The Role of Serotonin in Psychosis

So the third kind of emerging hypothesis related to psychosis and schizophrenia entails serotonin and its activity. So the serotonin theory of psychosis proposes that there is hyperactivity or at least some imbalance of serotonin particularly at the serotonin 5-2a receptors and as a result it causes psychosis. Now disruption of serotonin functioning which would lead to positive symptoms of psychosis can hypothetically be due to neurodevelopmental abnormalities in schizophrenia neurodegeneration in diseases like parkinson's hallucinations and in order to understand how the hyperactivity of serotonin particularly at the 5-ht2a receptors could lead to these positive symptoms of psychosis in various disorders We'll need to review serotonin and its various receptors and pathways. So serotonin begins also with an amino acid, and it's tryptophan, and it's transported into the brain from the plasma, and it's this precursor for what becomes serotonin. And the way that happens is through two enzymes that convert tryptophan into serotonin. So the first one is tryptophan hydroxylase, which converts tryptophan into 5-hydroxytryptophan, and then there's this aromatic amino acid decarboxylase, or 5-HTP decarboxylase is another way that you'll see that named, and it converts that 5-hydroxytryptophan into what becomes serotonin, so 5-HT. And so after that is synthesized, serotonin is taken up into synaptic vesicles by the vesicular monoamine transporter. or VMAT2 which we've seen before with dopamine and the action of serotonin is terminated when it is broken down and destroyed by the enzyme monoamine oxidase and then it's converted into an inactive metabolite so the serotonin neurons themselves contain monoamine oxidase b but it has a very low affinity for serotonin so really it's only broken down by that enzyme when it is high, when the concentrations of serotonin are high inside that cell. The serotonin neuron also has the presynaptic serotonin transporter pump, and it determinates serotonin's actions by pumping that serotonin that's there in that synaptic clath right back into the nerve where it is then taken up by the VMAT2. transporter and put back into the vesicles to be used later again for neurotransmission. So what is different from dopamine neurons, where some of them don't contain the dopamine transporter, all of the serotonin neurons as far as we know do contain serotonin transporters. And there's functional polymorphisms in the genes that codes for that serotonin transporter. which is a point of interest in research because they would alter the amount of serotonin, the synapse, and might predict which people are less likely to respond, as well as which ones are more likely to have side effects when given drugs that block the serotonin transporter. So we'll talk a bit about the serotonin receptors, and there's quite a few of them. I believe the number now is like 14. There's more than a dozen, I know that. much and at least half of them are known to have clinical relevance and the others were still trying to figure out you'll notice if you're looking at this picture here that there's only a few serotonin receptors that are located on the serotonin neuron itself you've got the 5-ht1a the 5-ht1b d and then the 5-ht2b receptors there and the purpose of the 5-ht receptor on that presynaptic serotonin neuron is to regulate the serotonin firing and how it releases and stores its own serotonin. Now all of the receptors, so that's including the ones that you're finding on the presynaptic neuron, they're also all available and located postsynaptically as serotonin receptors. And so we'll talk a bit more about the differences between the serotonin receptors that are presynaptic and the serotonin receptors that are postsynaptic, and ultimately how postsynaptic serotonin receptors can regulate pretty much every other neurotransmitter through downstream circuitry. So as I said on the previous slide, there's three receptors that are located presynaptically, and this is where serotonin neurons are different than like norepinephrine and dopamine neurons, because On dopamine and norepinephrine, they have neuron, or excuse me, receptors that are located both on their dendrites and soma and on their terminals. But with serotonin, some of the receptors are located on the dendrites and soma, so they're called somatodendritic autoreceptors, and that would be 5-HT1A and 5-HT2B. Those are the ones located on the somatodendrite. areas and then there's the one that's located on the axon terminal and that's serotonin 1bd and depending on where they are located will depend on the action that they have as far as regulating and contributing to serotonin's release so with the serotonin 1a auto receptor it's uh As I said, located on the cell body and the dendrites, which is why we call it a somatodendritic autoreceptor. And whenever serotonin is released somatodendritically and it binds to those 5-HT1A receptors, it causes a shutdown of the serotonin impulse flow. And so you can see in the picture then it reduces or blocks the release of serotonin into that synaptic space. With serotonin 2B, which is also a somatodendritic autoreceptor, whenever serotonin binds to that receptor site, it actually causes an increase in the serotonin impulse flow. And so then you'll see that that increased electricity increases the release of serotonin into the synaptic space. And the serotonin BD receptor is the axon terminal autoreceptor. and its job is to detect the presence of serotonin in that synaptic space and whenever there's a buildup of it and it's enough to bind to that autoreceptor it then shuts down any further serotonin release and acts like a gatekeeper so the bottom line is that of the three presynaptic serotonin receptor sites all three of them regulate serotonin's actions and release, but depending on where they're located and depending on the receptor depends on what action it carries out. So we know that the downregulation and desensitization of presynaptic 5-HT1A receptors is critical to the antidepressant actions of drugs that block serotonin reuptake. And we know that 5-HT2B and 5-HT1A work in opposition to each other. So when you stimulate 5-HT2B receptors, they activate serotonin and they cause more impulse flow and increased serotonin release from that presynaptic nerve terminal, where the 5-HT1A receptors work more in a negative feedback kind of way, where when they are stimulated they inhibit and therefore prevent further downstream release of serotonin. So we know that each neurotransmitter can control its own synthesis and release from presynaptic sites, and each neurotransmitter regulates its own release. What we now know, though, is that each neurotransmitter also controls the actions of the other neurotransmitters, and they do so through their postsynaptic actions on networks and brain circuits. So that makes things really complicated of course. If serotonin, just like dopamine and norepinephrine, can interact with other neurons and the neurotransmitters those neurons release, you know, it's very difficult then to figure out the net effect of a drug that's acting at a receptor if those receptors are all over the place and they do different things at different sites. That's part of what makes psychiatry really complex. But the action that serotonin has once it's released depends not only on what receptor site it's interacting with but also what neuron it's communicating with and the neurotransmitter that that neuron releases so we'll talk about how serotonin can regulate and control the other neurotransmitters via its postsynaptic actions and then explore maybe some of the therapeutic and or side effects potentials that these postsynaptic receptor sites have as far as we know. So as you look at this picture, don't get too overwhelmed by this. I just want you to kind of take note and appreciate the complexity of the serotonin network that's within the brain and look at all the options that serotonin has for it to exert its control. It can either excite or it can inhibit. depending on the serotonin receptor subtype where it's interacting and whether the postsynaptic neuron itself releases the excitatory neurotransmitter glutamate or the inhibitory neurotransmitter gaba and look at all the various areas of the brain that it interacts with depending on which area of the brain it's communicating with and to that's going to influence the other neurotransmitters like norepinephrine with the locus coeruleus and dopamine with the ventral tegmental area and histamine and the tuberoma millery nucleus and acetylcholine in that basal forebrain all these connections that the serotonin network modulates both with itself directly and indirectly influences virtually all other neurotransmitter networks So recall that all of the receptors that are presynaptic as far as serotonin goes can also be located postsynaptically. So when talking about the 5-HT1A receptor that is postsynaptic, it can help promote the release of other neurotransmitters. And 5-HT1A receptors are always inhibitory, but don't confuse that to mean that that always slows things down. because it depends on the post-synaptic neuron that it's inhibiting as far as the downstream effect that it's going to have. So with 5-HT1A receptors, many of them are localized on post-synaptic GABA neurons. So then if you were to inhibit a GABA neuron, you're inhibiting the inhibitor because that's what GABA does. Therefore, the net downstream effect is the lack of inhibition, which means it's excitatory. So that's why, depending on where it's acting, it can inhibit or disinhibit the release of norepinephrine, dopamine, and acetylcholine, which you can see in this picture here. So recall that the 5-HT1A receptors can be located presynaptically and postsynaptically, and they're always inhibitory, and it just depends on their location as to whether or not that translates into a net excitatory or a net inhibitory effect. But 5-HT1A on the postsynaptic receptors can affect the... downstream release of dopamine. And so the agents that we have that partially agonize that receptor therefore have an important role in the side effects and the therapeutic effects that they can have based on that. So 5-HT1A receptors located on descending glutamate neurons that indirectly innervate the nigrostriatal dopamine neurons in the substantia nigra, when you partially agonize those receptors, they will reduce the glutamate output in the substantia nigra, which then would lead to reduced activity of that GABA interneuron and therefore disinhibition of the nigrostriatal dopamine pathway. So what happens with that then is an increase in dopamine release in that motor striatum. which would reduce motor side effects caused by agents that block dopamine to either fully or partially because there's now more dopamine to compete with that D2 binding. 5-HT1A receptors located on pyramidal neurons that indirectly innervate mesocortical dopamine neurons would reduce glutamate output in the ventral tegmental area when partially agonized. So then that would lead to a reduced activity of the GABA interneuron and therefore disinhibition of that mesocortical dopamine pathway. That would lead to an increase in dopamine release there in the prefrontal cortex which would theoretically reduce the cognitive negative and affective symptoms of psychosis. The serotonin 1b receptors are really interesting because they function in an inhibitory manner when they're acting as heteroreceptors on non-serotonin presynaptic nerve terminals. So a heteroreceptor literally means other receptor and this is when you have a receptor for a neurotransmitter other than the one that the neuron uses as its own neurotransmitter. So in these examples you can see in this picture you have norepinephrine neurons, therefore they would generally be using the neurotransmitter norepinephrine, but in these cases they have a serotonin receptor located on their presynaptic nerve terminals. And that receptor would be a heteroreceptor since serotonin is another receptor different from norepinephrine, right? And so whenever serotonin is released upon these non-serotonin presynaptic heteroreceptors, it inhibits the release of that home neurotransmitter. So it would inhibit norepinephrine when. on the serotonin 1b hetero receptor on a norepinephrine neuron. It would inhibit dopamine on a dopamine neuron and so forth. 5HT2A receptors, which are only postsynaptic, are interesting in that they can both promote and inhibit the release of other neurotransmitters. And this receptor is always excitatory But it of course depends on the neuron that it is affecting because it could lead to a net downstream inhibitory effect. So for example, when a 5-HT2A receptor is located on a glutamate neuron, then that excitatory action on that glutamate neuron would lead to more glutamate release, which would then generally trigger more neurotransmitter release. But if it is located on a GABA interneuron that ultimately would innervate glutamate neurons, if you were to excite or stimulate that GABA interneuron, which always functions in an inhibitory role, it's like you're putting the gas on the inhibition. So therefore, it would decrease or inhibit glutamate release, which then would lead to downstream decreased neurotransmission. So it all depends on how it is acting and on which neuron that it's acting as far as whether it's going to inhibit or excite. 5-HT2A receptors regulate downstream dopamine release. Now recall, as we discussed earlier, that 5-HT2A receptors are postsynaptic. and they are excitatory and this would be relevant when we later talk about the treatment of psychosis because it depends on where they are located as far as how they will regulate various neurotransmitters and whether it has an inhibitory or an excitatory downstream effect but there are three separate populations of descending glutamate neurons that 5-ht2a receptors are located on And these neurons either directly or indirectly innervate certain dopamine pathways, which then impact the way that dopamine is released. So one of those descending glutamate neurons is located in such a way that it directly innervates the mesolimbic slash mesostriatal dopamine neurons. And so if you have excessive activity in that pathway, it will lead to the positive symptoms of psychosis because of the increase in downstream dopamine release other 5-ht2a receptors are located in such a way that they indirectly innervate the nigrostriatal dopamine neurons. And they do this via GABA interneurons in the substantia nigra. So if there's excessive stimulation of those receptors, it leads to a reduction in dopamine release in that motor striatum. And so in that case, we would see side effects like drug-induced Parkinsonism. And the third 5-HT2A receptors are located on glutamate neurons that also indirectly innervate the dopamine pathway but this particular pathway is the mesocortical neurons and they do so via a gaba interneuron in the ventral tegmental area so if that's excessively stimulated it leads to a reduction of dopamine in that prefrontal cortex area which would then lead to the manifestation of cognitive dysfunction negative symptoms of schizophrenia, and other emotional symptoms that you see. So just to reiterate what the slide with the picture says, 5-HT2A receptors are located on cortical glutamate pyramidal neurons, and they're stimulated by serotonin, and then release glutamate downstream. These three neurons regulate three distinct dopamine pathways. One of them directly innervates the mesolimbic and mesostriatal pathway, which then mediates the positive symptoms of psychosis. So anything that increases activity there leads to downstream release of dopamine, which would then cause positive symptoms. The second pathway, which is the nigrostriatal pathway, indirectly innervated by these 5-HT2A receptors. Therefore, it would mediate motor side effects. And then the last one innervates the mesocortical pathway indirectly, and it mediates the negative, cognitive, and affective symptoms that you see with psychosis. So the pituitary lactotroph is responsible for the secretion of prolactin in both D2 receptors and 5-HT2A receptors are located on the membranes of these cells. So serotonin and dopamine have reciprocal roles in the regulation of prolactin secretion. Dopamine inhibits prolactin via the stimulation of the D2 receptors, and serotonin promotes promactin release via stimulation of the 5-HT2A receptors. So when dopamine receptors are blocked, by dopamine 2 blockers, then dopamine cannot inhibit prolactin release so the prolactin levels rise. However, in situations where both dopamine 2 is blocked and 5-H2A is blocked, then there is an inhibition of the 5-HT2A receptor so serotonin can no longer stimulate prolactin release. So that then in turn will mitigate the hyperprolactinemia of the D2 blockade. The 5-HT2C receptors are another example of how the location and the type of neuron that it is acting on will really influence whether the end result is an increase or decrease of neurotransmitter release. So generally speaking, 5-HT2C is excitatory. But it's mostly located on GABA interneurons. So remember, GABA interneurons function in an inhibitory role. So if you are exciting the inhibitory GABA, then you are sort of putting the gas on the GABA and increasing that sort of inhibition. So then the ultimate kind of net effect of the 5-HT2C receptors are the inhibition of downstream neurotransmitter release wherever those GABA interneurons are projecting to. So 5-HT3 receptors are located in the chemoreceptor trigger zone which is in the brain stem as well as in the gastrointestinal tract and those receptors can help mediate nausea, vomiting, and other GI kind of side effects. But when they're localized in other parts of the brain, and in particular in the prefrontal cortex, they're primarily located on a specific type of a GABA. interneuron and so kind of like what we saw with 5HT2C, 5HT3 is excitatory, but because it's located on those inhibitory GABA interneurons, the net effect is inhibitory and it has an inhibiting action wherever those GABA interneurons end up going. So in the cortical area, the prefrontal cortex of the brain, 5-ht3 stimulation will decrease or inhibit the release of norepinephrine and acetylcholine whereas if it's located near a glutamate neuron it actually will inhibit the release of serotonin so then in a weird kind of roundabout way serotonin's action at the 5-ht3 receptors will reduce its own And it does so through the way that it acts on glutamate, because glutamate and serotonin regulate each other through this 5-HT3 stimulation. So just like we've seen with 5-HT1A, 5-HT2C, and 5-HT3, 5-HT7 receptors are also excitatory. But since they're frequently located on inhibitory GABA interneurons, they tend to have a net inhibitory effect. wherever it is that these GABA interneurons go. So cortically, the 5-HT7 stimulation will lead to an inhibition of glutamate and an inhibition of serotonin. It inhibits glutamate by basically putting the gas on the GABA inhibition with that GABA neuron connecting to a pyramidal neuron. Whereas with serotonin, it inhibits that release by putting the gas on that GABA neuron that's connected to a serotonin neuron. So then in this kind of weird roundabout way, 5-HT7 also helps regulate serotonin's release. So as the previous slides have revealed, serotonin receptors and their synapses are located really... almost in every area of the brain and throughout the brain. And so connecting these dots between how problems with serotonin can lead to psychosis kind of helps us understand the serotonin hypothesis of psychosis. And that hypothesis states essentially that there's hyper functioning of serotonin receptors and it's specifically caused by an imbalance in the excitatory 5-HT2A receptor. on glutamate pyramidal neurons and those glutamate neurons are directly innervating the ventral tegmental area as well as the mesostriatal hub which are connected to dopamine neurons and the visual cortex neurons so we know this to be true based on the effects of hallucinogen substances like LSD mescaline and psilocybin All of those work by agonizing 5-HT2A. So by agonizing those sites, they induce symptoms very similar to what we see in schizophrenia and psychosis, like with dissociative experiences and visual hallucinations. And all of that's because of that overstimulation of the 5-HT receptors in that prefrontal cortex and the visual cortex. and we know that if we block those 5-ht2a receptors with antagonist agents the hallucinogen experience by that 5-ht2a stimulation is mitigated so that's one way that we know that there's a correlation there but we also know that in individuals with parkinson's that a lot of the psychotic symptoms that happens in these patients particularly later on in the disease is caused not only by a loss of the dopamine nerve terminals that they have in that motor part of the nigrostriatal pathway but they also have a loss of serotonin nerve terminals in that prefrontal and visual cortex so as the next slide will show there's a bit of a difference between how the psychotic symptoms are manifesting in their relation to 5-ht2a receptors compared to like what happens when there's drugs of abuse involved So with Parkinson's disease, the loss of serotonin and the serotonin nerve terminals causes an upregulation and therefore too many 5-HT receptors to be produced in the cortex. And the reason that happens is it's this effort, it's a futile effort, to try to overcome the serotonin loss that's happening as a result of the disease. So with there being this excessive amount of 5-HT2A receptors, it creates this imbalance in the excitatory actions that those receptors have on the glutamate dendrites from what's left of the serotonin in that cortex and that leads to kind of the similar manifestation that you would see if there was substance induced psychotic symptoms so similarly we know that drugs that antagonize or block the 5-ht2a receptor can actually help manage the symptoms of parkinson's disease related psychosis and nicely they don't exacerbate some of the motor symptoms like we see with the dopamine blocking psychotic drugs so then lastly we have dementia related psychosis and it is also linked to serotonin hyperfunctioning but it too as you see on the next slide is different from parkinson's and even substance induced uh psychotic symptoms that we see and how that's related to 5-HT2A receptors. So with dementia and dementia-related psychosis, there doesn't appear to be this upregulation of 5-HT2A receptors like you would see in Parkinson's-related psychosis. So there's a difference in kind of like the pathophysiology here. Instead, what we believe is happening is because of the accumulation of either the plaques or the tangles or like with Lewy body's dementia, that the presence of those Lewy bodies or in a stroke just the damage that happens because of that whatever the mechanism it knocks out the cortical neurons and leads to this lack of inhibition of the surviving glutamate neurons so if you don't have enough of those in GABA inhibition neurons to counteract the normal 5-ht 2a stimulation that's going to occur with what's left of the glutamate neurons that project to the ventral tegmental area and the mesostriatum and the visual cortex it's going to cause an excess in that stimulation and therefore lead to psychosis in these dementia related patients and it is now known then that if we can selectively balk 5ht2a it can reduce those symptoms of dementia and some of those behavioral problems that we see in patients with psychosis related to dementia so to wrap all of this up succinctly what have we learned but we've learned that serotonin does not only regulate its own release and it does that through presynaptic serotonin receptor actions but it also regulates all the other major neurotransmitters and this is largely through the postsynaptic receptor actions. And serotonin hyperactivity or an imbalance of serotonin specifically at 5-HT2A receptors on glutamate neurons in the cerebral cortex is linked to psychosis. And the 5-HT2A receptor actions, in addition to the NMDA receptor actions, it hypothetically leads to hyperactive dopamine activity in downstream mesolimbic pathways. which helps connect the dots between the positive and eventually the negative symptoms that are associated with psychosis and schizophrenia.

So serotonin begins also with an amino acid, and it's tryptophan, and it's transported into the brain from the plasma, and it's this precursor for what becomes serotonin. And the way that happens is through two enzymes that convert tryptophan into serotonin. So the first one is tryptophan hydroxylase, which converts tryptophan into 5-hydroxytryptophan, and then there's this aromatic amino acid decarboxylase, or 5-HTP decarboxylase is another way that you'll see that named, and it converts that 5-hydroxytryptophan into what becomes serotonin, so 5-HT.

And so after that is synthesized, serotonin is taken up into synaptic vesicles by the vesicular monoamine transporter. or VMAT2 which we've seen before with dopamine and the action of serotonin is terminated when it is broken down and destroyed by the enzyme monoamine oxidase and then it's converted into an inactive metabolite so the serotonin neurons themselves contain monoamine oxidase b but it has a very low affinity for serotonin so really it's only broken down by that enzyme when it is high, when the concentrations of serotonin are high inside that cell. The serotonin neuron also has the presynaptic serotonin transporter pump, and it determinates serotonin's actions by pumping that serotonin that's there in that synaptic clath right back into the nerve where it is then taken up by the VMAT2.

transporter and put back into the vesicles to be used later again for neurotransmission. So what is different from dopamine neurons, where some of them don't contain the dopamine transporter, all of the serotonin neurons as far as we know do contain serotonin transporters. And there's functional polymorphisms in the genes that codes for that serotonin transporter.

which is a point of interest in research because they would alter the amount of serotonin, the synapse, and might predict which people are less likely to respond, as well as which ones are more likely to have side effects when given drugs that block the serotonin transporter. So we'll talk a bit about the serotonin receptors, and there's quite a few of them. I believe the number now is like 14. There's more than a dozen, I know that. much and at least half of them are known to have clinical relevance and the others were still trying to figure out you'll notice if you're looking at this picture here that there's only a few serotonin receptors that are located on the serotonin neuron itself you've got the 5-ht1a the 5-ht1b d and then the 5-ht2b receptors there and the purpose of the 5-ht receptor on that presynaptic serotonin neuron is to regulate the serotonin firing and how it releases and stores its own serotonin. Now all of the receptors, so that's including the ones that you're finding on the presynaptic neuron, they're also all available and located postsynaptically as serotonin receptors.

And so we'll talk a bit more about the differences between the serotonin receptors that are presynaptic and the serotonin receptors that are postsynaptic, and ultimately how postsynaptic serotonin receptors can regulate pretty much every other neurotransmitter through downstream circuitry. So as I said on the previous slide, there's three receptors that are located presynaptically, and this is where serotonin neurons are different than like norepinephrine and dopamine neurons, because On dopamine and norepinephrine, they have neuron, or excuse me, receptors that are located both on their dendrites and soma and on their terminals. But with serotonin, some of the receptors are located on the dendrites and soma, so they're called somatodendritic autoreceptors, and that would be 5-HT1A and 5-HT2B.

Those are the ones located on the somatodendrite. areas and then there's the one that's located on the axon terminal and that's serotonin 1bd and depending on where they are located will depend on the action that they have as far as regulating and contributing to serotonin's release so with the serotonin 1a auto receptor it's uh As I said, located on the cell body and the dendrites, which is why we call it a somatodendritic autoreceptor. And whenever serotonin is released somatodendritically and it binds to those 5-HT1A receptors, it causes a shutdown of the serotonin impulse flow. And so you can see in the picture then it reduces or blocks the release of serotonin into that synaptic space.

With serotonin 2B, which is also a somatodendritic autoreceptor, whenever serotonin binds to that receptor site, it actually causes an increase in the serotonin impulse flow. And so then you'll see that that increased electricity increases the release of serotonin into the synaptic space. And the serotonin BD receptor is the axon terminal autoreceptor.

and its job is to detect the presence of serotonin in that synaptic space and whenever there's a buildup of it and it's enough to bind to that autoreceptor it then shuts down any further serotonin release and acts like a gatekeeper so the bottom line is that of the three presynaptic serotonin receptor sites all three of them regulate serotonin's actions and release, but depending on where they're located and depending on the receptor depends on what action it carries out. So we know that the downregulation and desensitization of presynaptic 5-HT1A receptors is critical to the antidepressant actions of drugs that block serotonin reuptake. And we know that 5-HT2B and 5-HT1A work in opposition to each other. So when you stimulate 5-HT2B receptors, they activate serotonin and they cause more impulse flow and increased serotonin release from that presynaptic nerve terminal, where the 5-HT1A receptors work more in a negative feedback kind of way, where when they are stimulated they inhibit and therefore prevent further downstream release of serotonin.

So we know that each neurotransmitter can control its own synthesis and release from presynaptic sites, and each neurotransmitter regulates its own release. What we now know, though, is that each neurotransmitter also controls the actions of the other neurotransmitters, and they do so through their postsynaptic actions on networks and brain circuits. So that makes things really complicated of course. If serotonin, just like dopamine and norepinephrine, can interact with other neurons and the neurotransmitters those neurons release, you know, it's very difficult then to figure out the net effect of a drug that's acting at a receptor if those receptors are all over the place and they do different things at different sites. That's part of what makes psychiatry really complex.

But the action that serotonin has once it's released depends not only on what receptor site it's interacting with but also what neuron it's communicating with and the neurotransmitter that that neuron releases so we'll talk about how serotonin can regulate and control the other neurotransmitters via its postsynaptic actions and then explore maybe some of the therapeutic and or side effects potentials that these postsynaptic receptor sites have as far as we know. So as you look at this picture, don't get too overwhelmed by this. I just want you to kind of take note and appreciate the complexity of the serotonin network that's within the brain and look at all the options that serotonin has for it to exert its control.

It can either excite or it can inhibit. depending on the serotonin receptor subtype where it's interacting and whether the postsynaptic neuron itself releases the excitatory neurotransmitter glutamate or the inhibitory neurotransmitter gaba and look at all the various areas of the brain that it interacts with depending on which area of the brain it's communicating with and to that's going to influence the other neurotransmitters like norepinephrine with the locus coeruleus and dopamine with the ventral tegmental area and histamine and the tuberoma millery nucleus and acetylcholine in that basal forebrain all these connections that the serotonin network modulates both with itself directly and indirectly influences virtually all other neurotransmitter networks So recall that all of the receptors that are presynaptic as far as serotonin goes can also be located postsynaptically. So when talking about the 5-HT1A receptor that is postsynaptic, it can help promote the release of other neurotransmitters.

And 5-HT1A receptors are always inhibitory, but don't confuse that to mean that that always slows things down. because it depends on the post-synaptic neuron that it's inhibiting as far as the downstream effect that it's going to have. So with 5-HT1A receptors, many of them are localized on post-synaptic GABA neurons.

So then if you were to inhibit a GABA neuron, you're inhibiting the inhibitor because that's what GABA does. Therefore, the net downstream effect is the lack of inhibition, which means it's excitatory. So that's why, depending on where it's acting, it can inhibit or disinhibit the release of norepinephrine, dopamine, and acetylcholine, which you can see in this picture here.

So recall that the 5-HT1A receptors can be located presynaptically and postsynaptically, and they're always inhibitory, and it just depends on their location as to whether or not that translates into a net excitatory or a net inhibitory effect. But 5-HT1A on the postsynaptic receptors can affect the... downstream release of dopamine.

And so the agents that we have that partially agonize that receptor therefore have an important role in the side effects and the therapeutic effects that they can have based on that. So 5-HT1A receptors located on descending glutamate neurons that indirectly innervate the nigrostriatal dopamine neurons in the substantia nigra, when you partially agonize those receptors, they will reduce the glutamate output in the substantia nigra, which then would lead to reduced activity of that GABA interneuron and therefore disinhibition of the nigrostriatal dopamine pathway. So what happens with that then is an increase in dopamine release in that motor striatum. which would reduce motor side effects caused by agents that block dopamine to either fully or partially because there's now more dopamine to compete with that D2 binding. 5-HT1A receptors located on pyramidal neurons that indirectly innervate mesocortical dopamine neurons would reduce glutamate output in the ventral tegmental area when partially agonized.

So then that would lead to a reduced activity of the GABA interneuron and therefore disinhibition of that mesocortical dopamine pathway. That would lead to an increase in dopamine release there in the prefrontal cortex which would theoretically reduce the cognitive negative and affective symptoms of psychosis. The serotonin 1b receptors are really interesting because they function in an inhibitory manner when they're acting as heteroreceptors on non-serotonin presynaptic nerve terminals. So a heteroreceptor literally means other receptor and this is when you have a receptor for a neurotransmitter other than the one that the neuron uses as its own neurotransmitter. So in these examples you can see in this picture you have norepinephrine neurons, therefore they would generally be using the neurotransmitter norepinephrine, but in these cases they have a serotonin receptor located on their presynaptic nerve terminals.

And that receptor would be a heteroreceptor since serotonin is another receptor different from norepinephrine, right? And so whenever serotonin is released upon these non-serotonin presynaptic heteroreceptors, it inhibits the release of that home neurotransmitter. So it would inhibit norepinephrine when. on the serotonin 1b hetero receptor on a norepinephrine neuron.

It would inhibit dopamine on a dopamine neuron and so forth. 5HT2A receptors, which are only postsynaptic, are interesting in that they can both promote and inhibit the release of other neurotransmitters. And this receptor is always excitatory But it of course depends on the neuron that it is affecting because it could lead to a net downstream inhibitory effect.

So for example, when a 5-HT2A receptor is located on a glutamate neuron, then that excitatory action on that glutamate neuron would lead to more glutamate release, which would then generally trigger more neurotransmitter release. But if it is located on a GABA interneuron that ultimately would innervate glutamate neurons, if you were to excite or stimulate that GABA interneuron, which always functions in an inhibitory role, it's like you're putting the gas on the inhibition. So therefore, it would decrease or inhibit glutamate release, which then would lead to downstream decreased neurotransmission. So it all depends on how it is acting and on which neuron that it's acting as far as whether it's going to inhibit or excite.

5-HT2A receptors regulate downstream dopamine release. Now recall, as we discussed earlier, that 5-HT2A receptors are postsynaptic. and they are excitatory and this would be relevant when we later talk about the treatment of psychosis because it depends on where they are located as far as how they will regulate various neurotransmitters and whether it has an inhibitory or an excitatory downstream effect but there are three separate populations of descending glutamate neurons that 5-ht2a receptors are located on And these neurons either directly or indirectly innervate certain dopamine pathways, which then impact the way that dopamine is released.

So one of those descending glutamate neurons is located in such a way that it directly innervates the mesolimbic slash mesostriatal dopamine neurons. And so if you have excessive activity in that pathway, it will lead to the positive symptoms of psychosis because of the increase in downstream dopamine release other 5-ht2a receptors are located in such a way that they indirectly innervate the nigrostriatal dopamine neurons. And they do this via GABA interneurons in the substantia nigra. So if there's excessive stimulation of those receptors, it leads to a reduction in dopamine release in that motor striatum.

And so in that case, we would see side effects like drug-induced Parkinsonism. And the third 5-HT2A receptors are located on glutamate neurons that also indirectly innervate the dopamine pathway but this particular pathway is the mesocortical neurons and they do so via a gaba interneuron in the ventral tegmental area so if that's excessively stimulated it leads to a reduction of dopamine in that prefrontal cortex area which would then lead to the manifestation of cognitive dysfunction negative symptoms of schizophrenia, and other emotional symptoms that you see. So just to reiterate what the slide with the picture says, 5-HT2A receptors are located on cortical glutamate pyramidal neurons, and they're stimulated by serotonin, and then release glutamate downstream.

These three neurons regulate three distinct dopamine pathways. One of them directly innervates the mesolimbic and mesostriatal pathway, which then mediates the positive symptoms of psychosis. So anything that increases activity there leads to downstream release of dopamine, which would then cause positive symptoms. The second pathway, which is the nigrostriatal pathway, indirectly innervated by these 5-HT2A receptors.

Therefore, it would mediate motor side effects. And then the last one innervates the mesocortical pathway indirectly, and it mediates the negative, cognitive, and affective symptoms that you see with psychosis. So the pituitary lactotroph is responsible for the secretion of prolactin in both D2 receptors and 5-HT2A receptors are located on the membranes of these cells. So serotonin and dopamine have reciprocal roles in the regulation of prolactin secretion.

Dopamine inhibits prolactin via the stimulation of the D2 receptors, and serotonin promotes promactin release via stimulation of the 5-HT2A receptors. So when dopamine receptors are blocked, by dopamine 2 blockers, then dopamine cannot inhibit prolactin release so the prolactin levels rise. However, in situations where both dopamine 2 is blocked and 5-H2A is blocked, then there is an inhibition of the 5-HT2A receptor so serotonin can no longer stimulate prolactin release.

So that then in turn will mitigate the hyperprolactinemia of the D2 blockade. The 5-HT2C receptors are another example of how the location and the type of neuron that it is acting on will really influence whether the end result is an increase or decrease of neurotransmitter release. So generally speaking, 5-HT2C is excitatory.

But it's mostly located on GABA interneurons. So remember, GABA interneurons function in an inhibitory role. So if you are exciting the inhibitory GABA, then you are sort of putting the gas on the GABA and increasing that sort of inhibition. So then the ultimate kind of net effect of the 5-HT2C receptors are the inhibition of downstream neurotransmitter release wherever those GABA interneurons are projecting to. So 5-HT3 receptors are located in the chemoreceptor trigger zone which is in the brain stem as well as in the gastrointestinal tract and those receptors can help mediate nausea, vomiting, and other GI kind of side effects.

But when they're localized in other parts of the brain, and in particular in the prefrontal cortex, they're primarily located on a specific type of a GABA. interneuron and so kind of like what we saw with 5HT2C, 5HT3 is excitatory, but because it's located on those inhibitory GABA interneurons, the net effect is inhibitory and it has an inhibiting action wherever those GABA interneurons end up going. So in the cortical area, the prefrontal cortex of the brain, 5-ht3 stimulation will decrease or inhibit the release of norepinephrine and acetylcholine whereas if it's located near a glutamate neuron it actually will inhibit the release of serotonin so then in a weird kind of roundabout way serotonin's action at the 5-ht3 receptors will reduce its own And it does so through the way that it acts on glutamate, because glutamate and serotonin regulate each other through this 5-HT3 stimulation. So just like we've seen with 5-HT1A, 5-HT2C, and 5-HT3, 5-HT7 receptors are also excitatory. But since they're frequently located on inhibitory GABA interneurons, they tend to have a net inhibitory effect.

wherever it is that these GABA interneurons go. So cortically, the 5-HT7 stimulation will lead to an inhibition of glutamate and an inhibition of serotonin. It inhibits glutamate by basically putting the gas on the GABA inhibition with that GABA neuron connecting to a pyramidal neuron.

Whereas with serotonin, it inhibits that release by putting the gas on that GABA neuron that's connected to a serotonin neuron. So then in this kind of weird roundabout way, 5-HT7 also helps regulate serotonin's release. So as the previous slides have revealed, serotonin receptors and their synapses are located really...

almost in every area of the brain and throughout the brain. And so connecting these dots between how problems with serotonin can lead to psychosis kind of helps us understand the serotonin hypothesis of psychosis. And that hypothesis states essentially that there's hyper functioning of serotonin receptors and it's specifically caused by an imbalance in the excitatory 5-HT2A receptor. on glutamate pyramidal neurons and those glutamate neurons are directly innervating the ventral tegmental area as well as the mesostriatal hub which are connected to dopamine neurons and the visual cortex neurons so we know this to be true based on the effects of hallucinogen substances like LSD mescaline and psilocybin All of those work by agonizing 5-HT2A.

So by agonizing those sites, they induce symptoms very similar to what we see in schizophrenia and psychosis, like with dissociative experiences and visual hallucinations. And all of that's because of that overstimulation of the 5-HT receptors in that prefrontal cortex and the visual cortex. and we know that if we block those 5-ht2a receptors with antagonist agents the hallucinogen experience by that 5-ht2a stimulation is mitigated so that's one way that we know that there's a correlation there but we also know that in individuals with parkinson's that a lot of the psychotic symptoms that happens in these patients particularly later on in the disease is caused not only by a loss of the dopamine nerve terminals that they have in that motor part of the nigrostriatal pathway but they also have a loss of serotonin nerve terminals in that prefrontal and visual cortex so as the next slide will show there's a bit of a difference between how the psychotic symptoms are manifesting in their relation to 5-ht2a receptors compared to like what happens when there's drugs of abuse involved So with Parkinson's disease, the loss of serotonin and the serotonin nerve terminals causes an upregulation and therefore too many 5-HT receptors to be produced in the cortex.

And the reason that happens is it's this effort, it's a futile effort, to try to overcome the serotonin loss that's happening as a result of the disease. So with there being this excessive amount of 5-HT2A receptors, it creates this imbalance in the excitatory actions that those receptors have on the glutamate dendrites from what's left of the serotonin in that cortex and that leads to kind of the similar manifestation that you would see if there was substance induced psychotic symptoms so similarly we know that drugs that antagonize or block the 5-ht2a receptor can actually help manage the symptoms of parkinson's disease related psychosis and nicely they don't exacerbate some of the motor symptoms like we see with the dopamine blocking psychotic drugs so then lastly we have dementia related psychosis and it is also linked to serotonin hyperfunctioning but it too as you see on the next slide is different from parkinson's and even substance induced uh psychotic symptoms that we see and how that's related to 5-HT2A receptors. So with dementia and dementia-related psychosis, there doesn't appear to be this upregulation of 5-HT2A receptors like you would see in Parkinson's-related psychosis.

So there's a difference in kind of like the pathophysiology here. Instead, what we believe is happening is because of the accumulation of either the plaques or the tangles or like with Lewy body's dementia, that the presence of those Lewy bodies or in a stroke just the damage that happens because of that whatever the mechanism it knocks out the cortical neurons and leads to this lack of inhibition of the surviving glutamate neurons so if you don't have enough of those in GABA inhibition neurons to counteract the normal 5-ht 2a stimulation that's going to occur with what's left of the glutamate neurons that project to the ventral tegmental area and the mesostriatum and the visual cortex it's going to cause an excess in that stimulation and therefore lead to psychosis in these dementia related patients and it is now known then that if we can selectively balk 5ht2a it can reduce those symptoms of dementia and some of those behavioral problems that we see in patients with psychosis related to dementia so to wrap all of this up succinctly what have we learned but we've learned that serotonin does not only regulate its own release and it does that through presynaptic serotonin receptor actions but it also regulates all the other major neurotransmitters and this is largely through the postsynaptic receptor actions. And serotonin hyperactivity or an imbalance of serotonin specifically at 5-HT2A receptors on glutamate neurons in the cerebral cortex is linked to psychosis.

And the 5-HT2A receptor actions, in addition to the NMDA receptor actions, it hypothetically leads to hyperactive dopamine activity in downstream mesolimbic pathways. which helps connect the dots between the positive and eventually the negative symptoms that are associated with psychosis and schizophrenia.

Transcript for:The Role of Serotonin in Psychosis

Transcript for:
The Role of Serotonin in Psychosis