2025-09-25

The Variabilities of Dopamine (₯) - PART IX: Serotonin, a friend and foe, going or waiting? MeSH:D012701

 

Historically, research on cognitive behavior has focused on dopamine’s role in learning and memory, particularly through associative learning, linking stimuli (causes) to specific outcomes. Dopamine was believed to capture the core multicellular biological processes underlying neurobehavior. However, recent scientific advances have revealed that serotonin(5-hydroxytryptamine; 5HT), which interacts antagonistically with dopamine, plays a crucial role in shaping this picture. 

To understand their relationship, we begin with a brief overview using the National Library of Medicine’s Medical Subject Headings (MeSH) knowledge tree. Figure 2 illustrates the MeSH classification for dopamine (MeSH:D004298 or ChEBI:18243) and serotonin (MeSH:D012701 or ChEBI:28790). Both are monoamines, with serotonin descending from the tryptamine family. A deeper exploration of serotonin’s classification via the Chemical Entities of Biological Interest (ChEBI) will be provided in a future article.

One long-standing theory in neuroscience, the opponency hypothesis, proposes that two systems encode emotional events: one for positive (appetitive) responses and another for negative (aversive) ones. These systems inhibit each other or exert opposing effects on shared outputs. Physiologically, this model compensates for the absence of negative affect. In this framework, dopamine drives immediate action, while serotonin promotes patience, dopamine encourages behavior, serotonin inhibits it, helping organisms weigh risks and rewards. 


Another theory, the synergy hypothesis, suggests that dopamine handles short-term rewards while serotonin manages long-term benefits. This model integrates dopamine’s role in temporal-difference learning with serotonin’s influence on emotional regulation. Despite their appeal, both hypotheses have been difficult to verify due to limitations in manipulating multiple neuromodulatory systems within individual subjects.

A breakthrough study from Stanford University, “Opponent control of reinforcement by striatal dopamine and serotonin,” introduced a novel experimental model that directly validates the antagonistic and synergistic roles of these neurotransmitters. Researchers developed a genetic strategy to simultaneously access dopamine and serotonin systems in the same mouse. By labeling dopamine and serotonin neurons with distinct fluorescent proteins, they identified the posterior-medial nucleus accumbens (NAc) as a convergence point for both signals.

During reward-learning tasks, dopamine levels increased while serotonin levels decreased when mice received a reward. Using optogenetics to selectively block or stimulate each system, researchers found that disabling both systems impaired learning entirely. Conversely, simultaneous dopamine stimulation and serotonin inhibition enhanced learning more than dopamine stimulation alone.

Replicating these findings in the nucleus accumbens confirmed that dopamine and serotonin act in opposition yet synergistically to support reward learning. The study likens their interaction to a car’s accelerator and brake: dopamine signals “go” when outcomes exceed expectations, while serotonin signals “stop” or “wait,” encouraging long-term consideration over impulsive action.

Clinically, this insight opens new possibilities. Addiction treatments might benefit from dampening dopamine while boosting serotonin, whereas depression therapies could aim to enhance both systems to improve motivation and planning.

In essence, effective learning depends on the interplay between dopamine’s drive and serotonin’s restraint. As you read this, these neurotransmitters are shaping your brain’s reward-learning mechanisms: balancing action and inhibition to help you navigate opportunities wisely.

 

REFERENCE

  • MeSH:D004298; ChEBI:18243; MeSH:D012701; ChEBI:28790
  • Cardozo Pinto, D. F., Pomrenze, M. B., Guo, M. Y., Touponse, G. C., Chen, A. P., Bentzley, B. S., ... & Malenka, R. C. (2024). Opponent control of reinforcement by striatal dopamine and serotonin. Nature, 1-3.
  • Weiler, N. Dopamine and serotonin work in opposition to shape learning, Neuroscience News, Stanford University. Nov 25 2024.

2025-07-17

The Variabilities of Dopamine (₯) - PART VIII: Trust or Distrust? MeSH: D035502

In neurobiology, the study of trust has historically been dominated by oxytocin, the so-called "social hormone." This hormone is known to reduce anxiety and increase empathy, fostering a sense of trust. Conversely, increased levels of steroid hormones like testosterone can inhibit oxytocin secretion, thereby reducing empathy and trust. Amidst the scientific focus on these two key chemicals, dopamine was often relegated to a supporting role, thought to merely assist in regulating oxytocin to enhance the pleasure derived from cooperation and relationship-building. At best, it was considered a secondary player in the mechanism of trust.

However, since the early 21st century, cognitive neuroscience has begun a wider and deeper exploration of the relationship between dopamine and trust. This interdisciplinary field integrates applications from economic exchange games (such as trust games), psychological frameworks (motivation, emotion, and cognition), and neuroscience (brain circuits, hormones, and neurotransmitters). For example, the ventral striatum (vSTR), a key part of the mesolimbic pathway, regulates reward motivation and promotes reinforcement learning. When individuals learn to trust others through repeated interactions, dopamine neurons cause the vSTR to activate. This activation encodes a "reward prediction error" signal, the difference between an expected reward and the actual reward received. This dopaminergic neural mechanism provides the foundation for neuroeconomic models that explain how the human brain establishes and maintains trust (as illustrated in Figure 2).

The knowledge structure of trust can also be understood through its classification in the U.S. National Library of Medicine's Medical Subject Headings (MeSH). Under the ID D035502 (Figure 3), "Trust" is defined as "Confidence in or reliance on a person or thing." The MeSH hierarchy places "Trust" under the parent term "Interpersonal Relations," which itself falls within the "Behavior and Behavior Mechanisms" category. Its sibling terms include "Social Interaction" and "Social Skills." Furthermore, this classification reveals the relationship between trust and other topics previously discussed in the " Variabilities of Dopamine " series. For instance, "Behavior" has a descendant term "Exploratory Behavior" (curiosity); "Emotion" includes "Happiness," "Fear," and "Pleasure"; and "Motivation" includes "Goals." All these concepts fall under the broad umbrella of "Behavior and Behavior Mechanisms."


Strong evidence for the role of dopamine in trust comes from studies on its receptors. A 2023 neuroimaging study in the Nature Communications linked behavioral performance in trust-based tasks to neural activation. The study found that blocking the dopamine D2/D3 receptors in male participants altered activity in brain regions associated with trust, such as the prefrontal cortex and striatum. This research examined the relationship between dopamine and trust using the concept of "belief volatility": the stability of one's trust-related beliefs. This was measured using a Bayesian inference model, where beliefs are updated based on new evidence. The core concepts include:

  • Prior Belief: the initial level of trust before encountering new evidence.
  • New Evidence (Likelihood): new information or actions from the other person. 
  • Updated Belief (Posterior Belief): the modified level of trust after considering the new evidence.
"Belief volatility" is a metric derived from this statistical framework.

The study showed that antagonizing (blocking) D2/D3 receptors increased the volatility of trust-related beliefs. Higher volatility indicates less confidence; it means that an individual's assessment of another's trustworthiness is unstable and changes rapidly in response to new information. Conversely, lower volatility reflects more stable beliefs, and thus higher confidence, that are less swayed by new evidence. The experimental study by Mikus et al. (2023) provides direct behavioral evidence that dopamine regulates the stability of our beliefs about others.

So how does dopamine shape these trust-related beliefs?

A study by Schuster and Lamm (2025) at the University of Vienna highlights how recent experimental and clinical work has advanced our understanding of this process. It demonstrates that dopamine's role can be conceptualized within Bayesian inference frameworks, involving processes like precision-weighted prediction error computation and hierarchical belief updating. Until recently, dopamine was discussed primarily in the context of reinforcement learning. It was known that phasic (short-burst) dopamine firing tracks the magnitude of reward prediction errors, but growing evidence shows that tonic (sustained) dopamine levels signal the precision or certainty associated with those predictions. In essence, dopamine appears to mediate multiple aspects of belief updating on different time scales. The two key types of dopamine signals are:

1. Phasic Dopamine Signals: these are rapid, short-lived bursts of dopamine, often triggered by unexpected or rewarding events. Think of them as brief flashes that signal a surprise.
2. Tonic Dopamine Signals: this refers to the baseline, sustained level of dopamine in the brain. It sets the overall tone for how sensitive we are to new information.

This research clarifies that dopamine helps the brain update beliefs by managing the uncertainty of new information, allowing it to function optimally by minimizing surprise. According to Schuster and Lamm, modern tools like functional magnetic resonance imaging (fMRI) show that shifts in belief following a prediction error (a phenomenon known as Bayesian surprise) are encoded in dopamine-rich areas of the midbrain. Figure 5 illustrates the key substantia nigra/striatum and midbrain-cortical dopamine pathways involved in trust-based learning.

Schuster and Lamm's work further emphasizes that D2/D3 receptors are key to how the dopamine system regulates belief volatility. These receptors are crucial for distinguishing meaningful information from "noise." Imbalances in D2/D3 receptor function can be detrimental. If signaling is too high, we may struggle to distinguish important information from noise. If it is too low, we might fail to recognize new information that should cause us to update our beliefs. This function also regulates the speed at which we update our views of others. These findings provide new insights into the potential mechanism by which antipsychotic drugs targeting D2/D3 receptors can effectively reduce symptoms of severe distrust, such as paranoia.

In the context of "trust or distrust," variable dopamine helps the brain balance the influence of prior beliefs (old information) with incoming evidence (new experiences). By modulating this system, dopamine adjusts how much weight we give to new information. Increased dopamine signaling can make the brain prioritize new data over established beliefs. It is now clear that the decision to trust or distrust is not just a matter of social hormones but is fundamentally modulated by dopamine.

REFERENCE

  1. Zak, P. J. (2008). The neurobiology of trust. Scientific American, 298(6), 88-95; Zak, P. J. (2019). How Our Brains Decide When to Trust. Harvard Business Review
  2. Krueger, F., & Meyer-Lindenberg, A. (2019). Toward a model of interpersonal trust drawn from neuroscience, psychology, and economics. Trends in neurosciences, 42(2), 92-101.
  3. MeSH: D035502 ; MeSH: D005106 ; MeSH: D005239; MeSH: D006240; MeSH: D009042; MeSH: D006040
  4. Mikus, N., Eisenegger, C., Mathys, C., Clark, L., Müller, U., Robbins, T. W., ... & Naef, M. (2023). Blocking D2/D3 dopamine receptors in male participants increases volatility of beliefs when learning to trust others. Nature Communications, 14(1), 4049.
  5. Schuster, B. & Lamm, C. (2025). How dopamine shapes trust beliefs, Progress in Neuro-Psychopharmacology and Biological Psychiatry, Volume 136. Preprint Online Version, Nov.28.2024. 




2025-05-08

The Variabilities of Dopamine (₯) - PART VII: the Dopamine Transporter, MeSH: D050483

Dopamine is a crucial neurotransmitter governing motivation, reward, and motor control. For its signaling to be precise, however, the message must be terminated after delivery. This critical task of cleanup and recycling falls to a specialized protein: the Dopamine Transporter (DAT), as a powerful and efficient dopamine "vacuum cleaner," a metaphor used by neuroscientists[1].

Function: A Molecular Cleanup Crew

Fig1: Dopamine transporter (DAT) vacuum cleaner metaphor
Source: Author provided/AI collaborative graphics

Often likened to a molecular "vacuum cleaner," or Dopamine Carriers, DAT is a membrane protein on dopaminergic neurons. Its primary role is to pump dopamine from the synapse, the space between neurons, back into the original neuron for storage and reuse. This process, known as reuptake, efficiently terminates the dopamine signal and restores synaptic balance, preparing the neuron to fire again.

The proper functioning of DAT is essential for neurological health. If its activity is too low, excess dopamine lingers in the synapse, leading to an overstimulation linked to psychiatric symptoms and psychosis. Conversely, a significant loss of these transporters is a hallmark of Parkinson's disease, contributing to its characteristic motor deficits[2].

Historical Context

Fig 2: Mechanisms involved in neurotransmitter release and termination | Source: Author adapted from Iversen (1971) Figure 1/DAT symbol added

The concept of neurotransmitter reuptake gained traction in the late 1960s. The next two decades were primarily a target for pharmacological exploration of transporters, and the 1990s saw the rapid development of comprehensive transporter research[3]. In particular, the work of neuropharmacologist Leslie L. Iversen, who proposed the transmitter uptake hypothesis in the 1970s, was foundational. He theorized that a dedicated “membrane transport system” cleared neurotransmitters from the synaptic cleft, a principle that guided decades of research into transporters like DAT[4].

Scientific Classification

According to the U.S. National Library of Medicine's Medical Subject Heading (MeSH: D050483), the DAT is defined as:

Sodium chloride-dependent neurotransmitter symporters located primarily on the PLASMA MEMBRANE of dopaminergic neurons. They remove DOPAMINE from the EXTRACELLULAR SPACE by high affinity reuptake into PRESYNAPTIC TERMINALS and are the target of DOPAMINE UPTAKE INHIBITORS.

Fig 3: DAT MeSH knowledge tree | Source: Author adapted from the National Library of Medicine

Today, DAT is well-characterized and belongs to several key protein families:

  • Catecholamine Plasma Membrane Transport Proteins or Catecholamine Carrier: A group of membrane transport proteins that transport biogenic amine derivatives of catechol across the PLASMA MEMBRANE. Catecholamine plasma membrane transporter proteins regulate neural transmission as well as catecholamine metabolism and recycling.
  •  Symporter or Co-Transporter: Membrane transporters that co-transport two or more dissimilar molecules in the same direction across a membrane. Usually the transport of one ion or molecule is against its electrochemical gradient and is powered by the movement of another ion or molecule with its electrochemical gradient. 
  •  Solute Carrier Proteins or SLC Proteins: A large diverse group of membrane transport proteins whose families are generally classified according to function. Most SLCs localize to the CELL MEMBRANE; however, some families such as SLC25, localize to MITOCHONDRIAL MEMBRANES or other ORGANELLES.

DAT, a family member of catecholamine transporters, is familiar to us. Like dopamine, it inherits the properties of catecholamines. Compared to the two major families, DAT has the fewest siblings, as observed in the MeSH knowledge tree. Symporters, on the other hand, utilize the inward movement of one molecule to pull in another against the gradient. In the case of DAT, this involves a mechanism involving sodium and chloride ion movement (Na+/Cl-dependent neurotransmitter transporters). This mechanism, based on the difference in ion concentrations across the cell membrane, facilitates dopamine reuptake into the cell, thereby resetting dopamine signaling. Another common name for DAT is SLC6A3 protein, a family 6 member 3 protein, based on its solute carrier family classification.

In short, DAT, which flexibly controls dopamine signaling, participates in the dopamine biosynthesis process, including dopamine uptake for synaptic transmission, neurotransmitter biosynthesis, and regulation of dopamine catabolism and transmembrane transport. DAT is responsible for retrieving dopamine from the interneuronal cleft back to the preneuronal cleft. Therefore, the proper functioning of the transporter DAT is crucial for maintaining a balanced dopamine concentration.

Conclusion

If we imagine our brain as a vast communication network, constantly sending messages back and forth, dopamine is one of the key signals in this network, sending "short messages" such as movement, goals, motivation and reward, emotions, fear, experiencing novelty, and even entrepreneurial motivation. To keep everything running smoothly, another specialized protein in the brain, called the dopamine transporter (DAT), acts like a robotic vacuum cleaner: after dopamine sends its message, DAT appears, picks up the remaining dopamine, and brings it back to the brain cells for recycling or storage. Without these transporters, dopamine lingers, and signals become mixed, much like a phone that starts to freeze and malfunction after receiving too many text messages at once. 

Thus, DAT helps keep the brain's communication system efficient and uncluttered, ensuring that signals like our emotions and motivations are clear and effective. So, the next time you feel that rush of pleasure or motivation, call upon the throbbing master of organization, DAT, the master of purge and recycling, who loves to organize your brain's dopamine, keeping everything organized and tidy, and ensuring that your brain doesn't become overly active due to dopamine overload and turn into a party paradise. 



[1] Neuroscience News. How Dopamine is Transported Within the Brain. Jan 26.2016

[2] 張志玲, 調控精神與情緒的操盤手--多巴胺轉運體, 科學發展月刊, 2015.03 (507), 72-73 

[3] Reith, M. E., Xu, C., & Chen, N. H. (1997). Pharmacology and regulation of the neuronal dopamine transporter. European journal of pharmacology, 324(1), 1-10.

[4] Iversen, L. L. (1971). Role of transmitter uptake mechanisms in synaptic neurotransmission. British journal of pharmacology, 41(4), 571.

5. MeSH: D050483: http://id.nlm.nih.gov/mesh/D050483

 

2025-02-13

The Variabilities of Dopamine (₯) - PART VI: MeSH: D016520, D058068 and ICD11 (Just want to start a business)

“We [entrepreneurs] have incredible enthusiasm, and I think part of the success of any entrepreneur is energy.” 

(Dame Anita Roddick)

When we think of entrepreneurs, it's easy to think of their indomitable spirit - passion, energy, and insatiable drive. Anita Roddick, the brilliant founder of The Body Shop, once remarked in an interview with BBC’s Martin Lewis. This succinctly encapsulates the essence of entrepreneurs in the eyes of the general public—boundless enthusiasm and vitality.

Yet, the true nature of entrepreneurial passion runs deeper, as revealed by the intricate dance of neuroscience. This is vividly illustrated in the title of a scientific paper, "Baby, I'm addicted!" This research delves into the intoxicating world of dopamine, the chemical conductor orchestrating the pleasure-pain symphony of entrepreneurial addiction. Driven by dopamine, entrepreneurs often view their ventures as their offspring, forging an intense psychological bond that transforms initial fervor into an addiction to the entrepreneurial journey itself.

The unseen force propelling entrepreneurs—dopamine—is a fascinating, yet seldom highlighted, aspect of entrepreneurship. The U.S. National Library of Medicine’s Medical Subject Headings (MeSH) knowledge tree intriguingly maps entrepreneurship within the domains of "Technology, Industry, and Agriculture" and "Health Services Management." It defines entrepreneurship as the organization, management, and assumption of risk in a business venture, typically involving elements of change, challenge, and novel opportunities. In the realm of dopamine-fueled neurophysiology, these changes and challenges are intrinsically linked to our innate desires, rewards, goals, and the pursuit of novelty.

But dopamine's role in entrepreneurial zeal is just one facet of a burgeoning field—neuroentrepreneurship. Since 2009, this discipline has blossomed, spotlighting the profound influence of brain function on business decisions. Leading the charge in this nascent research are the United Kingdom, the United States, and India, with over 75% of studies emerging in the past five years. These investigations weave together neuroscience and entrepreneurship, exploring neurotechnology applications in business, the neural traits of entrepreneurs, and the ethical considerations of neuroentrepreneurship. Researchers delve into the brain regions involved in decision-making, the cortical activations that pave the way for business triumphs, and how an entrepreneurial mindset enhances the identification, evaluation, and exploitation of opportunities, ultimately refining decision-making processes.

In the grand tapestry of entrepreneurship, it's not just passion and energy that drive success, but a complex interplay of neurological impulses, challenges, and a relentless quest for novelty and rewards.

In the vibrant world of scientific inquiry, the year 2024 witnessed an intriguing collaboration between European and American scientists, spearheaded by Freeman and his team. Their article, titled "Dopamine and entrepreneurship: 
Unifying entrepreneur personality traits, psychiatric symptoms, entrepreneurial action and outcomes" unfurled a tapestry of understanding, weaving together the threads of dopamine and entrepreneurship.

This scholarly endeavor provided a comprehensive framework from a dopaminergic perspective, delving into the nexus of personality traits and psychiatric symptoms within the entrepreneurial sphere. The study deftly linked positive dopaminergic traits—such as openness, extroversion, and conscientiousness—with psychiatric conditions including bipolar disorder, obsessive-compulsive personality disorder (OCPD), attention deficit/hyperactivity disorder (ADHD), and behavioral addiction. Freeman and his colleagues painted a vivid picture, distinguishing between "dopaminergic superpowers" and the more shadowy "dopaminergic vulnerabilities."

The beauty of the dopaminergic perspective lies in its ability to furnish an analytical lens through which we can examine entrepreneurship. At its core, personality traits are etched into the brain's intrinsic functional neural networks, mirroring the interplay between enduring neurobehavioral tendencies and a spectrum of environmental stimuli. Among the Big Five personality traits, openness, extraversion, and conscientiousness stand as dopaminergic hallmarks. The dopaminergic system emerges as a maestro, orchestrating motivation and behaviors conducive to entrepreneurship—sensory and novelty seeking, exploratory actions, opportunity recognition, goal engagement, impulsivity, aggression, creativity, and cognitive prowess.

Dopamine, it appears, is the silent architect behind the scenes, driving the pursuit of reward goals. It sifts through salient information (opportunity recognition) and propels the achievement of goals that yield rewards (value creation), all within the dynamic landscape of entrepreneurial risk-taking.

Freeman et al.'s exploration began with the entrepreneur's "endophenotype" biomarker—dopamine. This intriguing term, rooted in the MeSH knowledge tree, encompasses measurable biological, behavioral, or cognitive markers. From this vantage point, the study illuminated how hyperdopaminergia and variations in dopamine physiology manifest across a spectrum of entrepreneurial traits and mental health syndromes:

  1. Conscientiousness: This trait may intertwine with compulsive behaviors, echoing the patterns seen in OCPD and addiction.
  2. Entrepreneurship addiction: An intriguing phenomenon where individuals find it impossible to resist the siren call of starting new ventures.
  3. Impulsivity and reward sensitivity: These traits are linked to emotional and risky decision-making, fueling the energy, speed, and action-orientation needed for entrepreneurial success.
  4. ADHD and bipolar disorder: Impulsive risk-taking and substance use, common in these conditions, reflect the same impulsivity and reward sensitivity seen in entrepreneurs. The brain's mesolimbic and cortical regions, through individual differences in dopamine processing, regulate the tendency to opt for smaller immediate rewards over larger delayed ones, sometimes leading to reckless mistakes and adverse business outcomes.

In essence, the intricate dance of dopamine within the entrepreneurial mind offers a rich tapestry of insights, revealing the delicate balance between the superpowers that drive success and the vulnerabilities that accompany the journey.

The 11th revision of the World Health Organization's International Classification of Diseases (ICD-11) offers a fascinating window into the world of "dopaminergic fragility." This term encompasses four intriguing conditions—addiction, bipolar disorder, obsessive-compulsive personality disorder (OCPD), and attention deficit/hyperactivity disorder (ADHD).

By utilizing the dopaminergic framework, we uncover a spectrum of traits associated with risk-taking and gain insight into why the admirable qualities of entrepreneurs may sometimes veer into darker territories like hubris, ruthlessness, and deviant behavior. The delicate balance of an entrepreneur’s dopaminergic superpowers and vulnerabilities can herald business success or failure and even personal derailment. Cognizant of this delicate balance, Freeman and his colleagues advocate for core competencies in self-awareness, emotional and behavioral regulation, and self-care (adequate sleep, defecation, and diet) as essential for entrepreneurs.

Neurobiologists have meticulously charted the dopaminergic highs and lows within the entrepreneurial psyche. From studies on endophenotypes—measurable biological markers of internal processes—we observe how abnormal dopamine levels manifest in broad personality traits and mental health syndromes. Compared to typical business managers, entrepreneurs display higher dopaminergic characteristics and psychiatric symptoms on average, a trait that could be linked to the factors driving their risk-taking successes. The hidden potential of dopamine means that while not everyone may fall into the thrall of entrepreneurship, the right environmental triggers and genetic expressions at pivotal moments could make the allure of starting a business irresistible.

The thought of entrepreneurship may not be a mere fleeting fancy, 

but a profound and, sometimes, inescapable call driven by the very chemistry of our brains.

Reference

  • Wikiquote: Entrepreneurs, https://en.wikiquote.org/wiki/Entrepreneurs  
  • Sinha, R. S. (2022). Baby, I'm addicted! The pleasure-pain pathway that shifts entrepreneurial passion to entrepreneurial addiction: Pivotal role of dopamine. Journal of Business Venturing Insights, 18, e00340.
  • MSH:D016520: http://id.nlm.nih.gov/mesh/D016520  
  • Juárez-Varón, D., Zuluaga, J. C. S., & Recuerda, A. M. (2024).Neuroentrepreneurship: state of the art and future lines of work. International Entrepreneurship and Management Journal, 1-15.
  • Freeman, M., Lerner, D., & Rauch, A. (2024). Dopamine and entrepreneurship: Unifying entrepreneur personality traits, psychiatric symptoms, entrepreneurial action and outcomes. Journal of Business Venturing Insights, 21, e00461.
  • International Statistical Classification of Diseases and Related Health Problems,ICD, ICD11: 334423054: http://id.who.int/icd/entity/334423054 (2025-01 version)