think of the neurotransmitter (DA) and the receptor as a key and a lock. In this case, DA is the key and is called a ligand in biochemistry. A ligand is something that forms a complex with biological molecules to achieve a purpose. The word "ligand" comes from the Latin word "ligare," meaning "to bind." The ligand must fit well with its receptor, like a key fitting into a lock, to activate or inhibit protein activity, thus starting or stopping cellular responses. (part of the illustration of dopamine receptors uses BioRender components)

Next, let's dive into the expert definition of dopamine receptors.  

Figure 2 shows that, according to the Medical Subject Headings (MeSH) of the U.S. National Library of Medicine, the ID number for the dopamine receptor is D011954. It's defined as: “Cell-surface proteins that bind dopamine with high affinity and trigger intracellular changes influencing the behavior of cells.” From the MeSH dendrogram (a type of diagram showing relationships), we can see that the dopamine receptor is part of a larger protein family, which includes neurotransmitter receptors, biogenic amine receptors, and GPCRs. It's related to adrenergic receptors and has subcategories like D1 and D2 receptors, along with their subtypes D5, D3, and D4. 

○      Receptors, Dopamine D1: A subfamily of G-PROTEIN-COUPLED RECEPTORS that bind the neurotransmitter DOPAMINE and modulate its effects. D1-class receptor genes lack INTRONS, and the receptors stimulate ADENYLYL CYCLASES.

  • Receptors, Dopamine D5: A subtype of dopamine D1 receptors that has higher affinity for DOPAMINE and differentially couples to GTP-BINDING PROTEINS.

○      Receptors, Dopamine D2: A subfamily of G-PROTEIN-COUPLED RECEPTORS that bind the neurotransmitter DOPAMINE and modulate its effects. D2-class receptor genes contain INTRONS, and the receptors inhibit ADENYLYL CYCLASES.

  • Receptors, Dopamine D3: A subtype of dopamine D2 receptors that are highly expressed in the LIMBIC SYST­EM of the brain.
  • Receptors, Dopamine D4: A subtype of dopamine D2 receptors that has high affinity for the antipsychotic CLOZAPINE.

Simply put, dopamine receptors are divided into two different families based on their effects on adenylyl cyclase, an intracellular signal transduction and key enzyme involved in cell regulation: D1 and D2, or "D1 like receptors: D1, D5" and "D2 like receptors: D2, D3, D4", depending on whether their activation leads to stimulation or inhibition of the enzyme , and pharmacological differences.

Secondly, different descendant families are subdivided based on homology, pharmacological and biochemical properties. Endogenous dopamine or exogenous dopamine drugs activate receptors, also known as dopamine receptor agonists, and the activated protein activity can initiate cellular responses and increase dopaminergic activity in the brain, which helps It is used to reduce the symptoms of Parkinson's disease (dopamine deficiency); on the contrary, antagonists inhibit protein activity, shut down cell responses, and are used in schizophrenia with overactive dopamine.

In addition, dopamine receptors are also closely related to biological neuropsychological functions. In fact, the research on dopamine receptors was about 15 to 20 years behind the research on dopamine. The journal "Neuropsychopharmacology" mourned the late Canadian pharmacologist Philippe Philippe who was famous for his dopamine receptors. Philip Seeman mentioned that people's awareness of the existence of two dopamine receptor subtypes (later designated as D2) began with Professor Seeman's antipsychotic drug research in 1974. In 2024, scientists Kawahata and others from Tohoku University in Japan and the University of Melbourne in Australia reviewed nearly 40 years of research (1984~2023) and sorted out the impact of dopamine D1-D5 receptors in the brain on health and disease. They pointed out in the paper, biological functions of dopamine receptors extend beyond functions such as movement, cognitive memory, motivation, and drug addiction, revealing another potential reason why polypeptide dopamine is so variable. This study reviews the distribution of dopamine D1-D5 receptors, based on the physiological significance and disease correlation represented by different regions in the brain. It not only advances our basic knowledge of the central nervous system, but also provides powerful clues for therapeutic intervention.

In summary, the focus of Kawahata et al.'s research includes five major areas: striatum: ventral, dorsal, and nucleus accumbens; prefrontal cortex; subthalamic nucleus; limbic system: amygdala, hippocampus; midbrain : Substantia nigra pars compacta (SNc) and ventral tegmental area (VTA). The psychological and physiological functions of dopamine receptors D1 to D5 in Figure 3 include:

  • The "happy" function is mainly located in D2 in the ventral striatum.
  •   "Motivation and reward" are widely reflected in D1 to D4 of the striatum; D2 and D3 of the prefrontal cortex; D2 and D3 of the subthalamic nucleus; D3 of the amygdala; D2 of the substantia nigra and ventral tegmental areas D1 and D3. D4.

In addition, regarding the response to "novel things", last time we focused on the working cells dopaminergic neurons (DAN). This time we can combine dopamine receptors to more completely understand how brain neurons arouse curiosity. In response to novelty, D4 receptors may have the greatest contribution. "D4 curiosity" is mainly reflected in the dorsal striatum, prefrontal cortex, subthalamic nucleus and amygdala, and has a role in coping with novel things in the substantia nigra. 

Research on D4 receptors and their link to curiosity and novelty-seeking behavior is fairly recent, starting around 1996 (less than 30 years from now). Since studies vary based on the groups of people studied, methods used, and statistical tests applied, the findings may differ. To sum it up, dopamine receptors from D1 to D5 each have unique features, are distributed differently in the brain, and respond to dopamine in their own ways. 

Interestingly, more and more evidence suggests that different ways dopamine affects these receptors can influence our brains in surprising ways we didn't realize. Are you feeling curious about this now? Dopamine is doing its job! (to be continued)


 Reference

  1. 金克寧, 現代藥物標靶—G蛋白偶合受體之研究解析, 科學月刊. 516期. 2012.12.01
  2. 林書瑤,【化學奇境】受體‧受體‧受體, 台大科教中心CASE報科學, 2010.12.23
  3. wikipedia：ligand
  4. MeSH(D011954)
  5. Madras, B., George, S. In memoriam professor Philip Seeman (February 8, 1934-January 9, 2021). Neuropsychopharmacol. 46, 1229–1230 (2021).
  6. Kawahata, I., Finkelstein, D. I., & Fukunaga, K. (2024). Dopamine D1–D5 Receptors in Brain Nuclei: Implications for Health and Disease. Receptors, 3(2), 155-181. ; this study is limited to dopamine receptors in the central nervous system of the brain. Other non-central nervous system dopamine receptors including the heart, lungs, renal system, and pancreas are not discussed in this scope.
  7. Oak, J. N., Oldenhof, J., & Van Tol, H. H. (2000). The dopamine D4 receptor: one decade of research. European journal of pharmacology, 405(1-3), 303-327.; Paterson, A. D., Sunohara, G. A., & Kennedy, J. L. (1999). Dopamine D4 receptor gene: novelty or nonsense ? Neuropsychopharmacology, 21(1), 3-16.
  8. BioRender (2022). Distribution of Dopamine Neurotransmitters in the Human Brain.

 

 

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