Introduction to Neurotransmitters

Welcome to Brain Science, the podcast that explores how recent discoveries in neuroscience are unraveling the mystery of how our brain makes us human. This is episode 210, and I'm your host, Dr. Ginger Campbell. If you're new to brain science, I want to encourage you to jump right in and don't be discouraged if you don't get everything on the first listen. My goal is to make neuroscience accessible to everyone because I strongly believe that understanding how our brain really works is essential to being a citizen in the 21st century. Before I tell you about today's episode, I want to remind you that you can find complete show notes and episode transcripts at brainsciencepodcast.com, and you can send me feedback at [email protected]. I also want to make sure you know that the brain science mobile app is now called Brain Science Podcast. This update fixed the problem of the app crashing. The brain science podcast app is available for all mobile devices and it's a great way to access both free and premium content. You can get episode show notes automatically every month if you just sign up for the free brain science newsletter at eitherbrainsciencepodcast.com or by texting brain science all one word to 55444. That's brain science all one word to 55444. When you sign up, you will get a free gift in type of five things you need to know about your brain. Brain science relies on the financial support of listeners like you. You can learn more about this at brainsciencepodcast.com/premium. This month's episode is a little unusual because for the last 15 years or so, I have focused on interviewing neuroscientists and exploring how their work is important to understanding ourselves and each other. But today I'm reviewing an important but complex topic, neurotransmitters. Even if you've never heard this word before, you've no doubt heard about molecules like dopamine. Unfortunately, most media coverage is superficial and often inaccurate, which is one reason this episode is long overdue. I last talked about neurotransmitters back in episode 8, which was released in 2007. The basic principles remain the same, but the discoveries in this area have really exploded. The main reason I'm devoting this month's episode to neurotransmitters is that next month molecular biologist Seth Grant will be returning for his record sixth time. He is incredibly good at making his work understandable, but I hope this extra background information will be helpful. Obviously, this material is going to be completely new to some of you and just review for others. Please listen all the way to the end of the episode because I will review the key ideas and share a few brief announcements, including an update on my move to New Zealand. Okay, let's jump in to this month's episode. I'm going to start with a few basics. Neurons and glial cells are the key cells of the nervous system. Neurons are distinguished by their ability to generate action potentials, which are all or nothing electrical spikes that spread from neuron to neuron. The outgoing fiber from the neuron is called the axon and the place where the little extensions that receive axon signals are called dendrites. Molecular biology and genomics are revolutionizing our understanding of how the brain works. That's one reason why I enjoy so much talking with Seth Grant, who will be back next month to tell us more about what's going on inside the synapse. Anyway, the human genome project has determined that the human genome only has about 20,000 genes that cope for proteins. This was actually a surprise they were expecting the number to be more like 100,000. The nervous system expresses about 14,000 of these genes, and there are 6,000 proteins that appear to be unique to neurons. The Allen Brain Institute has a term that different brain areas actually express different proteins. That means different genes are turned on, and Seth Grant has determined that gene expression actually changes throughout the lifespan. In fact, it's predictable, like a calendar. One reason molecular biology has become so important in neuroscience is that knowing which genes code for certain proteins allows molecular biologists to tag the proteins in various ways, and they can also study what happens if a normal gene is replaced with one with a mutation. Neurons can be classified in several different ways. Traditionally, they were classified by morphology, which is what they look like under the microscope, but now they are classified by their genetic makeup, and they also are classified by which neurotransmitter they release. It used to be assumed that they could only release one type that's been proven to be false, but they're usually identified by the main neurotransmitter that they release. Now the glial cells actually outnumber the neurons, although the exact ratio is debated. They used to be seen just as scaffolding, but we now know they do much more. They take up important molecules like neurotransmitters. They modulate synaptic transmission. They actually release their own important substances. Oligodendrocytes and swan cells are types of glial cells that actually make myelin, which coats the axon to make transmission faster, and glial cells also appear in the interic nervous system, which I'll talk about shortly. If you want to know more about glial cells, I refer you to episode 169, which is an encore episode with Doug Fields about what glial cells do. I also want to briefly just talk about brain structure starting from front to back. Again, there's more details about this in episode 118, which is an interview with David Bainbridge, author of Zonyls of Zen, a really cool introduction to brain anatomy. Anyway, there's the cortex, which is the covering of the brain. It covers the lobes of the brain known as the frontal, parietal, temporal, and occipital lobes. The temporal lobes, which are on the sides of your heads, like above your ears, they include auditory and all-factory cortex, and then structures in the middle or medial structures like the hippocampus and the amygdala. The amygdala is actually part of the temporal lobe, although it has a sub-cortical structure. What this means is that it has nuclei or clusters of neurons instead of the layering structure of the cortex. There's other lobe called the insular lobe, which people don't usually think about, because it is the only region you can't see from the surface. It's located within the lateral sulcus between the temporal, frontal, and parietal lobes, sort of where they come together. This is where interoception appears to be processed. Association areas are really important, and the parietal cortex is known to have association areas for integrating sensory information. The temporal cortex also has association areas for auditory information and language processing. As we start to move back or down in the brain, we get to the sub-cortical structures. The basal ganglia are very important to voluntary movement, and then there's the brain stem, which is the area below the cortex before you get to the spinal cord. It's essential for basic life functions, like breathing. It consists of the midbrain, which actually contains also the superior colliculus, which is important in visual processing, and then the other structures are called the ponds and the medulla. Tucked underneath the occipital lobe is the cerebellum. Now rather than to get to boggown in basic neural anatomy, I again refer you back to episode 2018, and like I said, the book "Besonials of Zen" is really good, and also Frank M. Thor's book "Neuroscience for Dummies" has a good description of all the basic neuroanatomy ideas. Instead, what I want to do today is to focus on neurotransmitters and the synapse. My goal is to give you background for next month's interview with molecular biologist Seth Grant. One key idea I want to share is that neurons are actually very different than the way they are modeled in the field of artificial intelligence. In a sense, they're hybrid because they have both analogue and digital properties. You could think of the action potential as a digital signal, since it's basically an on/off kind of thing, but at the synapse, there are chemical signals called neurotransmitters that are released, and this is very much an analogue process. When the action potential reaches the synapse, a neurotransmitter is released by the pre-synaptic neuron, then the neurotransmitter interacts with the receptor on the post-synaptic neuron, or if it's the neuromuscular juncture, a receptor on the muscle. One key idea that I'm going to say many times today is that what happens next is determined by the receptor, not by the specific neurotransmitter. This is why modern neuropharmacology is trying to target specific receptors rather than trying to block or mimic the neurotransmitters. To understand how neurotransmitters work, we need to know a little bit about the structure of cell membranes. The cell membrane is the essential barrier between inside the cell and the outside world. This made up of something called a lipid bilayer. Now lipid molecules have two ends. A fatty hydrophobic end, and a so-called hydrophilic polar group that contains phosphate. The key idea here is that the polar head has a slight electrical charge that causes it to be attracted to water while the fatty end repels water. That's why oil and water don't mix. To picture this, just imagine that your fingers are fatty acids, and the knuckles of your hand are the phosphate group. If you point your fingers toward each other, this is the way the fatty acids line up to create the lipid bilayer that surrounds every cell. So this lipid bilayer is embedded with carbohydrates and proteins, with proteins making up more than half of the actual cell membrane. Even proteins create channels that allow ions and other small molecules to go in and out. That's why it's considered a semi-permeable membrane. There are only a very few, very small molecules that can just go through the membrane by simple diffusion. This is gases like oxygen, carbon dioxide, and nitrous oxide, and ethanol. Some of the ion channels allow passive diffusion down a concentration gradient, but most of the movement requires what's called active transport, which means it uses energy in the form of ATP. For example, the sodium potassium pump, which is ubiquitous in all cells, pumps, 3 sodiums out, and 2 potassium in to create a voltage difference that's known as the resting potential of the cell. All the pumps work with a similar method. Some are voltage gated, which means their opener clays based on voltage. The action potential basically changes the voltage inside the cell from negative to positive. For more on this, I refer you back to neuroscience for dummies and also the episode about the spike with marked comfries. That was episode 186, and neuroscience for dummies is 197. So now we're ready to talk about the types of receptors, because the receptors are where the action is. There are two types. One is called ionotropic or ligand gated, and the second is called metabolotropic or g-protein couple. And usually they'll be called, now they're usually called metabolotropic, g-protein couple, altogether. These names are tongue twisters, but the basic difference between them is really pretty straightforward. The ionotropic receptors are actually ion channels that are directly opened and shut and closed by the ligand, which may be the neurotransmitter. The metabolotropic receptors use the so-called second messenger, which means that they initiate a series of intracellular events. Just remember ionotropic means that ion channels are involved, and they act rapidly because it's a direct opening, closing, whereas the second messengers are involved with the metabolotropic receptors, so they act more slowly. Since I first talked about these two types of receptors back in episode 8, much more has been learned. And this includes identifying many different receptors with many different behaviors. Again, I refer you back to neuroscience for dummies for a very basic discussion of this. For example, glutamate is the main excitatory neurotransmitter in the central nervous system, but it actually has its own families of receptors, including the famous NMDA receptor, that Frank Emther and I talked about in episode 197. The NMDA receptor is interesting, both from a clinical and a basic science perspective because it actually requires two molecules of glutamate and two molecules of glycine, because it has an additional voltage channel that is blocked by a magnesium ion. So let's review briefly what happens during an action potential. The resting potential inside the cell is usually around -65 millivolts. The threshold of -55 millivolts opens the sodium channels and the sodium channels Russian and this produces the positive spike. So it's digital because it always looks exactly the same. Later on, the potassium channels open and they say open a while, which this allows the cell to actually get more negative than its resting potential. And that's called the refractory period because there's action potentials not going to happen during the refractory period. So there's a limit to how often any given cell can generate action potential. And the action potentials are propagated along the axon of a neuron. They are not propagated directly between neurons and I'll talk more about this in a minute. So what happens at the synapse? That tiny gap between the axon of a neuron and the dendrite of the post-synaptic neuron? First it's interesting to note that while mammalian cells rely on chemical synapses, the ones that are described in every textbook, invertebrates can also have electrical synapses. And these cura was called a gap junction. They're very rapid, but the post-synaptic response leads to a much smaller signal. So they're not good for long distance communication. In contrast, chemical synapses are slower, but they're more adaptable. They allow the signal to be boosted and even inverted, and they allow for the very important role of second messengers. So two types of chemical transmission occur that are corresponding to the two types of receptors. There's fast direct transmission involving the ionotropic receptors and then there's slow indirect transmission, which is involving the G, couple of proteins and second messengers and this is actually neuro-modulation. Now some neurotransmitters can do both depending on which type of receptor is present. The key idea is that this multiplies the power of the primary neurotransmitters and increases their flexibility. I want to mention at this point, a great book called The War of the Supes and the Sparks, which describes the discovery of the first neurotransmitter that was discovered, which is acetylcholine. And you can get this book on Kindle, I highly recommend it. So let's talk a little bit about the categories of neurotransmitters. Acetylcholine was the first one discovered and acetylcholine is what's known as a mean. Then there are others that are basically small neurotransmitters of different types. Identices what's known as a purine, the mono amines, which I'll talk about more later, which includes histamine, dopamine, serotonin, epinephrine, nor epinephrine, amino acids, glutamate, aspartate, GABA, glycine, and finally, there are neuropeptides. I'm going to talk about these different things as we go a little bit further along, but going back to acetylcholine, the criteria for what constitutes a neurotransmitter is actually based on acetylcholine. So here are the requirements for something to be considered a neurotransmitter. It has to be endogenously produced or present in the presynaptic neuron. When stimulated, the presynaptic neuron must release the chemical, and it must produce a response in the postsynaptic neuron. That response must be mimicked by exogenous application. That means if you add that same molecule to the postynaptic neuron, you should see the same response as you got as if it was stimulated by the presynaptic neuron. And the chemical has to be endogenously removed at the synapse, and you'll understand why that's important in a little while. So if all those requirements are met, then it's considered a conventional neurotransmitter, which is released from vesicles, and the conventional small molecule neurotransmitters are synthesized by enzymes at the presynaptic terminal. And that includes the compounds that I just mentioned. There's also a second group that acts neurotransmitters, which are neuropeptides, and they're a little bit different because they aren't made at the presynaptic terminal. They're made in the cell body, and also they tend to be released actually away from the synapse and have more of a neuromodulatory and slower effect, but I'll talk more about neuropeptides in a few minutes. As I was saying, the criteria for a conventional neurotransmitters based on the behavior of acetyl holy, but in recent years there have been several what they call unconventional neurotransmitters identified. They are considered neuromodulator. They aren't packaged, and vesicles are released by exotytosis. They are synthesized and released during synaptic transmissions, instead of beforehand. And they're oftentimes in response to another neurotransmitter release. They are modulators, and they may even be providing feedback. One of the things that's interesting about them is that they're hydrophobic, so they're able to go right through the cell membrane and interact with proteins inside both the presynaptic and the postynaptic neurons. Examples of these are gases like nitric oxide and carbon monoxide, and lipid metabolites like endocannabinoids, which I'll talk a little bit more about near the end of the episode. So what does cause a neurotransmitter to be released? In a conventional neurotransmitter, the vesicles merge with the cell membrane and release the neurotransmitter into the synapse, which is called exotytosis, and this requires an influx of calcium. But in the end, everything comes down to the neurotransmitter receptors. At least 100 genes have been identified that code for different receptors. The types of receptors, again, are under the same as the membrane types of receptors that are present in all cells, ionotropic, ligand-gated, or neurotransmitter-gated ion channels that have a fast effect, and then metabolitropic, G-protein-coupled ones that are slow, indirect, and neuromodulatory. And most neurotransmitters interact with both types of receptors. So I would do want to talk just briefly about the structure and function of the two types of receptors. The ionotropic receptors are pretty simple. They have a place where the extracellular, what's called the extracellular binding domain, which is where the neurotransmitter binds, and then the transmit and bring ion channel. Now, some ionotropic receptors are more complex, and the NMDA receptor is an example of this. However, the metapotropic G-protein-coupled receptors are much more complex because they use the second messenger, and there's a wide variety of effects that include indirectly opening or closing ion channels, but can go as far as turning genes on and off. One situation where ionotropic receptors actually use a second messenger is they open a calcium channel, and then that calcium comes in and acts as a second messenger. And when this happens, calcium actually can act as a second messenger by regulating a wide variety of proteins, the inflecting cause of the small excitatory signals that are called excitatory post-synaptic potentials. As opposed to when the negative ion chloride comes in, it causes what's called inhibitory post-synaptic potential. I must mention that communication between neurons is not limited to synaptic transmission. There's another kind of transmission called volume transmission, such as when neuromodulators are released into the extercellular speech or the CSF, and so the targets outside the synapse. This was first described in the 1980s because they had noticed that there was a mismatch between where they found the receptors and where neurotransmitters were being released, and the receptors were being found far away from the known release places. Now, volume transmission can involve a conventional neurotransmitter, an unconventional neurotransmitter, or even a neuropeptide. Some examples of things that might have volume transmission, neurohormones, neurotropic factors and immune modulators. Some specific examples, there's something called glutamate, spillover, and the endocannabinoids actually do their neuromodulation via volume transmission. In fact, they seem to bind to presynaptic receptors, but the key idea is that neurotransmitters and neuropeptides can have effects that happen far away from where they were actually released. And I mentioned that calcium influx pushes the cell toward depolarization while chloride ions push it in the opposite direction. So the excitatory and inhibitory postsynaptic potentials are summing up both temporarily and spatially, and so when a threshold is reached then an action potential happens and is transmitted. And also synaptic transmission not fixed, and we'll talk a little bit more about house plasticity happens when we talk with Seth Grant next month. So it turns out that the receptors are more interesting and complex than the neurotransmitters. Most of the so-called conventional neurotransmitters are relatively small molecules that occur even in single cell lifeforms. Outside the context of the nervous system, they have a wide variety of activities. I'm afraid that if I did a detailed description of the main neurotransmitters and neuropeptides, your eyes would start to glaze over, so I'm going to try to provide a high level view and use acetylcoline as examples. Remember that the two types of receptors are ionotropic and metabotropic. I mentioned that it's the receptors that determine what happens. It's also interesting to know that the target neurons may have both types of receptors. And this makes sense if you remember that the ionotropic receptors at quickly well than metabotropic receptors have slower, more varied modulatory actions. Let's talk about acetylcoline in a little bit more detail. And as I mentioned, you want to go to the book, The War of the Soups and the Sparks, to learn more about how this was figured out. If a neuron releases acetylcoline, it's called a colonurgic neuron, and you'll often hear doctors talk about anti-colonurgic side effects, and that is what it's referring to is things that affect the receptors for acetylcoline. There are two types of colonurgic receptors, one called nicotinic and one called muscarinic. These names reflect the fact that they were discovered before there was a distinction appreciated between the ionotropic and metotropic receptors. The nicotinic receptors are ionotropic. They are activated by nicotine, which is a plant alkaloid. There are two types, musculotype and neuronal type, and the neuronal type is the one that is 50 times more sensitive to nicotine. There are all non-selective cation channels permeable to both sodium and potassium. Some antagonists are dexamathorophane, tuba-curine, and toxins from snake venom. Non-selectic orinic receptors are the metabotropic, G-protein-coupled receptors. There are five subtypes. These actually regulate both ion channels and second messenger pathways involving kinases and phosphatases, which are enzymes. So there's a wide variety of downstream effects, some are short-term and some are long-term. They affect everything from membrane potential to gene expression. To agonist, they're activated by muscarine, which is a mushroom toxin. In the peripheral nervous system, the targets of all post-ganglionic parasympic neurons and a few sympathetic neurons have these muscarinic receptors. The targets of all the post-ganglionic parasympathetic neurons and a few sympathetic neurons have acetylcholine receptors. The CNS has a wide spread concentration of receptors. The pre-ganglionic neurons in the spinal cord release acetylcholine at the adrenal medulla, which then releases epinephrine as a hormone, and then the lower motor neurons in the spinal cord release acetylcholine at the neuromuscular junction. The neuromuscular junction is the junction between the lower motor neuron from the spinal cord and the skeletal muscle, and it was the first and best characterized chemical synapse. It's excitatory. When the action potential in the pre-synaptic neuron reaches the axon terminal, it activates the voltage-gated calcium channels and allows calcium to flow in, down its concentration gradient into the cell. It's the calcium that causes the vesicles that contain the acetylcholine to merge with the membrane and release acetylcholine into the synapse. The nicotinic receptor opens sodium channels, which causes a depolarization to about minus 40 millivolts. This travels passively along the muscle, allowing additional voltage-gated sodium channels to open, which eventually triggers the action potential. The action potential allows more calcium to flow in, and this is what triggers the steps that lead to muscle contraction, which is why if you don't have any calcium, you have no muscle contraction. It's also important to know that acetylcholine is broken down by an enzyme called acetylcholine esterate, which is what allows the contraction to end. Reversible anti-colon esterase drugs are actually being used to treat early Alzheimer's disease, but the esterase is also targeted by insecticides and so-called nerve gases like seren gas. This is why organic phosphate poisoning is so dangerous. This acetylcholine has a role throughout the nervous system. It's not surprising that it's been implicated in a wide variety of disorders, including the psychotic symptoms of schizophrenia and Parkinson's disease and the cognitive deficits of dementia. Now I'm not really going to be focusing on these clinical aspects for several reasons. One is that the details get overwhelming pretty quickly, but the main reason is that our understanding of the actual mechanisms involved is very poor and often speculative. For example, the idea that depression or any other mental illness is due to a shortage or excess of one or more neurotransmitters has been disproven long ago, but still hangs around. In fact, even as we've progressed from this primitive idea, why the various drugs work is still very poorly understood? So I prefer to focus on what we do know and I want to emphasize again, it's the receptor that actually determines what happens. One major problem with designing drugs is that even if they're aimed at the receptors, they almost always have unintended side effects. Even a particular type of metapotropic receptor triggers different pathways and some of those might be best left alone. But before I leave acetylcholine, I want to mention two more important roles. So the cholinergic acetylcholine is important in the autonomic nervous system. All the presynaptic neurons are cholinergic. All the postsynaptic parasympathetic neurons are cholinergic. The presynaptic neurons interact with rapid-acting nicotinic receptors. The postsynaptic parasympathetic neurons interact with muscarinic receptors with a wide variety of effects. Additionally, in recent years, the enteric nervous system has been classified as a separate division of the peripheral nervous system. These neurons function autonomously to control the GI tract. The enteric nervous system also uses cholinergic neurons. In addition to our new appreciation for the enteric nervous system, we now also appreciate that cholinergic neurons are important in the brain. The three main areas are the basal forebrain, basal ganglia, and brainstem. But from their projections go everywhere. It appears that a loss of cholinergic neurons projecting to the neocortex and hippocampus are one of the earliest changes of Alzheimer's disease. The spinal cord involves both types of receptors and cholinergic transmission in the CNS is mostly neuromodulatory. So this might be time we could consider the question, why is nicotine so addictive? This has to do with the role of nicotinic receptors in the reward circuits of the brain. The normal role is to encourage people or animals to repeat rewarding behavior like eating. But nicotine also creates a false signal that the activity, such as smoking, is rewarding even when it's not. And this is why most people consider intentionally putting nicotine in products unethical. The tobacco industry has been proven that the tobacco industry suppressed the evidence that nicotine was addictive for many, many years. So I think we now have a little bit of time left to talk about neurotransmitters whose names might be familiar. Feel free to take a break if you want to and come back. One key thing to remember is that all the so-called conventional neurotransmitters are small molecules that are either simple amino acids or derived from a single amino acid. Two important examples that are simple amino acids are glutamate and GABA. Glutamate is the main excitatory neurotransmitter while GABA is the main inhibitory neurotransmitter. Glutamate also appears to be an inhibitory transmitter in the spinal cord, but participates in excitatory functions in the CNS, such as the co-activation of the NMDA receptor. So GABA has both ionotropic and metabolitropic or G-protein-coupled receptors. The ionotropic ones are ligand-gated chloride channels. Remember chloride is negative, so when it enters the cell, it pushes it away from depolarization. That's why GABA is an inhibitory neurotransmitter. So-called GABA agonists, that is, drugs that interact with the GABA receptors include barbitwits, ethanol, benzodiazepines, and drugs like ambient. Drugs like ambient can actually be hallucinatory and I have personally experienced that effect. Now, there are also the GABA-B receptors, which are metabotropic, G-protein-coupled receptors. They seem to be involved in the oscillatory activity of the brain, and their dysregulation is associated with substance abuse, anxiety, and depression. Neurons that make glutamate, release glutamate are called glutaminergic, and they are usually excitatory. They are the most abundant in the brain, so they affect most aspects of brain function. Maint is the main excitory neurotransmitter in the mammalian brain. It has both ionotropic and metabotropic G-protein-coupled receptors. I think it's actually kind of interesting that the NMDA receptors actually ionotropic, even though it's really very complex. It's not just a simple ion channel. Many familiar neurotransmitters are classified as monoamines, and this just means that they contain a single amine group. The so-called catecholamines are derived from the amino acid tyrosine. The pathway is tyrosine to L-dopa, to dopamine, to norepinephrine, to epinephrine. Dopamine is the one that everybody is kind of heard of as the reward neurotransmitter, which is very inaccurate. The dopamine neurons are located in the mid-brain region of the brainstem, in the subtenction migra and the ventral-tagmental area and in the hypothalamus, but they get then projected all over the brain. The subtenction migra is involved in voluntary movement, and it's particularly vulnerable to loss of neurons in Parkinson's disease. Dopamine is involved in at least two reward pathways. But it's important to realize that dopamine is involved in much, much more. Like every other neurotransmitter, its effect depends on which receptor it activates, as well as the location of that receptor. Dopamine has important roles outside the nervous system, and it's released by non-neuronal cells, yet reduces GI motility and protects GI mocosa. It inhabits insulin synthesis in the pancreas, yet increases sodium secretion and urine output in the kidneys. Dopamine has five subtypes of tropic G protein coupled, receptors that are divided into D1, like and D2, like. The D1 type are the mostly postinaptic, they can be excitatory or inhibitory, and they're the most abundant receptor in the human. The D2-like is also located either prior postinaptically, usually inhibitory, and this is the dysregulation of the D2 type that's associated with schizophrenia and bipolar disorders. Then, it has to also be removed, like any other neurotransmitter, and there's disorders that involve deficits in the transport or removal of dopamine, and this can also be targeted by drugs of abuse and by therapeutics. So we go from dopamine, which then can be synthesized to nor epinephrine. The nor epinephrine neurons are located in the brainstem, in three particular brainstem regions, and then they project all over the brain, see the theme here, they're involved in sleep, and dreaming, attention, emotion, cognition, they have similar triggers to the things that trigger the sympathetic nervous system, that is to mobilize the body for action. In the peripherals nervous system, remember that the pre-gangual neurons are going to release acetylcholine, but most of the post-gangalionic sympathetic neurons are going to then release nor epinephrine to the various organ systems leading to the construction of the pupils, regulation of heart rate and blood flow, and also going to the adrenal medulla, which rule then release nor epinephrine and epinephrine. And remember that once these are released, since they're released into the bloodstream, at that point, the nor epinephrine and epinephrine are not acting as neurotransmitters, they're acting as hormones. In the body, they cause basically a constriction-increased heart rate. From the nor epinephrine, you can synthesize the epinephrine, which was originally called adrenaline. Its effects are pretty similar to nor epinephrine, but also include sexual arousal, appetite, and metabolic control. And then again, remember that the sympathetic activity would then lead to both release of both nor epinephrine and epinephrine. The receptors for nor epinephrine and epinephrine were actually discovered before the appreciation of the classification system that I described before, but they're basically metabolropic G-protein-coupled receptors. Then they're common in alpha and beta types. They're expressed in many regions of the brain. The beta-1 dominates in the cortex and the beta-2 receptors in the cerebellum. They have a variety of neuromutulatory effects. I have to mention that when I was in medical school, we learned about beta receptors in the context of blood vessels and airways and neurotransmitters weren't even on our radar. In the periphery, these determine the effects of sympathetic nervous systems such as the alpha receptors, mediate smooth muscle contraction. The beta receptors are mediating part muscle contraction, smooth muscle relaxation, and gluconeogenesis. So drugs that target these systems have a wide variety of applications from heart-related conditions to mental health problems. It's not hard to imagine that they are also affected by drugs of abuse as well as causing unintended side effects. An example of a drug would be a beta-blocker might be used for blood pressure. Now even beta-blockers are used for treatment. Because of all this stuff with the receptors, this is the reason why modern pharmacology is trying to make their drugs more targeted by trying to find the subtypes and then make their drugs more selected by targeting the subtypes. The older drugs tend to be what they call non-selective. So propanol, for example, which was the first beta-blocker, is very non-selective. It's going to block any beta receptor. Now still on the monoamines, we've got serotonin and histamine. Serotonin is another one that you've probably heard about since there's drugs that have serotonin in their name because they're serotonin reuptake inhibitors. Serotonin is synthesized from the amino acid, triptophan, and it's also known as five hydroxy triptamine, 5-H-T. So you'll often see it called 5-H-T instead of serotonin. So it's kind of a trick to remember that they're the same thing. Serotonin arctic neurons are located in nine nuclei in the reticular formation in the brain stem. So lower than some of the other ones we've talked about. And this is not surprising when you consider that it's one of the oldest neurotransmitters from an evolutionary standpoint and it gets projected, these serotonergic neurons from the reticular activating system go all over the brain. It's involved in a wide variety of functions including mood regulation, pain processing, and homeostatic mechanisms like appetite, thermoregulation, energy balance, and just basically the hypothelomic, pituitary, adrenal access. There are seven families of receptors for serotonin and only one of these is ionotropic. The rest are metabotropic, G, protein, coupled receptors and they mediate their effects. Their actions through the release of other neurotransmitters. The one that's an ionotropic one is called 5HT3. It's a nonselective cat time channel that's permeable to sodium, potassium, and calcium. I mention it because it's important. It's localized to these receptors are actually localized to the part of the brain stem that controls nausea and vomiting. And drugs that block this 5HT3 are receptor like Zofran are very important for treating and preventing nausea. These receptors are also located in other parts of the brain and their mutations are associated with bipolar disease, depression, anorexia, and irritable bowel. Some of the other serotonin receptors are associated with functions like memory and blood pressure and control. One of the receptors, the 5HT2R, was first noted as a target for psychedelic drugs like LSD. So you may have heard that serotonin receptors play role in depression since the particular class of drugs is called the serotonin reuptake inhibitors, which means that it targets the uptake, but I again want to emphasize that how these drugs work is not really, and the serotonin receptors also seem to be targeted by drugs of abuse. I want to emphasize several things. First, it's possibly because of its ancient origins, serotonin has a role in a wide variety of body functions related to homeostasis. Interestingly, the highest concentrations of 5HT are actually produced in the GI tract. It also has a role in the cardiovascular system where it may cause phasor constriction or vasodilation depending on the receptor type. This is a very strong demonstration of the principle I've been emphasizing throughout this episode. In the end, everything comes down to the receptors. Life seems to have been using a handful of small molecules since it emerged millions of years ago, and long before nervous systems appear. We have explored this with Seth Grant in the past and we'll explore it further with him next month. Before I talk briefly about neuropeptides and unconventional neurotransmitters, I want to mention histamine because it's another monoamine neurotransmitter that you probably associate with allergic reactions since it has an important role in the immune system, and it's also released in the GI tract. Histamineurgic neurons are located in the posterior hypothalamus and these go to several regions in the cortex. There are four types of metatabletropic G-protein coupled receptors for histamine. H1 receptors increase weightfulness and prevent sleep. The histamine neurons actually stop firing completely during sleep, which is kind of interesting. And so when you get a drowsiness from taking an histamine like a venadryl, it's because of its effects on the HA1 receptor. And the newer histamines that don't make you sleepy are ones that target different histamine receptors and miss this one that does this. Before we finish, I want to spend a few minutes talking about neuropeptides and unconventional neurotransmitters. I mentioned both of these earlier on, but I want to just go back over them briefly. The neuropeptides, what is a neuropeptide? A neuropeptide is just a small peptide, three to about 40 amino acids in length that acts like a neurotransmitter, really more like a neuromodulator. So what we have is in the human genome, we have genes that go for about 90 precursors that can be processed into about 100 neuropeptides. So actually, when you hear that there's hundreds of 100 neurotransmitters, not really true, really the basic conventional neurotransmitters is a pretty small batch, but then we have all these other substances that are neuropeptides. So most neurons are going to make at least one conventional neurotransmitter, say glutamate or GABA, and then one or more neuropeptide, which is going to be a co-transmitter, which modulates the effect of the basic neurotransmitter. So peptides are similar to peptide hormones, well, actually, they're the same exact thing except it's about where they're released. They are the same compound, if it's released in the synapse or extracellular space, be called a neuropeptide. If it's in the bloodstream, it gets called a hormone, okay? An example of this is oxytocin, and I'll give you some more examples in a minute. So how is a neuropeptide different from a neurotransmitter? First of all, it's not synthesized at the synapse. It's synthesized in the cell body and a place called the rough endoplasmic reticulum. And then usually it gets released away from what's called the active zone of the synapse. And very importantly, it does not get recycled back into the presynaptic neuron. And this means that it can wander off and do other things away from where it's released, which is very important. And it can have a more prolonged action. Many of the neuropeptides were originally discovered in the context of regulation of hormone release. And this includes many pituitary hormones. Neuropeptides activate metapotropic G-coupled protein receptors and a usually act as neuromodulators. In fact, they are mostly actinous co-transmitters with conventional, small neurotransmitters. But their effects can include modulation of gene expression. Neuropeptides are distributed throughout the brain, but they've been most extensively studied in the hypothalamus, which is an ancient highly conserved brain structure involved in homeostasis. When we say it's conserved, it means that the human hypothalamus is very similar to that of other mammals and even other vertebrates. So, let's think of some examples of neuropeptides. The most abundant is one you probably haven't heard of. It's called neuropeptide Y. It has made up of 36 amino acids, functions in both the central nervous system and the peripheral nervous system. In the peripheral nervous system, it's produced by sympathetic neurons, along with nor epinephrine, causing vasoconstriction among other effects. It's high levels in the hypothalamus and five different receptors have been identified that will interact with neuropeptide Y. It has many roles including promoted food intake and fat storage. Now, you've probably heard that the brain makes its own opioids. These are also neuropeptides and they appear to be made by a special set of neurons in the hypothalamus and then get distributed throughout the brain. They're often released with other conventional neurotransmitters. Some additional examples of neuropeptides are the hypothalamus, hormones like oxytocin and vasopressin, substance P and glucagon. So you may recognize some of these things as being hormones. So just remember that you can't tell from the name what a polypeptide does since the same molecule will be considered a hormone if it's released into the bloodstream, but act as a neuromodulator if it's released within the nervous system. This is one reason why we are learning that the immune system and the nervous system are highly integrated. If you listened to last month's episode about the entangled brain, you may get a sense of an ongoing theme. Just break the body down into separate systems, but most of these systems interact and this interaction leads to a level of complexity that is not always appreciated either by scientists or laypeople. So what about unconventional neurotransmitters? This means the so-called gastrotransmitters and endocannabinoids. They are not synthesized, stored, or released by presynaptic neurons. That's why they're unconventional. They're actually hydrophobic and they're usually synthesized in response to a conventional neurotransmitter. They actually diffuse directly across the membrane into the target that's inside the cell. In case a unconventional neurotransmitter is not going to have a receptor on the cell membrane like you normally think of. They can go inside. They go into the presynaptic, the postynaptic, or the adjacent neurons. Gases like nitric oxide seem to be made in a regulated manner and have specific functions at the physiological level. Nitric oxide has actually been implicated in plasticity and abnormal nitrous oxide, stagony may have a role in neurodegenerative diseases. Now at least two endogenous endocannabinoids have been identified and then demide and two erected donal glycerol, which is usually called 2AG. These are lipids that are produced by the postynaptic neuron in response to neurotransmitters that increase calcium in flux. So they get released into the estercellular space and then they bind to the cannabinoid receptors. There are two types of metabotropic G-protein coupled receptors that have been identified. The CB-1 in the neural CNS and the CB-2 in the peripheral nervous system. And THC, which comes from cannabis, is also binding to these receptors, which many of you recognize the cannabinoid part of the name. These have shown that the CB-1 receptors at the presynaptic membrane inhibit neurotransmitter release. The CB-2 receptors also have functions in the immune system. Endocannabinoids and THC affect regulation of appetite, eating, sleep, pain relief, motivation and pleasure, and then to mind, and THC can impair memory and adult neogenesis in rodent models. Obviously, there's a need for more research about both endogenous and exogenous cannabinoids. One interesting thing to note is that although the endocannabinoids obviously have a physiologic function, they are not conventional neurotransmitters. There's no such thing as a cannabinoid neuron. Instead, they're released by a neuron along with a conventional neurotransmitter. And since they interact with the metabotropic receptors, their effects are somewhat indirect. On the other hand, as lipids, they can diffuse directly across the cell membrane, and this may account for their rapid action both when used recreationally, and it may also explain why the topical agents seem to be effective. Because in order to get a drug to go transdermally or cross your skin, it needs to be a lipid, or tie to a lipid in some way. Now, I realize that many of you are interested in learning more about cannabinoids, and this has not been a very deep discussion. It may not even be the most up-to-date since I used a textbook for it, unfortunately, as a part of my move, some of my other books on this subject are not accessible to me at this time. But I will look for the opportunity to explore this topic further when I get a well-referenced book on the topic. Before I review some of the key ideas, I just have a few brief announcements. The first one is a special request for those of you who enjoy YouTube. Please subscribe to the Brain Science Podcast YouTube channel, and then actually listen to at least one full episode. This will help me meet the requirements for monetization. I won't make very much, but every little bit helps. I will try to keep my announcements short today, but I do want to remind you that today's show notes include an extensive list of books and previous episodes for those who want to learn more about topics like neuroanatomy and action potentials. Although it's not listed in this month's show notes, I also want to mention that Luis Pisoa's new book, The Entangled Brain, is a great book for both new listeners and even for those of you who were around the last time I talked about neurotransmitters back in 2007. You'll find these show notes in your audio app or at brainsciencepodcast.com. And please do send me feedback at [email protected]. You can also get the show notes for free in the Brain Science mobile app, which is now called Brain Science Podcast. This app is available for all mobile devices and is a great way to access both free and premium content. Now, for an update on my move to New Zealand. I was expecting to be there by the end of May 2023, but it took over six months for the medical council of New Zealand to approve my palliative medicine credentials. That finally happened in June, so I was finally able to apply for my work visa. And I now hope to be in Auckland by mid-August 2023. Unfortunately, that means I had to give away my tickets for the women's world cup. It has been fantastic hearing from listeners for both Australia and New Zealand. Please do reach out to me if you haven't already done so. My email is brain [email protected]. 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So please support the show in whatever way you can, and don't forget to subscribe and listen on YouTube if you can. Obviously, this was a fairly limited discussion of the fascinating topic of neurotransmitters. I started out by discussing some of the basic subprain anatomy and neuron structure, along with a very brief discussion of how an action potential is produced. If you want to learn more about these topics, I highly recommend going to BrainSciencePodcast.com and looking at the show notes, or looking at the show notes in your audio app, presuming that the app preserves the links. The show notes include both books and links to previous episodes on these topics. The meat of this episode was a discussion on neurotransmitters and their receptors. Most neurotransmitters are small molecules that have functions outside the nervous system. If a molecule, histamine, for example, is released into the bloodstream, it functions as a hormone, but it's only considered neurotransmitter if it's released by a neuron and interacts with a specific receptor, usually on a different neuron. The key to the incredible flexibility and diversity of neurotransmitters comes down to the increasing complexity and diversification of their receptors, and we will explore this from an evolutionary perspective next month with Seth Grant. Despite their diversity, the receptors come in two basic types – ionotropic or ligand gated, and the tapotropic G protein coupled. It is easy to remember which is which by remembering that the ionotropic receptors are actually ion channels that are opened and closed when the ligand, that is to say the neurotransmitter, interacts with a receptor protein in the cell membrane. This is a direct effect that can occur fairly quickly on the order of a tenth of a millisecond. In contrast, the tapotropic G protein coupled receptors use one or more second messengers to kick off everything from indirectly opening and closing channels to changing gene expression. And while the actual synaptic transmission is only slowed down to about 0.5 to 3 milliseconds, the actual effects may occur much later, especially in the case of gene regulation. Thus this interaction with these receptors is called neuro-modulation. Obviously, the most basic categorization of neuron activity is to ask whether it is excitatory or inhibitory. This depends on which ion channels are opened or closed. Anything that allows a positive cat time such as sodium to flow into the cell will make it less negative until a threshold is reached and then the action potential fires. In contrast, if negative anions like chloride are allowed to enter the cell becomes more negative and it is inhibited from triggering an action potential. Obviously, any individual nerve on is receiving anywhere from 1000 to 10,000 individual signals on these sum up over time and space and determine whether the neuron depolarizes. Glutamate is the most common excitatory neurotransmitter. It has several ionotropic receptors that are non-selective cat time channels that produce fast excitatory responses. In contrast, GABA binds to an ionotropic receptor that allows the anion chloride to come in, which inhibits the polarization by making the cell more negative. This might give you the impression that there is a one-to-one correspondence between each neurotransmitter and what it does, but this is not true because the tapotropic G-protein coupled receptors are much more diverse than that. And like many neurotransmitters, glutamate interacts with both types of receptors. The monoamine is like histamine, dopamine, noripinipin and epinephrine. They only have metabotropic G-protein coupled receptors. From my reading, it appears that glycine is the only one that has only ionotropic receptors. Depending on your background, you may have found this material either too basic or completely overwhelming. Whatever your background, I want you to focus on a few key ideas. The most important one is that each neurotransmitter has many complex functions that are determined by which receptors that it binds to and where these receptors are located. It is inaccurate to describe any neurotransmission by a single action. For example, do not think of dopamine as the reward molecule because although it is important in the reward circuits of the brain, that's not the only thing that it does. And that really is probably the same message that I communicated way back in episode 8. It's all about the receptors. I mean, it's actually kind of surprising how simple the actual neurotransmitters are. And as we will talk further with the Seth Grant, it's probably because these simple molecules have been having a signaling role since the beginning of life and before the evolution of nervous systems. I hope that this episode has given you a sense of how this works. Feel free to let me know what errors I made as I'm sure I made some. I tried to be accurate, but this is a complex subject and I won't be offended if you, those of you who know more about it than I do, point out if I made a mistake. But I do think that the key idea that the average person needs to know is that the receptors are where the action is. And if you hear somebody tell you that dopamine does this or serotonin does that, you know that that is an oversimplification and might even be totally wrong. This month, I'm going to be talking with Seth Grant some more about the synapse, its evolution, and his more recent discoveries about how diverse synapses really are in terms of which molecules, like the receptors, which ones are actually there is very, very varied. So you'll want to be sure to come back for that next month. In the meantime, I hope you'll check out my other podcasts, Books and Ideas and Grain Bows and send me email at [email protected]. Thanks again for listening. I look forward to talking with you again next month. Brain Science is copyrighted to Virginia Campbell MD. You may copy this episode to share it with others, but for any other uses or derivatives, please contact me at [email protected]. The theme music for brain science is "Mindfire" written and performed by Tony Katratia. You can find his work at syncopationnow.com.