Neurotransmitter Lecture Notes PDF

All right, we're ready to get started here. So today's topic is, and actually the rest of the topics from here on out are gonna be focused on neurotransmitter by neurotransmitter by neurotransmitter, okay? So I want you to think about these lectures as being zoomed in to a specific neuron that's usi...

All right, we're ready to get started here. So today's topic is, and actually the rest of the topics from here on out are gonna be focused on neurotransmitter by neurotransmitter by neurotransmitter, okay? So I want you to think about these lectures as being zoomed in to a specific neuron that's using a specific neurotransmitter. We're gonna be talking about how that works and the respective drugs that might modulate this neurotransmitter, okay? So on Monday, we heard about GABA very generally. So what was your takeaway about GABA from Monday in that basal ganglia circuitry? Yeah, it's an inhibitor, fantastic. It is the main inhibitory neurotransmitter, okay? So whether you think of that right now from our diagrams is just a red arrow and a minus. We're gonna be talking about how those GABA signals anywhere in the central nervous system, but a great example of that would be from that basal ganglia circuitry. This, for example, is how the IGP signals to the thalamus. It is a inhibitory signal using GABA as the neurotransmitter. Its effect on the thalamus varies based on just how much signaling is occurring. Back to that idea of a dimmer switch. If the dimmer switch is full blast, we've got a lot of GABA signaling. If the IGP is being repressed, that's gonna be turned down, then we're gonna have very little GABA signaling, which is, in essence, how the thalamus is controlled, okay? I know we had a lot of people at office hours, so keep chugging away at that basal ganglia circuitry. I anticipate diagramming it a lot in office hours, so feel free to stop by or send me questions as you continue to work your way through it. But I wanted to kind of set the stage as to the next few lectures. We're really, we've divided it up by neurotransmitter by neurotransmitter. Today is GABA. Friday, we're actually doing dopamine and serotonin, which means we're gonna be talking a lot more about Parkinson's and Parkinson's treatment, and serotonin, like SSRIs, for example. Then the following Monday, we'll be doing glutamate, which I want you to think is the opposite of GABA. GABA is the inhibitory neurotransmitter. Glutamate is the main excitatory neurotransmitter, okay? All right, so let's go ahead and work through this material together. We've got our learning objectives for today. And then this would be our take-home slide for today. And I picked this one because whether we're talking about how GABA signaling works post-synaptically, or we're talking about barbiturates or benzodiazepines, this one picture shows all of that. So we're gonna be talking a lot about the GABA A receptor, which is visualized here. GABA binds actually in two places to open this receptor and allow chloride to flood in, okay? So we should start to be thinking, okay, we just said GABA is the main inhibitory neurotransmitter. We're talking now about how it's the main inhibitory neurotransmitter. It allows primarily negatively charged ions in the form of chloride into a cell, okay? So that would dramatically affect the resting membrane potential of that cell, right? It's going to what we would call hyperpolarize, right? Move it further away from that resting membrane potential, making a subsequent action potential very challenging. We'll work our way up to talking about how benzodiazepines or benzos for short and barbiturates modulate GABA A signaling to promote this effect, okay? So that generally, I want you to remember that benzodiazepines, barbiturates, and any of the other drugs we talk about today, they're working to depress the central nervous system, okay? All right, so we've mentioned in our introduction lecture to central nervous system, a number of neurotransmitters. Those of you that like structural diagrams, this is your slide, but you'll notice there is no learning objective on this one. I just want to point out the respective neurotransmitters that we'll be talking about. So we're going to be talking today a lot about GABA. We have already mentioned a little bit about dopamine, which we'll get to on Friday, and Friday will also be serotonin, and then the following Monday we'll get to glutamate, which can be seen up here, okay? So they do fall in respective groups. For example, the two main neurotransmitters of the central nervous system fall structurally into the group that's referred to as amino acid neurotransmitters. So what we see here is an example of that, kind of the opposing outcomes of GABA signaling versus glutamate signaling. GABA signaling is going to come from an inhibitory synapse and it's going to generate an IPSP, right? Inhibitory signal, where glutamate or dopamine is going to generate an excitatory response. They are going to do that by modifying the movement of different ions. Just for clarity, if you're looking at the secondary text, notice that we're going to refer to it as GABA, but it comes from a much longer name that we will be using GABA in our discussions today. So the receptors, right? So GABA is coming from a neuron, right? It's gonna be released and it's going to signal on the postsynaptic neuron, okay? So that is where we're talking about when we're looking at these receptors. So notice that for GABA, there's what's considered direct effects and indirect effects, okay? We, in terms of drugs, we are going to be focused on this effect here on the left, okay? And that it's direct effects. But do notice that when GABA is signaling normally and we're causing a lot of chloride to come in to that postsynaptic neuron, there are going to be what we call indirect effects. This is because cells respond to changes in resting membrane potential. And so we have, for example, like leaky potassium channels that will then have what we term indirect effects. So there is going to be some potassium efflux when chloride is coming in, okay? It's nonspecific, it's considered an indirect effect of when GABA is signaling, but it does contribute to this hyperpolarization, because you have a lot of negatively charged ion coming in and you have a significant amount of positively charged ions going out, okay? So which results in that hyperpolarization that I mentioned. For context, I did put glutamate on here. We're gonna have a whole lecture on that, but they are often talked about as opposites and they function and signal in that same way. So notice that when we talked about the direct and the indirect effects, if you're talking about the amount of movement, GABA signaling actually generates a net outward current, okay, that there is so much, so many ions moving out that the net effect is an outward movement. This results in terms of resting membrane potential and what we were calling that hyperpolarizing effect, okay? It's driving the resting membrane potential. If we were looking at it in like a diagram here, right? Where zero is like up here, maybe normally it's at minus 70. If we have GABA signaling occur, that means that resting membrane is going this way. It's getting more negative, okay? Which is why we call it hyperpolarizing. It's gonna be very hard to generate an action potential when that resting membrane potential of a neuron is now minus 90 or minus 120 millivolts if you wanna think about it more in terms of numbers, okay? So in terms of the clinical effects of GABA signaling, we have three primary drug classes that modulate GABA neurotransmission. We're gonna be focused on benzodiazepines, we're gonna shorthand call it benzo is their nickname, and barbiturates. We will get to gabapentin in another section of our course, but just for context sake, gabapentin is a similar mechanism in a very common drug. Compared to glutamate, right? The other, the excitatory neurotransmitter, it's opposing effects, GABA neurotransmission modulation has a lot more clinical effects than glutamate, okay? I want you to remember that because there are more clinical scenarios where we need to depress the central nervous system than needing to enhance the central nervous system, okay? And one of the reasons, if you recall back to when we talked about Huntington's disease and it's an abundance of dopamine, an inappropriate abundance of dopamine, results in what we call exocytotoxicity. Too much excitatory signaling is a bad thing. It can actually cause neuronal death, okay? And so all the drugs we're gonna talk about today, first and foremost, depress the central nervous system, which means they have wide- ranging effects, treating stress, anxiety, insomnia, different types of anesthetics, okay? So we're gonna mention a few examples, but broadly, we want you to know that if we're modulating GABA signaling, it's to enhance GABA neurotransmission, which has an overall effect of depressing that central nervous system, which means we need to be pretty careful with these kind of drugs because depressing the central nervous system can lead to an unconscious state as well. So let me make sure that I started talking about this. I wanna make sure I covered what you have on here. Yep, pretty much. We're depressing the central nervous system that has a wide variety of effects. We're gonna cover the workhorses in terms of this modulating GABA neurotransmission. But prior to getting to modulating it, we need to know a little bit about its metabolism because there are some drugs that affect GABA metabolism. So given what I just mentioned is that most of these drugs that we're gonna talk about, they wanna enhance GABA neurotransmission, these drugs that target GABA metabolism promote its metabolism or they ensure that it doesn't get degraded, okay? So they're gonna try to sweeten the pot, if you will, of the amount of GABA neurotransmitters that are there. So what we need to know from a physiological standpoint is that GABA is synthesized from glutamate, okay? And the only enzyme you'll want you to know in this process is glutamate-glutamic acid decarboxylase, also referred to as GAD, okay? Whether we don't need to know structures, some people understand it better. If you want to look at that, it looks like this. Glutamate is going to, or sorry, GABA is gonna be derived from glutamate via GAD. You already probably started or trained now to look for these inhibitors here. So we'll talk about by GABA trend here in a minute. But then GABA, once it's synthesized, it has to be packaged into a synaptic vesicle, right? Neurotransmitters don't just get made and spilled out of that pre-synaptic cleft, right? They get packaged into a synaptic vesicle. Well, that packaging has, they don't just magically get into a synaptic vesicle. GABA and a number of other neurotransmitters are moved into that synaptic vesicle via a transporter called VGAT. Then once you have an action potential that's coming to the pre-synaptic end of the neuron, you're going to have calcium flood in, you're gonna have that snap-snare complex pull and fuse and allow GABA to be released into the synaptic cleft. And then we have to, of course, terminate GABA signaling under normal conditions, right? So what we're seeing here is the pre- synaptic nerve terminal. Here's our post-synaptic neuron and signaling. And then we have what we like to call the helper cells, the astrocytes, okay? And so in this little ecosystem here, what we're seeing is some of what we just talked about. Glutamate is going to turn, is going to be synthesized into GABA by GAT here. It's gonna be packaged in this synaptic vesicle via VGAT, which is this little transporter right here. You can also see it labeled here, okay? And then when the appropriate signaling occurs, it will diffuse into that synaptic cleft from area of high concentration to low concentration. But we wanna point out a couple players here that are in normal physiology, but then we'll mention how they're affected by a couple drugs. So when GABA is signaling, it can diffuse out of that synaptic cleft. One way it can terminate its signaling is getting taken back up by either an astrocyte or that nerve terminal itself. And so these GAT transporters, they are present on both the astrocytes, those helper cells, or the nerve terminal themselves. They act as like a recycling, if you will, okay? Now notice that if it goes into an astrocyte, it gets converted because there's enzymes there that will convert GABA to glutamate to glutamine. And then via a glutamine transporter, they're going to move that back in to the nerve terminal, okay? So this is all a process of GABA neurotransmission recycling, right? But it's also a way that the signal is going to stop in terms of, it's either gonna bind a receptor, it's gonna get flushed out of the synaptic cleft and oftentimes be recycled by either an astrocyte or the nerve terminal directly. And this is where we encounter one of our first drugs, okay? So this is a drug that is known as an inhibitor of GABA metabolism, okay? So, Tiagabine, I want you to think, is just simply a GABA reuptake inhibitor. This type of mechanism of action is not gonna be novel across the many different kinds of neurotransmitters we're gonna talk about. Has anyone heard of an SSRI selective serotonin reuptake inhibitor? Very common, okay? This is no different than that mechanism, okay? We're just, rather than selectively inhibiting the uptake of serotonin to treat anxiety and depression, we are selectively reducing the uptake of GABA. So that means we now have more GABA available. We're increasing the amount of GABA neurotransmission. You can see in this textbook diagram here that they're gonna, Tiagabine is going to inhibit these reuptake, which just means there's gonna be more GABA here. I mentioned that we're gonna talk about benzodiazepines and barbiturates. Notice that they have a fundamentally different target on the postsynaptic neuron. Right now, we're talking about a reuptake inhibitor, which increases the amount of GABA in the synaptic cleft. This is often given orally, and it has a high level of bioavailability. But as is the case with all of the drugs we're gonna talk about, a risk is high GABA activity, okay? So if we have a lot of GABA neurotransmission, what would you predict to be some of the adverse effects of this drug, as is relevant to all of the classes that we're gonna be talking about? We suddenly increase the amount of GABA signaling, yeah? Drowsiness, sleepiness, that would be more mild type of adverse effect, yep. We're not gonna go all the way into, so for SSRIs, yes, so I don't know if you heard what Neil said, Neil said serotonin syndrome. Serotonin syndrome will be relative to, we will inhibit the reuptake of serotonin. Right now, we are inhibiting the reuptake of GABA. So it goes back to that simple principle that GABA has the ability of depressing the central nervous system. So a generalized, a diverse effect is too much depression of the central nervous system, because now we're increasing the amount of neurotransmission of GABA, okay? All right, Vigabatrin uses a term that we will use, but you can see why it's a slightly insensitive term in the literature, is known as what's called a suicide inhibitor, okay? And this term is used with drugs that bind enzymes and do not, and they cause the degradation, they lead to the degradation of that enzyme, hence that term, suicide. So their duration, sorry, I should say their binding affinity is so strong that it eventually will only dissociate when the enzyme degrades. Yes, good question. So the question is, if we are with a prior drug, so if we go back here, if we are inhibiting gas signaling, you would, you're correct in your thinking that there's gonna be less recycling, but it doesn't necessarily mean, if that was the only supply of GABA, then you might limit the signaling. I think the question was, is there no more GABA made? Okay, which is a great thought process. There is more GABA made, due in part because it's not the sole source of GABA, okay? GABA can be made in each neuron from glutamate. So it just really, it does affect the recycling, but it doesn't have then an abundance effect. Now, when we talk about SSRIs, that'll be slightly different, okay? Because SSRIs can cause a desensitization, which is why if you or anyone you know has been prescribed an SSRI, they tell you that it takes two or three weeks so you see any type of clinical effects, where with our GABA drugs here, there's not a lag in their effects, that when administered, they take effect very quickly. Great discussion here. So back to our Vigabatrin, okay? So different mechanism, but same space, if you will, right? So tigabine here is affecting the amount of GABA in the synaptic cleft. So we are still, we are talking about mechanisms that are on the pre- synaptic terminal, right? Whereas we talk about benzodiazepines and barbiturates, we'll be gonna be talking about that post-synaptic neuron. So simply, Vigabatrin is an inhibitor of the conversion or the breakdown of GABA to succinic semaeldehyde. And so this means that if you're inhibiting GABA-T, you're not permitting GABA to be degraded or changed into an inactive conformation. So this is another albeit different mechanism to ensure that there is more GABA capable of signaling, okay? So that will of course then result in higher concentrations of GABA. This is a treatment commonly used in epilepsy, because you can see epilepsy is where seizures are induced, so it's a high, inappropriately high neuronal activity. So using this as a mechanism to depress that hyper-excitability is why it's used in epilepsy, but it's an ongoing being investigated in other disease states that would benefit from a depression of the central nervous system. And so as we articulated earlier, those adverse effects would be similar. Depressing of the central nervous system could result in confusion, drowsiness, and other symptoms. Now, as we move on to talking about barbiturates and benzodiazepines, we need to talk a little bit more, and this was on our take-home slide, about the receptor that they modulate, okay? So now we're moving to the post-synaptic transmembrane, right? We were talking about the pre-synaptic neuron with those prior two drugs, and now we're moving down to what GABA binds, okay? So we want you to be aware that there are lots of GABA receptors, okay? We are gonna talk only about GABA A, okay? And the reason there are lots of GABA receptors, there's lots of dopamine receptors, there's lots of serotonin receptors, is to confer specific responses, okay? So the GABA receptor that we're gonna be talking about is expressed throughout the central nervous system, and it's the same receptor that's modulated by barbiturates and benzodiazepines. So it's considered ionotrophic GABA receptors, where GABA B is a metabitropic, you see on the left here, we're only highlighting GABA A, okay? So we don't have a picture of GABA B. And in the lower picture, I'm just gonna point out a few things, like benzodiazepines, like barbiturates, and then GABA itself is right here. So those pluses just mean that they are GABA A agonist, okay? They promote the activity of GABA A, but you'll notice there's probably a couple drugs on here that we're not covering that you recognize, like penicillin, you might recognize the diuretic furosemide, that also bind this same receptor and modulate it, although in the, as an antagonist, okay? So this can be challenging when a receptor has a lot of drug targets, this can cause drug effects. And so just to be aware that this receptor has lots of binding sites for both GABA, but also the two main drugs that we're gonna cover. You'll notice though, that none of them bind the same sites of GABA, right? Okay, they have independent sites on GABA A that they are binding. And so when we look at this, so what we're doing here in the lower diagram, if you were to kind of take a cross section here, and then we're looking down this pore, that's what we see here, okay? They have mapped these binding sites because there are different expression patterns, and when you design drugs, you want to bind sites that aren't gonna interact with other drugs or with some of the endogenous physiology. So what I'm gonna point out here is that physiologically, GABA actually binds two spots. So two GABA neurotransmitters bind, when GABA neurotransmission happens, to open this receptor and expose the chloride pore that chloride can then go into this cell, okay? BZD is benzodiazepines, okay? So you can see the distinct site there, and it's different. And on this particular diagram, it doesn't show barbiturates, but you can see that when we compare benzos to barbiturates, they are fundamentally different sites on that receptor. Think again, I got ahead of myself, and now you have these as your study points here. We'll keep going. So as we, to connect back to our prior topics, GABA signaling is going to induce in IPSPs, inhibitory postsynaptic currents, right? And so this needs to be done very quickly with bursts of GABA signaling, right? It starts to get really wild when you start to learn all these steps that are important for your daily functions and to think that they're ongoing in your body, even as you're sitting here maintaining your posture, right? So when we are going to modulate GABA neurotransmission, there is a risk of what's known as desensitization, okay? So when we are modulating and having agents that are agonists of this receptor, there can be a desensitization where increasing the dosage might be warranted to overcome that desensitization. So again, just to remind you that when we have the modulation specifically, so this is your, this is now, we can label this more effective. This is a GABA A receptor here, okay? So when we have barbiturates or benzodiazepines that bind, this is going to make the likelihood of any type of excitatory stimuli very less likely, okay? So think of it as if you're putting GABA and glutamate head to head, it's gonna take an abundance of glutamate to induce any type of signaling, especially if you're combining that, if you have a drug like barbiturates, and that is the mechanism by how GABA neurotransmission is going to cause its effects. So as we mentioned, this has wide ranging effects. All of our GABA A receptor activators are going to treat things like anxiety. They can be used as general anesthesia, sedation, insomnia, control of seizures. It can also be post any type of head trauma. There's lots of uses for these drugs. So there will be a couple instances we're gonna ask you to associate particular drugs with their clinical effects, but appreciate that some of these drugs aren't only used, for example, as sleep aids, okay? They could have other clinical effects. So here's where we have seen this diagram of benzodiazepines and barbiturates. And benzodiazepines and barbiturates have very, very similar clinical usages. Barbiturates came to market first. They are in the highest class of controlled substances. So both of these are technically considered controlled substances. They aren't in different classes. So I want you to think of barbiturates as being the most protected class of controlled substances. It was the first to market. And one reason why it's considered less safe than benzos is because the dosage of which it takes to effectively overdose on barbiturates which is much smaller than benzodiazepines. Benzodiazepines are much safer because the dosage increments that are considered safe are much wider, okay? So when benzos came to market, that's when we saw less use, although barbiturates are still absolutely used, but benzos are far preferred because they have less chance of dependency. And I'm just really excited about this. I keep getting ahead of myself. So what we see here, these are a number of, this PAM here, so a lot of the lambs and PAMs are benzodiazepines as we'll talk about here in a minute. Phenobarbital, that's a barbiturate. You can see that effectively the lethal dose over the effective dose, the benzo is incredibly high because they are very, very safe. It would take effectively a thousand fold greater of a dose for it to be considered lethal. So that's why benzos have now become more in favor than barbiturates because they are arguably safer and more effective. Okay, so let's go back to this diagram and talk in just a little bit more detail about the bottom part, right? Let's remember that there's actually another GABA site here. So for clarity sake, we could add another GABA there, right? So benzodiazepines simply bind and they enhance the influx of chloride, okay? There is gonna be that indirect effect, but in terms of mechanism of action, they modulate and enhance the activity of GABA A, which is going to produce a longer opening of that chloride pore. And there's, you can see here on the left, we're not gonna go over all of these trade names, but I'm sure you've heard of Valium, Xanax, for example, these are all very commonly prescribed benzos. And this can be something that can be used to reduce anxiety. It can also be used as sleep aids and the duration of action will coordinate with the type of insomnia or type of restless sleep that someone exhibits. Classically, they are used to help treat seizures. So anticonvulsants is another very effective use of benzos as well as muscle reluctance. So these have, as we mentioned, wide ranging clinical effects. And another treatment usage would be schizophrenia, which is also a hyperactivity of the central nervous system. So using benzodiazepines to help bring down that hyperactivity can be used. Interestingly, there are forms of depression, which you would think of some forms that that seems counterintuitive, that depression would be aided in using this type of treatment, but depression is wide ranging in symptoms. And so there are some uses of benzos in treating depression. We're gonna talk in a little bit more detail about sleep disorders though, as an example of the clinical use of benzodiazepines. Because not all sleep disorders are the same. It is a huge difference in terms of someone that cannot go to sleep insomnia versus someone that frequently can fall asleep, but then frequently wakes up, okay? And so by utilizing benzos with varying durations of actions, this is how we can treat a variety of sleep disorders while trying to manage that potential, what we call the sedative effect, we can feel effectively like almost a hangover, right? Where we don't want benzos to linger in the system to where someone the next day got really restful sleep, but then they feel so groggy. And so managing that duration of action with the effective, there we go, sorry, should put both, effective amount of time that sleep is needed. So for example, an intermediate acting benzo is temezepam. And you'll notice how conveniently these are known as the PAMs and the LAMs, okay? Think of LAM like going to sleep, right? PAMs and LAMs. And so their duration of action can be associated with their clinical use. So temezepam is considered an intermediate acting agent where trizolalam is more of a short acting. Fluorazepam is very rarely used, but it's an example of a much more long acting benzo. And so let's make this association that temezepam is gonna be for frequent waking, okay? Because its sedative effects are about one to two hours. We wanna help this patient bridge the frequent waking at the beginning of sleep to get them into a restful stage of sleep so that that can be maintained. Where someone that has insomnia is going to have trouble going to sleep, okay? So for someone that experiences insomnia, we actually just need to use more of a short acting sleep aid to get them to sleep, okay? This can be, you have to think through it if you haven't experienced these things yourself. The difference between frequent waking and insomnia are very different. So we use different duration of actions of benzodiazepines. But I want you to understand that this is often used for, this is not long-term therapy for insomnia or frequently waking. Sadly, traumatic events could be warranted where someone would temporarily take benzodiazepines so that they can have some restful sleep after a traumatic event, for example. But it would not be used for someone that has chronic insomnia, okay? So in terms of inducing amnesia, most of you in this room have probably not had an endoscopy. I hear it's rather unpleasant, maybe some of you have. But shorter acting benzos can help with temporary amnesia. So mid-azolam is going to be a very short-acting benzo used to make a patient more comfortable during some procedures. And then specific benzos are used for seizures. For instance, lorazepam, which I've underlined, it's used the most for seizures, and diazepam are often those agents used during a seizure to stop that contracted muscle that often associates with seizures. And again, diazepam is not limited to seizures. Cerebral Palsy, MS, where there can be very painful muscle spasms is a common addition to treatment. And as a class, one of the reasons these drugs work well in the central nervous system is because they're lipophilic. And so they're going to be able to be rapidly absorbed and penetrate the central nervous system, which lots of drugs cannot. And so that is why they have, another reason why they have very wide-ranging clinical effects. So let's move on to barbiturates, okay, which we want you to think of as the former mainstay of treatments that would induce sedation and maintaining sleep. And just a reminder that these are considered the highest class of controlled substances. One of our patient podcasts that's on our page is one of our former students interviewing her brother who had a form of epilepsy that was temporarily on barbiturates. And so he talks about the lived experience of being on a controlled substance and what that is like. But largely, most patients are going to be on benzos rather than barbiturates. The mechanism of action, conveniently, is exactly the same as our benzos. And so they're going to prolong that opening of the chloride channel, albeit in a different binding site. The one thing that in addition it does have is it does also, barbiturates have the ability to block excitatory glutamate receptors, okay? So it does have an additional effect to where glutamate, so you're not only promoting GABA, but you're inhibiting glutamate. So this is why barbiturates are very strong agents. All of which is going to set up a situation where you're depressing neuronal activity because so benzos only affect GABA receptors. Barbiturates affect GABA receptors, but also can have an effect on glutamate, which really makes them really powerful. So similar to benzos, we're going to associate barbiturates with their duration of action. So for example, the ultra short-acting barbiturates like thiopental is something that has a duration of action very, very short, 30 minutes, okay? So this is gonna be a common drug that's associated with anesthetics, which we'll mention in more detail in a minute. Short- acting, so phenobarbital is more on like hours, where long, oh, sorry, I should say pentobarbital is hours, and phenobarbital can be longer than day. So you can imagine there are less clinical examples of phenobarbital than pentobarbital. So for example, thiopental, that very short-acting barbiturate can be used to induce anesthesia. If anyone's had general anesthesia, where they say, hey, count backwards, right? From a hundred, right? Okay, they're giving you at first thiopental, okay, to put you to sleep. Then they're gonna be administering a different anesthetic to maintain that state. Phenobarbital is, because of its duration of action, can be used to help treat as an anticonvulsant. It has to be used very carefully though. So this would, because it depresses the central nervous system in a very strong manner, it's oftentimes ill-advised to be given to children because their central nervous system is proportionately active at a different rate than adults are and can have some cognitive effects on children. And then in terms of their sedative or hypnotic usage, this is going to be more thought of as inducing a, depending on the duration of action, anything from a mild sedative or the intermediate acting can be thought of treating insomnia, right? Where going to sleep is the challenge. So intermediate acting barbiturates would be effective for insomnia. It can be used as a hypnotic to where you are suppressing that REM sleep more than particularly other stages. But these, of course, can have very much adverse effects and have a higher potential for tolerance and their addictive properties than benzodiazepines. So with that, we've covered our content for today, shockingly early. So I will take, if you guys have any questions, I'm happy to hang around. I know we've got a lot of content we've gotten through or feel free to take a break in between classes. I'll stop the recording, but I'm happy to take questions on content for today.