Feeling Good? Your Brain is Releasing Dopamine!
Have you ever wondered why we feel excited after receiving rewards? Or why do we feel the same thrill even before going on a trip? The answer lies in dopamine — a neurotransmitter that drives our motivation and pleasure. Dopamine is a key player in the brain’s reward system, reinforcing motivation rather than creating happiness directly. Natural rewarding stimuli, such as food, drinks, and social interactions, trigger dopamine release, allowing us to experience pleasure. Not only that, but dopamine also creates excitement before receiving a reward, which explains why activities like vacation planning are just as exciting as the experience (Dsouza, Chakraborty, and Veigas, 2020). Interestingly, dopamine is also the same chemical that is released when you take certain drugs, which plays a huge role in addiction as well (Wise and Robble, 2020)! Understanding dopamine’s role in motivation, pleasure, and addiction could help us make better decisions, improve focus, and even break free from unhealthy addictions.
Biosynthesis and metabolism of dopamine
Dopamine is a monoamine catecholamine neurotransmitter. The biosynthesis of dopamine occurs in a series of enzymatic reactions. L-phenylalanine in the liver is converted into L-tyrosine by phenylalanine hydroxylase (PAH). Subsequently, L-tyrosine is hydroxylated into L-DOPA via tyrosine hydroxylase (TH) in the presence of oxygen and Fe2+ cofactors. This reaction occurs in dopaminergic neurons and is the key regulatory step in dopamine production. DOPA decarboxylase (AADC) catalyzes the conversion of L-DOPA into 3,4-dihydroxyphenethylamine, which is known as dopamine, which is then transported into synaptic vesicles for storage and release. Under specific conditions, L-tyrosine can undergo an alternative minor pathway, converted into p-tyramine via aromatic-L-amino acid decarboxylase (AADC), and into dopamine. Dopamine is primarily synthesized in midbrain areas, including the substantia nigra and ventral tegmental area (Zahoor, Shafi, and Haq, 2018).
Once dopamine is released, it binds to dopamine receptors, which are found in different brain regions depending on the receptor class. The dopamine receptor belongs to the seven-transmembrane G protein-coupled receptor (GPCR) family and regulates motivation, emotion, and cognition. Dopamine receptors (D1–D5) are classified into two families based on pharmacologic properties and cAMP regulation (Mishra, Singh, and Shukla, 2018).
D1 and D5 receptors, classified as D1-like receptors, are mainly found in the striatum, nucleus accumbens, olfactory bulb, and substantia nigra. They are essential for regulating the reward system, motivation, and learning. Coupled with G stimulatory sites, they activate adenylyl cyclase, increasing cyclic AMP (cAMP) levels and protein kinase A (PKA) activity, enhancing dopamine signaling and promoting motivation.
In contrast, D2, D3, and D4 receptors, classified as D2-like receptors, are mainly found in the nucleus accumbens, hippocampus, amygdala, and cerebral cortex. They are involved in emotional regulation and cognitive functions. Unlike D1-like receptors, they are coupled to G inhibitory sites and inhibit adenylyl cyclase, reducing cAMP levels and dampening excitatory signaling, which affects emotional responses and stress regulation (Bhatia and Saadabadi, 2023).
Figure 1. Regulation of adenylyl cyclase by D1-like and D2-like dopamine receptors (Tocris Bioscience, 2020)
Once dopamine has triggered its effects on motivation and pleasure, it is taken up by dopaminergic neurons for metabolism. Dopamine undergoes a monoamine oxidase (MAO) pathway to be broken down into 3,4-dihydroxyphenylacetaldehyde (DOPAL) in the presence of FAD cofactor. DOPAL then undergoes inactivation to become 3,4-dihydroxyphenylacetic acid (DOPAC) via aldehyde dehydrogenase (ALDH). Finally, catechol-O-methyl transferase (COMT) catalyzes the conversion of DOPAC to homovanillic acid which is then excreted in the urine. In addition, dopamine could undergo an alternative catechol-O-methyltransferase (COMT) pathway to methylate into 3-Methoxytyramine (3-MT), which is then further metabolized into HVA and finally excreted in urine (Zahoor, Shafi, and Haq, 2018).
Figure 2. Biosynthesis and Degradation of Dopamine Pathways (Zahoor, Shafi, and Haq, 2018).
Dopamine Pathways: Mesolimbic and Mesocortical Pathway
Known as the reward system, the mesolimbic pathway generates pleasure and drives motivation. It projects from the ventral tegmental area (VTA) to the nucleus accumbens (NAcc). When we experience something enjoyable, such as having a good meal, achieving goals, or social interactions, dopamine is triggered to release in the nucleus accumbens. To experience these rewarding feelings again, the nucleus accumbens and dorsal striatum work together to reinforce behaviors—motivating us to work towards earning the rewarding feelings—a process known as incentive-based learning. In addition, the amygdala and hippocampus help associate emotions and memories with pleasurable experiences, helping us to remember and be more likely to seek them again in the future (Lewis et al., 2021).
In addition, the mesolimbic pathway is associated with biological rhythms, meaning that dopamine release can be influenced by sleep cycles and energy levels. However, drugs like cocaine, heroin, and nicotine can hijack the mesolimbic system, overstimulating dopamine release and creating intense artificial pleasure. Consequently, this disrupts the brain’s natural reward system, affecting sleep, mood, and motivation (Lewis et al., 2021).
On the other hand, the mesocortical pathway is involved in motivation and decision-making. It projects from the VTA to the prefrontal cortex, including the orbitofrontal cortex (OFC), ventromedial prefrontal cortex (vmPFC), medial prefrontal cortex (mPFC), and anterior cingulate cortex (ACC). The mesocortical pathway allows us to evaluate whether a reward is worth the effort, thereby influencing our decisions and motivation. It also determines the intensity of pleasure we feel after receiving a reward (Boyle et al., 2023).
Figure 3. Dopamine release in the mesolimbic and mesocortical pathways. Dopamine is released from the ventral tegmental area (VTA) into the nucleus accumbens (mesolimbic pathway) and the prefrontal cortex (mesocortical pathway) (Hedges, 2022).
Nevertheless, more research indicates that the relationship between reward and dopamine release might be more complex. It seems that the anticipated expectation of the reward, rather than the actual reward, is what raises dopamine. A rise in dopamine signaling occurs when a reward is anticipated. Reward learning takes place when the amount of reward exceeds expectations, and dopamine signals and the desire to repeat the behavior as a result. Dopamine signaling and the desire to repeat the behavior both decline if the reward level is lower than anticipated. This explains why, getting higher marks than expected for an exam, boosts our motivation in studying more, whereas when getting lower marks than expected, it makes us feel discouraged and disappointed about studying (Hedges, 2022).
Too much or too little dopamine is a problem.
The use of drugs can hijack the brain’s reward system, flooding it with dopamine and causing intense feelings of artificial pleasure. Over time, natural rewarding stimuli, like food, achievements, and social interactions, no longer feel enough. For instance, cocaine blocks dopamine reuptake into presynaptic VTA terminals whereas heroin and nicotine increase dopamine release from the VTA, creating a prolonged effect of dopamine signaling. Once the brain is used to a strong habit of drug use, there is a reduction in dopamine receptors to lower its sensitivity to the drug that was once pleasurable, increasing drug addicts' behavior to seek drugs as it is not enough for them. Not only that, drug addiction also lowers sensitivity to other non-drug-related rewards. Not only drugs that trigger burst firing, but the cues that predict the drug too. Consequently, drug addicts constantly seek drugs in an attempt to escape negative emotions and regain feelings of pleasure that the brain can no longer naturally produce, losing control over behavior in the long term (Wise and Robble, 2020).
Figure 4. Cocaine inhibits DAT, which stops dopamine from being reabsorbed. The reward circuit is more activated as a result of dopamine's heightened effect on the nucleus accumbens (Hedges, 2022).
Insufficient dopamine can have negative effects on mental health in the same way that excessive dopamine from drug use can cause desensitization and addiction. Patients who are suffering from anhedonia, where individuals cannot feel pleasure, is due to the dysfunctions in the dopamine system and is also a core symptom of major depressive disorder (MDD) (Belujon and Grace, 2017). In severe depression, the body compensates for low dopamine by increasing dopamine receptor numbers and reducing dopamine transporter (DAT) levels to retain dopamine signaling. Research shows that when patients with severe depression receive d-amphetamine, a drug that boosts dopamine, their brain's reward-processing regions show a much stronger response compared to those with mild depression. This suggests that they experience greater dopamine deficiency in their brain’s reward system.
An antidepressant is used to relieve depression symptoms by boosting dopamine transmission. Rather than targeting the dorsal striatum responsible for motor functions, antidepressant has a higher specificity for the ventral striatum that acts on motivation and reward. Antidepressants, such as tricyclic antidepressants (TCA) work by inhibiting the reuptake of dopamine, allowing dopamine to have longer signaling. Others, like monoamine oxidase inhibitors (MAOI), function by inhibiting dopamine from being broken down, extending its effects. The goal is to increase the amount of dopamine or dopamine receptors in the brain to process rewards with higher sensitivity (Dunlop and Nemeroff, 2007).
Lifestyle in boosting dopamine levels naturally
Although excessive gaming, binge-watching, and substance use might seem tempting and temporarily boost dopamine levels, there are many ways to increase dopamine naturally, including exercising regularly and eating dopamine-boosting foods. Regular exercising can increase dopamine levels in the brain and is known to improve mood. Similarly, eating dopamine-boosting foods, such as eggs and beef that have high levels of protein, is important for the production of dopamine, given that tyrosine is the precursor to the biosynthesis of dopamine. Additionally, high levels of saturated fat from butter, animal fat, and more can disrupt dopamine signaling. Thus, it is best to avoid overconsumption! Getting enough sleep and an appropriate amount of sunlight is evidenced to maintain a normal cycle of dopamine release and boost dopamine receptors, respectively. Not to forget—listening to the music you enjoy! (Baptist Health, 2022).
Article prepared by: Tong Jing Ying, MBIOS R&D Associate 24/25
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References
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