Ligands
What are ligands?
Ligands broadly refer to molecules that bind to larger molecules. In the brain, examples of ligands include neurotransmitters (i.e., neuron-released chemical compounds that cause a transfer of information from one neuron to another neuron or other body structure), hormones (i.e., signaling molecule that affects bodily processes), and peptides (i.e., short chains of amino acids).
Types of Ligands
GABA
Glutamate
There are many different kinds of ligands. Below are a few of the most common.
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Glutamate
Glutamate is an amino acid that acts as a neurotransmitter. In fact, it's our most abundant "excitatory" neurotransmitter, meaning it promotes cell activity. In general, the likelihood that a neuron will fire depends on the relative electrical charge inside vs. outside of the cell wall. When glutamate binds to a receptor, it sends out an excitatory signal, causing the neuron to release an action potential and communicate with another neuron. Glutamate can bind to different kinds of receptors.
GABA
GABA is our major “inhibitory” neurotransmitter (i.e., reduces neuron activity ). The salmon sashimi GABA is in the synapse outside of the neuron. There are also negative ions (i.e., chloride) in the synaptic space. Let’s assume the inside of the neuron is more positively charged than the outside of the neuron at our starting point.The GABA sashimi binds to its receptor on the nigiri ion channel, causing the channel to open. The negative ions rush into the neuron. The inside of the neuron becomes negatively charged. Comparatively, the outside of the neuron is now more positively charged. Neuron activity stops.
Dopamine
Happiness, sleep, learning, addiction, movement, eating, motivation, and pain. How are all of these seemingly different phenomena linked? The neurotransmitter, dopamine!
There are 4 main dopamine pathways with different types of dopamine receptors in each, resulting in this neurotransmitter's wide influence on behavior. All dopamine receptors are GCPRs.
Receptors D1/5 are considered "D1-like" receptors, whereas D2-D4 receptors are considered "D2-like". There are different amounts across the 4 dopamine pathways.
Nigrostriatal pathway - Originates in the substantia nigra. It is heavily involved in movement. Individuals with Parkinson's disease have a loss of dopamine neurons in this pathway, contributing to symptoms like tremors, rigidity, and poor balance.
Mesolimbic pathway - Originates in the ventral tegmental area (VTA) and spreads to subcortical regions like the nucleus accumbens and amygdala. It is involved in reward seeking behaviors, including evaluation of an outcome’s desirability, motivation to do a behavior that will get you a desirable outcome (like praise), motivation to stop doing a behavior that will result in an undesirable outcome (like pain), learning the relationship between the behavior-outcome to guide future actions, and craving of desirable outcomes. Clinically, dysfunction is mostly associated with symptoms of addiction, depression, and schizophrenia.
Mesocortical pathway - Originates in the VTA and spreads to cortical regions, like the medial prefrontal cortex. It has a close association with the mesolimbic pathway, so is involved in similar functions and clinical conditions.
Tuberoinfundibular pathway - Originates in the hypothalamus and projects to the pituitary gland. It is involved in regulation of prolactin, a hormone that controls breast milk production. Dysfunction is related to abnormal breast milk production, headaches, vision problems, and menstrual cycle changes.
Oxytocin
Oxytocin is affectionately nicknamed the "love hormone" and "cuddle chemical" due to its role in social bonding. This ligand is both a neuropeptide (i.e., small protein that acts as a neurotransmitter) and hypothalamic hormone. Oxytocin receptors are GCPRs. Along with oxytocin binding, these receptors require cholesterol and magnesium as allosteric modulators, or substances that indirectly influence the receptor's function.
Several studies in prairie voles have shown that manipulating levels of oxytocin changed male-female bonding/monogamy patterns after mating. Although popularized for being a romantic "love hormone," oxytocin's functions also include stimulation of uterine muscles during child birth, mother-child bonding after a baby is born, and lactation.
Oxytocin might also influence general social abilities in humans. Preliminary research using oxytocin or placebo delivered through nasal spray to kids with autism spectrum disorder suggests that those with oxytocin had a mild advantage in social skills improvement compared to placebo.
When you think of the neurotransmitter serotonin, the words “depression” and “happiness” might come to mind. This association is seen in pop culture thanks to one of the most popular classes of antidepressants, called selective serotonin reuptake inhibitors (SSRIs; e.g., Prozac, Zoloft). But, serotonin isn’t the only neurotransmitter involved in mood regulation; in fact, some scientists argue that pharmaceutical marketing has overstated the potential benefits of SSRIs and understated their potential risks. Further, researchers are still learning about the many functions of serotonin outside of mood regulation.
Serotonin
The chemical composition of serotonin is 5-hydroxytryptamine, highlighting that it is a monoamine neurotransmitter (i.e., contains one amino group) that is a derivative of the amino acid, tryptophan. Tryptophan is supplied in the diet. For example, people in the US might have heard about tryptophan in the context of Thanksgiving turkey and its “causal” role in post-meal sleepiness. This relationship can potentially occur because melatonin (a hormone important for sleep regulation) is also a derivative of tryptophan. There is modest evidence to suggest a link between melatonin and serotonin
production in the sleep problems that many people with depression experience.
Psychiatric conditions are most commonly associated with the serotonergic system, including depression, autism, obsessive-compulsive disorder, and anorexia. In the brain, the main site of serotonin production is thought to be a tiny structure on the brain stem called the raphe nucleus. But, did you know that most serotonin receptors are actually found outside of your brain? These receptors are located in most major organs, like your heart, lungs, bladder, and intestines.
One growing area of research is the link between serotonin and the “brain-gut axis,” or the communication system between your brain/spinal cord and gastrointestinal (GI) tract. Some studies have shown that tiny organisms in your GI tract called “microbiota” can influence how serotonin is made and transmitted along the brain-gut axis. Microbiota include things like bacteria, archaea, and viruses.
Because of the communication system between the brain and the GI tract, there can be a bidirectional relationship in how serotonin made in the GI tract influences psychiatric symptoms (e.g., mood, sleep) and how serotonin made in the brain influences GI symptoms (e.g., pain, constipation, diarrhea). This system might help explain why stress can cause digestive issues, why serotonin-based treatments are prescribed for people with irritable bowel syndrome, and why people taking SSRIs often experience GI side effects.
Outside of the GI tract, serotonin plays a role in cardiovascular function. Specifically, serotonin influences blood pressure regulation. Additionally, serotonin is linked with the pulmonary system (lungs), often associated with a condition called pulmonary arterial hypertension.
Opioids
Like many neurotransmitters and hormones, opioids are both found naturally in our bodies (i.e., “endogenous”) and synthetically in medications – (e.g., morphine and OxyCodone). Opioids are peptides that lock into neuron receptors of the opioid system. To date, it seems like there are 4 main types of opioid receptors and 4-5 main types of endogenous opioids.
Opioids are commonly associated with pain relief and happiness. If you’ve seen the movie Legally Blonde, you might remember the quote “exercise gives you endorphins and endorphins make you happy” (please don’t judge me for this reference). Well, endorphins are actually among endogenous opioids (see image). Legally Blonde wasn’t too far off either; some evidence does suggest that exercise influences how endogenous opioids bind to their receptors. Other behaviors also linked to endogenous opioids include laughter, expecting you will feel better after a treatment
(i.e., the placebo response), and eating.
There are 4 main opioid receptors (see image). Of these receptors, mu-opioids (MORs) are most commonly associated with pain and opioid pain medications. When endogenous or medication-based opioids bind to mu-opioid receptors, other neurotransmitters, hormones, and peptides can get released. Probably the most important to consider in the opioid epidemic is the release of dopamine – a neurotransmitter linked with addiction – after mu-opioid binding. The interaction between opioid and dopamine systems might contribute to opioid addiction.
References
[1] Herman, J. P., Mueller, N. K., & Figueiredo, H. (2004). Role of GABA and glutamate circuitry in hypothalamo‐pituitary‐adrenocortical stress integration. Annals of the New York Academy of Sciences, 1018(1), 35-45.
[2] Jučaitė, A. (2002). Dopaminergic modulation of cerebral activity and cognitive functions. Medicina, 38, 357-362.
[3] Parker, K. J., Garner, J. P., Libove, R. A., Hyde, S. A., Hornbeak, K. B., Carson, D. S., ... & Hardan, A. Y. (2014). Plasma oxytocin concentrations and OXTR polymorphisms predict social impairments in children with and without autism spectrum disorder. Proceedings of the National Academy of Sciences, 111(33), 12258-12263.
[4] Liu, Y., & Wang, Z. X. (2003). Nucleus accumbens oxytocin and dopamine interact to regulate pair bond formation in female prairie voles. Neuroscience, 121(3), 537-544.
[1] Healy D. (2004). Let them eat Prozac: The unhealthy relationship between the pharmaceutical industry and depression. New York: New York University Press
[2] Brody, H. (2017). Patient-Centered Care or Drug-Centered Care: The Influence of Pharmaceutical Marketing on Medical Science and Public Health. In Philosophical Issues in Pharmaceutics (pp. 109-124). Springer, Dordrecht.
[3] Gøtzsche, P. C. (2014). Why I think antidepressants cause more harm than good. The Lancet Psychiatry, 1(2), 104-106.
[4] Peuhkuri, K., Sihvola, N., & Korpela, R. (2012). Diet promotes sleep duration and quality. Nutrition research, 32(5), 309-319.
[5] Dmitrzak-Weglarz, M., & Reszka, E. (2017). Pathophysiology of Depression: Molecular Regulation of Melatonin Homeostasis–Current Status. Neuropsychobiology, 76, 117-129.
[6] Vaswani, M., Linda, F. K., & Ramesh, S. (2003). Role of selective serotonin reuptake inhibitors in psychiatric disorders: a comprehensive review. Progress in neuro-psychopharmacology and biological psychiatry, 27(1), 85-102.
[7] Hornung, J. P. (2003). The human raphe nuclei and the serotonergic system. Journal of chemical neuroanatomy, 26(4), 331-343.
[8] Berger, M., Gray, J. A., & Roth, B. L. (2009). The expanded biology of serotonin. Annual review of medicine, 60, 355-366.
[9] O’mahony, S. M., Clarke, G., Borre, Y. E., Dinan, T. G., & Cryan, J. F. (2015). Serotonin, tryptophan metabolism and the brain-gut-microbiome axis. Behavioural brain research, 277, 32-48.
[10] Watts, S. W., Morrison, S. F., Davis, R. P., & Barman, S. M. (2012). Serotonin and blood pressure regulation. Pharmacological reviews, pr-111.
[11] MacLean, M. R., & Dempsie, Y. (2009). Serotonin and pulmonary hypertension—from bench to bedside?. Current opinion in pharmacology, 9(3), 281-286.
[12] McDonald & Lambert, 2014, Brit J Anaesth
[13] Corder et al., 2018, Ann Rev Neurosci
[14] Árida et al., 2015, J Neurochem
[15] Manninen et al., 2017, J Neurosci
[16] Benedetti & Amanzio, 2013, Pulm Pharm & Ther
[17] Tuulari et al., 2017, J Neurosci
[18] Valentino & Volkow, 2018, Neuropsychopharm
[19] Volkow, 2010, Biol Psychiatry