Benjamin Tangkamolsuk, Quang La, Jack Williams
Medical Community and Research
Tuesday 5th March 2024
Abstract
The world of neurotransmitters in our body is a widely misunderstood and under researched topic that often goes unheard of. Most people just know this topic due to the word “Dopamine”, referring to the neurotransmitter that correlates with motivation, reward and addictive behaviors. This article goes over the truth regarding neurotransmitters and what exactly neurotransmitters do to our body.
Keywords: Neurophysiology, Physiology, Medicine, Health
Article
Introductory Paragraph
The world of neurotransmitters in our body is a widely misunderstood and under researched topic that often goes unheard of. Most people just know this topic due to the word “Dopamine”, referring to the neurotransmitter that correlates with motivation, reward and addictive behaviors. This article will outline things such as the role of serotonin in mood regulation, the role of dopamine on motivation and reward, GABA, Norepinephrine, Oxytocin and Vasopressin, Endorphins and how these neurotransmitters in our body influence our daily lives in various different ways, just to name a few.
Credit: Unsplash
The Impact of Serotonin on Mood Regulation and Its Implications for Mental Health Disorders
Before diving straight into the topic, I think it’s important to be one of the many neurotransmitters in our body. One that is not often talked about is Serotonin. Essentially, Serotonin is a neurotransmitter chemical that carries “messages” between the nerve cells in our nervous system. It’s responsible for things such as our fears, social behaviors and social decision-making. Essentially, it forms who we are as a person, or to put it simply, how we act, forming how others perceive us as us. But what is key about serotonin is that it is crucially important for mood regulation, affecting how we feel.
Because of this, it is involved in a wide range of mental capacities in our bodies such as emotional and impulse control. Therefore, it creates a drastic impact on one’s mental well-being hence linking into mental health. In addition to this, research has shown that low serotonin levels in our body directly correlate depression and anxiety.
In recent case studies, it was also found that individuals actively suffering from mental conditions often had dysfunction with their serotonin levels in the body. Simply by having an imbalance of serotonin in the body, it could cause mental health conditions to manifest and also hinder the severity of the mental condition. Whilst the physiological mechanisms of serotonin are deeply complex and intertwined, an exceeding quantity of research displays that managing serotonin levels in psychiatric patients is an effective and feasible way to manage the conditions of patients. With this, SSRIs, or selective serotonin reuptake inhibitors are often given to patients to help them increase their serotonin activity.
Furthermore, as previously mentioned, Serotonin has a drastic effect on social interaction and social decision making, which could result in interpersonal conflicts and impacts on complex social interactions hindering overall mental health.
Dopamine’s Influence on Motivation, Reward, and Addictive Behaviors
Dopamine is a unique neurotransmitter that modulates motivation, reward, and addictive behaviors among the many neurotransmitters that play an intricate role in brain function. Its complex dance within brain circuitry controls our desire for gratification, influences our choices, and supports our vulnerability to addiction.
Dopamine’s function in motivation — the inner drive that pushes us in the direction of our objectives and desires — lays the foundation for its influence. The mesolimbic pathway is a neuronal network that is made up of dopamine pathways that branch out from the ventral tegmental area (VTA) in the midbrain and project to other parts of the brain, such as the prefrontal cortex and nucleus accumbens. Dopamine release triggers this pathway, which in turn encourages reward-related behaviors and drives us to pursue enjoyable experiences and objectives. Dopamine controls the delicate relationship between effort and reward, influencing our motives and propelling us toward success. This relationship can be triggered by a variety of stimuli, such as the excitement of finishing a difficult activity, the anticipation of a good meal, or the satisfaction of social contact.
Dopamine affects not only motivation but also the reward experience itself. Dopamine neurons in the VTA emit bursts of activity in response to pleasurable stimuli, such as food, sex, or recreational drugs, flooding downstream parts of the brain with dopamine. The brain’s reward system is triggered by this spike in dopamine release, which reinforces the related behaviors and records the event as enjoyable. A crucial part of the brain’s reward system, the nucleus accumbens is essential for processing dopamine impulses and mediating the subjective sensation of pleasure. Dopamine modifies our perceptions and preferences, forming our motivations and propelling our actions in the pursuit of pleasure by registering the hedonic value of stimuli and rewarding activities that result in reward.
Although dopamine’s function in motivation and reward is crucial for adaptive behavior, dysregulation of the neurotransmitter can lead to maladaptive behavioral patterns, such as addiction. Abuse drugs, including cocaine, heroin, and methamphetamine, cause a huge release of dopamine and artificially increase neuronal activity in reward-related regions of the brain by taking over the brain’s reward system. These drugs cause neuroplastic alterations in dopamine pathways with repeated exposure, which modifies the brain’s susceptibility to natural rewards and feeds the cycle of compulsive drug-seeking, yearning, and consumption. Because the brain’s reward system grows more and more insensitive to dopamine surges caused by drugs and less sensitive to natural rewards, this neuroadaptation might eventually result in tolerance, dependence, and addiction. Addictive chemicals undermine dopamine’s regulatory function by taking over the brain’s normal reward circuitry, which results in a pathological pursuit of pleasure and a loss of control over behavior.
To sum up, dopamine plays a crucial part in determining our wants, choices, and behaviors because of its impact on motivation, rewards, and addictive behaviors. Dopamine controls the fine balance between motivation and self-control, defining human behavior and susceptibility to addiction. It does this by promoting our desire for pleasure and inducing maladaptive patterns of addiction. The neuroscience of motivation and addiction can be better understood by examining the complex ways that dopamine influences behavior. This can lead to the development of more potent interventions and treatments for addictive illnesses.
The Role of GABA and Glutamate in Anxiety and Stress Disorders:
GABA and glutamate are important components in the complex web of neurotransmitter communication, and they have a significant impact on how the brain regulates stress and anxiety reactions. Because of these neurotransmitters’ conflicting effects on neuronal excitability, emotional stability and stress tolerance are supported by a careful equilibrium.
Against excessive neuronal activity and encouraging relaxation, GABA, the principal inhibitory neurotransmitter in the central nervous system, calms the brain. GABA receptors, of which there are two main types: GABA-A and GABA-B, are the means by which GABAergic transmission takes place. GABA receptor activation reduces excitatory signals and promotes calm by inhibiting neuronal firing.
This delicate balance can be upset in anxiety and stress disorders by GABAergic system malfunction, which increases excitability and hyperarousal. The etiology of anxiety disorders, including panic disorder, post-traumatic stress disorder (PTSD), and generalized anxiety disorder (GAD), has been linked to decreased GABAergic activity. These circumstances may be developed and maintained in part by altered GABA receptor activity or decreased GABA production, which makes people more vulnerable to the harmful effects of stress- and anxiety-inducing events.
Glutamate is the primary excitatory neurotransmitter in the brain, mediating both synaptic plasticity and rapid synaptic transmission. This is in contrast to GABA. Numerous ionotropic and metabotropic glutamate receptors mediate glutamatergic signaling, with each one having a unique impact on synaptic strength and neuronal excitability.
The delicate balance between excitation and inhibition can be upset by dysregulation of glutamatergic transmission in anxiety and stress disorders, which can lead to hyperarousal and unhelpful stress reactions. Obsessive-compulsive disorder (OCD), social anxiety disorder, and post-traumatic stress disorder (PTSD) have all been linked to the pathophysiology of excessive glutamate release or abnormal glutamate receptor activity. Changes in glutamatergic signaling have the potential to prolong the cycle of anxiety and stress by increasing neuronal excitability, intensifying fear responses, and hindering the erasure of traumatic memories.
GABA and glutamate have complex interactions, whereby each neurotransmitter influences the activity of the other in a reciprocal manner. GABAergic interneurons modulate the balance between excitation and inhibition within brain circuits implicated in anxiety and stress processing by regulating glutamatergic transmission through inhibitory feedback mechanisms.
This delicate equilibrium can be upset by dysfunction in the glutamatergic and GABAergic systems, which can lead to the pathophysiology of anxiety and stress disorders. People who have imbalances in glutamatergic excitement and GABAergic inhibition may be more susceptible to the negative effects of stress, which could lead to maladaptive stress responses and mental health problems.
In summary, GABA and glutamate are essential for controlling the brain’s reactions to stress and anxiety. Anxiety and stress-related diseases might be partly caused by dysregulation of GABAergic inhibition and glutamatergic excitation, which can upset the delicate balance between excitation and inhibition. By comprehending the complex interactions between these neurotransmitter systems, new treatment therapies that target the GABA and glutamate signaling pathways can be developed, providing insights into the physiology of anxiety and stress. Researchers hope to lessen the burden of anxiety and stress-related psychiatric diseases by reestablishing the balance of these vital neurotransmitter systems, fostering emotional resilience and well-being in those who are impacted.
Norepinephrine and Its Contribution to Arousal, Attention, and Emotional Regulation
Before delving into the depths of this discussion, I would like to highlight the significance of another unheard of name amongst neurotransmitters in our body — norepinephrine. Norepinephrine, also known as noradrenaline, is a chemical messenger contributing to various vital functions within our physiological system. Much like serotonin, norepinephrine plays a crucial role in conveying essential “messages” among nerve cells in our nervous system, shaping our responses and behaviors.
A fundamental area where norepinephrine dominates its influence is in the modulation of arousal levels in the brain. This neurotransmitter is instrumental in maintaining wakefulness, alertness, and preparedness to respond to external factors. Considering as it is the central player in regulating arousal, norepinephrine significantly impacts an individual’s responsiveness and readiness for action.
Apart from arousal, norepinephrine’s also extends to the complex topic of attention regulation. The influence of norepinephrine within the human system closely intertwines with the modulation of attention processes, hindering an individual’s ability to focus on specific tasks or stimuli. A key to this process is norepinephrine’s role in maintaining attention over time, enhancing cognitive flexibility, and aiding in adapting to varying environmental demands.
The Interplay of Oxytocin and Vasopressin in Social Attachment and Bonding
Oxytocin and vasopressin are important players in the complex field of social behavior; they direct the establishment and upkeep of social attachment and bonding. These neuropeptides shape our affiliative behaviors and interpersonal relationships through a complex web of connections inside the brain that are based on their complimentary yet unique activities.
The primary function of oxytocin, also known as the “love hormone” or “bonding hormone,” is to aid in childbirth and lactation. But studies conducted in the last few decades have shown how important it is for regulating social behavior and emotional reactions. In response to several social cues, including physical touch, eye contact, and pleasant social interactions, the posterior pituitary gland releases oxytocin into the bloodstream, and is created in the hypothalamus.
From a neurobiological perspective, oxytocin works by attaching itself to oxytocin receptors found all across the brain, especially in areas like the amygdala, prefrontal cortex, and nucleus accumbens that are related to social cognition and emotion control. Oxytocin receptor activation strengthens interpersonal bonds, encourages trust and empathy, and improves prosocial actions. Additionally, oxytocin regulates stress reactions by lowering anxiety in social situations and attenuating the hypothalamic-pituitary-adrenal (HPA) axis’ activity.
Vasopressin has a complementary function in controlling social behaviors linked to aggression, territoriality, and mate bonding, even though oxytocin is frequently linked to maternal behaviors and social bonding. Vasopressin is a hormone produced in the hypothalamus that affects many different physiological and behavioral processes by being released both centrally and peripherally.
Vasopressin has been connected to paternal actions in monogamous animals as well as pair bonding in the context of social attachment and bonding. Vasopressin encourages mate guarding and territorial defense in male rats, but it also helps prairie voles develop pair bonds by acting on vasopressin receptors in the brain’s reward circuitry. Vasopressin plays a key role in forming interpersonal connections, as evidenced by the connection between genetic polymorphisms in the vasopressin receptor gene and variances in social behaviors and relationship quality in humans.
Although vasopressin and oxytocin have different impacts on social behavior, new research indicates that these neuropeptides interact intricately to influence social attachment and bonding. Many brain regions implicated in social behavior have co-expressed oxytocin and vasopressin receptors, which can result in either synergistic or antagonistic interactions between these systems depending on individual differences and contextual circumstances.
For instance, in specific situations, like while providing care for parents or in love relationships, vasopressin and oxytocin may work together to encourage affiliative behaviors and bonding. On the other hand, vasopressin may counteract the benefits of oxytocin in circumstances involving social rivalry or violence, which could result in heightened territoriality or defensive actions.
In conclusion, prosocial behaviors and bonding are facilitated by oxytocin, while aggression and mate bonding are regulated by vasopressin. These two hormones are critical in modulating social attachment and bonding. These neuropeptide systems interact in a complicated and context-dependent manner, profoundly influencing our social interactions and relationships. In addition to improving our understanding of social behavior, more research into the neurobiological processes underpinning oxytocin and vasopressin signaling may pave the way for the creation of innovative treatments that specifically address social deficiencies in mental illnesses.
The Relationship Between Endorphins and Pain Perception, Pleasure, and Addictive Behaviors
Endorphins, sometimes known as the body’s natural analgesics, have a variety of functions, including regulating how painful stimuli are perceived, enhancing pleasure, and affecting addictive behaviors. The brain and peripheral nervous system create these opioid peptides, which are important mediators in the complex interactions between sensory perception, mood, and reward processing.
Strong analgesic effects of endorphins reduce pain perception and encourage pain alleviation. They work by attaching themselves to opioid receptors spread across the central and peripheral nerve systems, preventing pain signals from being transmitted and altering the pathways that the body uses to process pain. Endorphins are naturally released in response to a variety of stimuli, such as physical activity, tension, and pain itself. This function makes them useful for managing pain and reducing stress.
Apart from their function in reducing pain, endorphins also play a part in producing feelings of happiness and exhilaration. Endorphins are released when you do rewarding things like work out, eat, and spend time with people. These activities make you feel happy and fulfilled. The “runner’s high,” for instance, is thought to result from the production of endorphins, which causes a euphoric and calming feeling after extended physical activity. Endorphins encourage people to participate in enjoyable activities by reinforcing survival and well-being-promoting actions by opening up reward pathways in the brain.
It is also possible for the development and maintenance of addictive behaviors to be facilitated by the pleasurable effects of endorphins. Abuse drugs imitate the effects of endorphins and create sensations of reward and happiness by taking over the brain’s endogenous opioid system. Examples of these drugs include cocaine, alcohol, and opioids. Long-term drug use can change endorphin signaling and sustain addictive behaviors by causing neuroadaptations in the brain’s reward system.
Moreover, people may self-medicate to relieve emotional distress or deal with depressive states by engaging in addictive behaviors. The release of endorphins in reaction to addictive substances or behaviors can momentarily lessen psychological distress and give a feeling of relief, which can feed the addiction cycle.
Endorphins and perception of pain, pleasure, and addictive behaviors have a complicated and nuanced interaction. Endogenous opioid system dysregulation can lead to pathological states like substance use disorders or chronic pain problems, even though endorphins are natural mechanisms for reward and pain relief. Furthermore, individual variations in endorphin availability or sensitivity may affect a person’s susceptibility to pleasure, pain, and addictive behaviors. This emphasizes the significance of customized pain management and addiction treatment strategies.
In summary, endorphins are essential for regulating how painful stimuli are perceived, enhancing pleasure, and affecting addictive behaviors. Their inherent pain-relieving properties come from their analgesic actions, and their role in reward processing enhances emotions of joy and wellbeing. Dysregulation of the endogenous opioid system, however, can result in pathological disorders such as addiction and persistent pain. Comprehending the intricate relationship between endorphins and pain, pleasure, and addiction is crucial for creating pain management and addiction treatment programs that work, eventually enhancing health and wellbeing.
Acetylcholine’s Involvement in Cognitive Function, Learning, and Memory
One of the many neurotransmitters in our body is Acetylcholine. Essentially, Acetylcholine is a neurotransmitter chemical that transmits messages between nerve cells in our nervous system. It plays a role in cognitive function, learning, and memory. This means that it has an impact on our abilities to think, learn, and remember things. It’s involved in several mental processes and therefore has effects on overall mental functioning. Additionally, research has shown that acetylcholine may have a role in memory disorders and cognitive decline.
The Impact of Neurotransmitter Imbalance on Mood Disorders such as Depression and Bipolar Disorder
Mood disorders, including bipolar disorder and depression, are intricate, multidimensional illnesses marked by abnormalities in mood stability, emotional control, and cognitive performance. Although the precise cause of these conditions is still unknown, a growing body of research indicates that neurotransmitter imbalance in the brain is a key factor in both their pathophysiology and symptomatology.
Known as the “feel-good” neurotransmitter, serotonin controls mood, hunger, and sleep-wake cycles. Depression’s etiology has been linked to dysregulation of serotonin signaling, which is defined by low serotonin levels or reduced serotonin receptor function. In a similar vein, depression symptoms such as low energy, motivation, and enjoyment have been connected to disturbances in norepinephrine and dopamine neurotransmission.
The recurrent episodes of mania and depression that characterize bipolar disorder are linked to neurotransmitter dysregulation as well, albeit in a more intricate way. Increased arousal, impulsivity, and pleasure are caused by an excess of monoaminergic activity, specifically dopamine and norepinephrine, during manic episodes. On the other hand, decreased monoaminergic activity during depressed episodes is similar to the neurotransmitter imbalances seen in unipolar depression.
In addition to monoamines, changes in glutamate and gamma-aminobutyric acid (GABA) neurotransmitter systems have also been linked to the pathophysiology of bipolar illness. The excitotoxicity and reduced synaptic plasticity associated with dysregulation of glutamatergic neurotransmission may be a factor in the mood swings and cognitive impairment linked to bipolar illness.
Beyond symptomatology, neurotransmitter imbalance affects therapy response and prognosis in mood disorders. The cornerstone of antidepressant therapy continues to be pharmacological interventions that target monoaminergic neurotransmission, such as serotonin-norepinephrine reuptake inhibitors (SNRIs) and selective serotonin reuptake inhibitors (SSRIs). In a similar vein, mood stabilizers for bipolar disorder, such lithium and anticonvulsants, work by regulating neurotransmitter activity.
The fact that different people respond differently to these medications, nevertheless, emphasizes the variety of neurotransmitter dysfunction seen in patients with mood disorders. Furthermore, fresh data points to the possibility that non-monoaminergic neurotransmitter systems, including the glutamatergic and GABAergic systems, may be potential targets for medications intended to treat mood disorders, opening up new possibilities for the creation and improvement of treatment.
In summary, neurotransmitter imbalance is a major factor in the pathophysiology of mood disorders, including bipolar disorder and depression. The onset and maintenance of manic and depressive symptoms are influenced by the dysregulation of monoaminergic, glutamatergic, and GABAergic neurotransmission, which also affects the prognosis and response to treatment. Future studies into the neurobiology of mood disorders and the processes behind neurotransmitter malfunction could lead to the creation of more individualized and successful interventions, which would ultimately improve the lives of those who suffer from these crippling illnesses.
Conclusion
To end it off, it can be concluded from the research that neurotransmitters such as dopamine, acetylcholine and serotonin all have a drastic effect in our mood and behavior, whether if that would be by affecting our social behaviors or our mood control, they all have an effect on our body one way or the other. But it does raise the question, if we are so deeply understood about neurotransmitters, how have we not put innovation and funding into creating a way to artificially create happiness?
MCR Committee: Physiology
Citations
1. Volkow, N. D., & Morales, M. (2015). The brain on drugs: From reward to addiction. Cell, 162(4), 712–725.
2. Berridge, K. C., & Kringelbach, M. L. (2015). Pleasure systems in the brain. Neuron, 86(3), 646–664.
3. Wise, R. A. (2004). Dopamine, learning and motivation. Nature Reviews Neuroscience, 5(6), 483–494.
4. Everitt, B. J., & Robbins, T. W. (2005). Neural systems of reinforcement for drug addiction: From actions to habits to compulsion. Nature Neuroscience, 8(11), 1481–1489.
5. Schultz, W. (2007). Multiple dopamine functions at different time courses. Annual Review of Neuroscience, 30, 259–288.
6. Lüscher, C., & Malenka, R. C. (2011). Drug-evoked synaptic plasticity in addiction: From molecular changes to circuit remodeling. Neuron, 69(4), 650–663.
7. Di Chiara, G., & Imperato, A. (1988). Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proceedings of the National Academy of Sciences, 85(14), 5274–5278.
8. Koob, G. F., & Volkow, N. D. (2010). Neurocircuitry of addiction. Neuropsychopharmacology, 35(1), 217–238.
9. Salamone, J. D., & Correa, M. (2012). The mysterious motivational functions of mesolimbic dopamine. Neuron, 76(3), 470–485.
10. Robinson, T. E., & Berridge, K. C. (2008). The incentive sensitization theory of addiction: Some current issues. Philosophical Transactions of the Royal Society B: Biological Sciences, 363(1507), 3137–3146.
11. Mohler, H. (2012). The GABA system in anxiety and depression and its therapeutic potential. Neuropharmacology, 62(1), 42–53.
12. Sanacora, G., & Saricicek, A. (2007). GABAergic contributions to the pathophysiology of depression and the mechanism of antidepressant action. CNS & Neurological Disorders-Drug Targets (Formerly Current Drug Targets-CNS & Neurological Disorders), 6(2), 127–140.
13. Kalueff, A. V., & Nutt, D. J. (2007). Role of GABA in anxiety and depression. Depression and Anxiety, 24(7), 495–517.
14. Carter, C. S. (2017). Oxytocin and vasopressin: Social neuropeptides with complex neuropsychiatric functions. In P. J. Conn & M. F. Jones (Eds.), Neurobiology of the Parental Brain (pp. 207–226). Academic Press.
15. Insel, T. R., & Young, L. J. (2000). Neuropeptides and the evolution of social behavior. Current Opinion in Neurobiology, 10(6), 784–789.
16. Young, L. J., & Wang, Z. (2004). The neurobiology of pair bonding. Nature Neuroscience, 7(10), 1048–1054.
17. Ross, H. E., & Young, L. J. (2009). Oxytocin and the neural mechanisms regulating social cognition and affiliative behavior. Frontiers in Neuroendocrinology, 30(4), 534–547.
Donaldson, Z. R., & Young, L. J. (2008). Oxytocin, vasopressin, and the neurogenetics of sociality. Science, 322(5903), 900–904.
18. Bartz, J. A., Zaki, J., Bolger, N., & Ochsner, K. N. (2011). Social effects of oxytocin in humans: Context and person matter. Trends in Cognitive Sciences, 15(7), 301–309.
19. Johnson, Z. V., & Young, L. J. (2017). Oxytocin and vasopressin neural networks: Implications for social behavioral diversity and translational neuroscience. Neuroscience & Biobehavioral Reviews, 76, 87–98.
20. Walum, H., & Young, L. J. (2018). The neural mechanisms and circuitry of the pair bond. Nature Reviews Neuroscience, 19(11), 643–654.
21. Landgraf, R., & Neumann, I. D. (2004). Vasopressin and oxytocin release within the brain: A dynamic concept of multiple and variable modes of neuropeptide communication. Frontiers in Neuroendocrinology, 25(3–4), 150–176.
22. Winslow, J. T., & Insel, T. R. (2004). Neuroendocrine basis of social recognition. Current Opinion in Neurobiology, 14(2), 248–253.
23. Bodnar, R. J. (2016). Endogenous opioids and feeding behavior: A 30-year historical perspective. Peptides, 75, 18–70.
24. Boecker, H., Sprenger, T., Spilker, M. E., Henriksen, G., Koppenhoefer, M., Wagner, K. J., … & Tolle, T. R. (2008). The runner’s high: opioidergic mechanisms in the human brain. Cerebral Cortex, 18(11), 2523–2531.
25. Comer, S. D., & Cahill, C. M. (2019). Buprenorphine: A unique drug with complex pharmacology. Current Neuropharmacology, 17(1), 5–22.
26. Koob, G. F., & Volkow, N. D. (2010). Neurocircuitry of addiction. Neuropsychopharmacology, 35(1), 217–238.
27. Ossipov, M. H., & Lai, J. (2003). Opioid receptors, opioid peptides, and the mechanisms of pain control. Clinical Journal of Pain, 19(6), 346–352.
28. Schultz, W. (2016). Dopamine reward prediction error coding. Dialogues in Clinical Neuroscience, 18(1), 23–32.
29. Schulteis, G., Markou, A., Cole, M., & Koob, G. F. (1995). Decreased brain reward produced by ethanol withdrawal. Proceedings of the National Academy of Sciences, 92(13), 5880–5884.
30. Spanagel, R., & Heilig, M. (2005). Addiction and its brain science. Addiction, 100(12), 1813–1822.
31. Taylor, B. K., Westlund, K. N., & Willis, W. D. (1995). Changes in the rostral ventromedial medulla after inflammatory hyperalgesia in the rat. Neuroscience Letters, 186(1), 13–16.
32. Zubieta, J. K., Smith, Y. R., Bueller, J. A., Xu, Y., Kilbourn, M. R., Jewett, D. M., … & Stohler, C. S. (2001). mu-Opioid receptor-mediated antinociceptive responses differ in men and women. The Journal of Neuroscience, 21(14), 999–1005.
33. Salters-Pedneault, K., & Goldman, R. (2023, May 11). Serotonin: What It Is, How to Increase It, and Can You Have Too Much? Verywell Mind. https://www.verywellmind.com/serotonin-what-you-need-to-know-89472