Serotonin - Jack of All Trades, Master of None

When I started to make this episode, I thought I would try to do a comprehensive review of all of the various functions of serotonin across its 15 or more receptor types, but I soon found myself overwhelmed.  More importantly, I found that some stories are more interesting to tell than others, so here I discuss serotonin and focus on how a few 5-HT receptors can not only help us survive, but also motivate ourselves to reach our goals, and, sometimes, convince us that we are fusing bodies with a tree.

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References and readings (when available) are posted at the end of each episode transcript, located at psydactic.buzzsprout.com. All opinions expressed in this podcast are exclusively those of the person speaking and should not be confused with the opinions of anyone else. We reserve the right to be wrong. Nothing in this podcast should be treated as individual medical advice.

Transcript

Welcome to PsyDactic - Residency Edition.  I am Dr. O’leary, a 4th year psychiatry resident in the US national capital region.  This is a podcast about psychiatry and neuroscience and I produce this by my lonesome because I love reading about neuroscience and this helps me to learn it better.  Plus, it is like having dictated notes.  If I need a refresher in the car, I can listen to myself ramble about a subject.  Aside from being a little narcissistic and weird, it helps to remind me how I approached a topic previously.  I need to warn you that I am not trying to express anyone else’s opinion and this includes the Department of Defense, the Defence Health Agency, the US Army or the Multidisciplinary Association for Psychedelic Studies.

When I started to make this episode, I thought I would try to do a comprehensive review of all of the various functions of serotonin across its 15 or more receptor types, but I soon found myself overwhelmed.  More importantly, I found that some stories are more interesting to tell than others, so I am going to talk about serotonin, but in the end I am going to focus on how a few serotonin receptors can not only help us survive, but also motivate ourselves to reach our goals, and, sometimes, convince us that we are fusing bodies with a tree.

Serotonin is a neurotransmitter, or more accurately, a neuromodulator.  It is generally released in a mode called volume transmission.  Volume transmission basically occurs by releasing a substance and letting it reach its receptors by diffusion or by hitching a ride on flowing extracellular fluid such as CSF (they call this convection).  This type of transmission is opposed to wired transmission where a synapse is relatively isolated from everything else and the path of the neurotransmitters is more tightly controlled.  In general volume transmission happens where the barriers to flow are not as tight and requires a larger relative amount of the neurotransmitter.  It has the benefit of being fine-tunable, based on what kind of signal is being sent.  Hormones and neuropeptides also use volume transmission, which can either be over the scale of micrometers or millimeters or over longer distances.

The most common medications that psychiatrists use are SSRIs.  These drugs reduce serotonin reuptake by blocking the presynaptic SERT, which allows serotonin to remain longer in the synapse and diffuse or convect farther or in greater volume than it normally would.  This means that serotonin is more likely to hit receptors more distant to the site of release or with lower affinities than it normally would.

Serotonin can also cross cell membranes via nonspecific facilitated diffusion.  However it doesn’t easily cross an intact blood brain barrier unless carried by something else.  This is a good thing, because the location of serotonin, even though it uses volume control, is tightly regulation.  Self proclaimed health experts on social media like to point out that most of the serotonin is made in the gut (about 90% of it), and that this facilitates a brain-gut connection.  Given that the serotonin in the gut does not readily cross the blood brain barrier and would likely wreak havoc if it did, this particular fact is not actually good evidence for a gut brain connection.  There are other facts that would be better to explain how our gut and brain influence each other, but that is not the subject of this episode.  The fact that most serotonin is produced in our GI tract is impressive, but not very informative by itself.  Some of the most common side effects of our serotonergic drugs like SSRIs are GI upset, nausea and diarrhea, and this is likely due to the large influence serotonin has on gut motility.

Although it is probably not making it from the gut to the brain in large amounts, serotonin that is made in the gut can get to other areas of the body including the brain by hitching a ride inside thrombocytes (aka platelets, that have SERT and can suck up free roaming serotonin).  Serotonin is involved in platelet aggregation and can also cause vasoconstriction which can help stop bleeding.  That is why serotonin reuptake inhibitors come with a small risk of increased bleeding.  Less serotonin in thrombocytes may impair their function.

Serotonin also has ionotropic and chronotropic effects on the heart which means it can affect the strength and speed of contractions.  This has caused some speculation that thrombotic events in the heart increase the chance of arrhythmias not only because of hypoxia and cell death, but also because of excess serotonin being released by platelets, which will affect cardiac myocytes.

I am going back up about a billion years now.  Serotonin is considered an ancient molecule, because it is involved in so many bodily processes and shared across so many distantly related species.  It was thought to have evolved between 750 million and 1 billion years ago as one of many antioxidant molecules derived from tryptophan.  Being an antioxidant was likely helpful in a world increasing full of oxygen.  Serotonin’s monoamine cousins norepinephrine and dopamine are also very old, and I have seen some phylogenies that suggest that D1 and D2 dopamine receptors evolved from a serotonergic ancestor.  Don’t quote me on that.

Melatonin, which is a derivative of serotonin and also a strong antioxidant, is likewise present widely across life forms including plants and fungi.  Another antioxidant derivative of tryptophan is psilocybin, which is a fungal compound that we can ingest.  In our body psilocybin is converted into psilocin which itself is a strong agonist of the 5HT2A receptors causing (among other things, hallucinations, illusions, and a loss of the sense of self as discrete from one’s surroundings), but that is getting ahead of myself.

The first serotonin receptor to have evolved and which is highly conserved today is the 5HT1A receptor.  There is a large family of 5HT receptors and I am going to discuss a few with relevance to psychiatry.  Serotonin has been described as (something to the effect of) being somehow involved in almost everything our body does but being primarily responsible for none of it.  It is a Jack of All Trades, but Master of None.  Serotonin is a modulator of cell activity, and we best know it as a modulator of brain and gut activity.

So let’s dive into a select few serotonin receptors, where you can find them and what they appear to do for us.

All 5HTRs are G-protein coupled receptors with the exception of 5HT3, which is a ligand gated cation channel, meaning it lets positively charged ions like K+, Na+, and Ca+ flow through it.  Remember that G-protein coupled receptors send signals that activate or shut down various metabolic pathways and can result in DNA transcription.  Ion channels are fast acting and will either result in depolarization or hyperpolarization of a neuron, causing a neuron to fire or reducing its chance of firing.

It seems weird to start with 5HT3 instead of 1, but because it is so unique, I feel like it is a good place to start.  5HT3 is probably most relevant to physicians because of its location in the GI tract and area postrema of the brainstem, where it is implicated in nausea and vomiting.   Ondansetron (a.k.a. Zofran in the US) is a medication that blocks 5HT3, reducing the response rate of its neuron and effectively reducing NV, especially in patients receiving chemotherapy.  5HT3 is also located in the hippocampus and in low concentrations in the VTA where it helps regulate dopamine release, and so antagonists of 5TH3 have been speculated to potentially have use as antipsychotics.  There are, in fact, antipsychotics that antagonize 5HT3, including clozapine, quetiapine, and olanzapine, as well as the antidepressants that antagonize 5ht3 such as mirtazapine and vortioxetine.  The cannabinoids, cannabidiol (CBD) and Delta-9-THC, also exert at least some of their antinausea effects by antagonizing 5HT3.

5HT3 may also be critical for neurogenesis in the hippocampus.  One of the actions of SSRIs when taken chronically is to increase neurogenesis in the hippocampus and 5HT3 may play a role in this.  Let me give a little background here.  Of the few places where CNS neurons are known to continue to regenerate in an adult, the subgranular zone (SGZ) of the dentate gyrus of the hippocampus is one of these.  Many chronic mental illnesses, especially depressive disorders, are associated with a loss of volume of the hippocampus and reduced neurogenesis.  This is one of the ways that depression can increase the chance of dementia.  A recent study using adult rats (because their brains are dissectable) showed that giving fluoxetine chronically increases neurogenesis and progenitor cell concentrations in the dentate gyrus.  They suspected that because fluoxetine was blocking the reuptake of serotonin, it was more available to stimulate 5HT3 and this was necessary for neurogenesis.  To test this, they gave ondansetron, which antagonizes 5HT3, along with the fluoxetine, and this effectively blocked the increase in neurogenesis.

I could say a lot more about 5HT3, especially because it is also present in the spinal cord and peripheral nerves, like the vagus nerve, and may help regulate autonomic activity.  As a quick review, 5HT3 is a cation channel that when activated increases the firing rate of its neuron.  We know it best as a target of antiemetic drugs, but it is widespread in the body.  With regard to mental illness, one of its most profound effects may be to increase neurogenesis in the hippocampus, a process that is often impaired in chronic mental illnesses.

Now lets move on to those G-protein coupled receptors that make up the vast majority of serotonin receptors.

Two classes of these receptors 5HT1 and 5HT5 are similar in action to the D2 receptors that I talked about in the previous episodes about antipsychotics.  Agonizing them reduces production of cAMP and 5HT1A agonists specifically can result in opening of K+ channels that hyperpolarizes the neuron, just like agonists of D2 receptors.  The end result of 5HT1 and 5 receptors is opposite that of 5HT3 activation.  5HT1 and 5 generally reduce the rate of neurotransmission in either or both the postsynaptic or presynaptic cell.  Put a break on neurotransmission can be extremely important.

The 5-HT1A receptor is ancient and found in many parts of our body.  Within our central nervous system 5HT1A is found to be especially dense as a postsynaptic receptor in the temporal pole and the medial temporal lobe including the hippocampus and amygdala, but also in the hypothalamus, the striatum, the insular cortex, the anterior and subgenual portions of the cingulate gyrus and and around the areas of the inferior parietal cortex and the operculum of the frontal lobe along with the medial occipital cortex.  It is far more widespread than this, but less dense.  

Given that distribution of density, the nerds in the audience may have already predicted that this receptor has been implicated in everything from the regulation of our basic functions, such as thermoregulation, autonomic regulation, feeding, cognition, and long-term memory, to our complex behaviors including reward seeking as well as regulation of mood and especially anxiety and threat responses.  5HT1A is also plays a large role in regulating the release of serotonin itself in the raphae nuclei, where serotonin in the CNS is primarily produced.  It does this primarily through its actions as a presynaptic autoreceptor that tones down the raphae neurons after they release their serotonin.  5HT1A is notably less abundant in our occipital lobe and cerebellum, but I am not sure of the significance of that.

Many papers that I read, highlighted 5HT1A’s role in regulating impulsive and aggressive behaviors.  It appears that agonists of 5HT1A, including serotonin itself can reduce impulsivity and aggression.  It appears to help us to think before we act. As an oversimplification, one could describe the 5HT1A receptor in the brain as densely limbic in distribution, extremely important for primary survival, adaptive behaviors, and basic emotional states.  The rest of the 5HT1 receptors, designated B thru F are not inconsequential, but to keep this podcast less than an hour I am going to skip over them for now.  I will be coming back to 5HT1A though.

I move on to what is currently my favorite serotonin receptor, 5HT2A.

5HT2A is more widespread in the central nervous system than 5HT1A, especially in our higher functioning area of the brain.  To make it easier to describe its distribution, it may be better to start with the places in the brain where 5HT2A is less abundant.  It is nearly absent in the brainstem and rare in the cerebellum.  It is especially famous for its expression on the dendrites of pyramidal cells in layer V of the cortex, where it affects all of our higher thinking.  You could think of 5HT2A as helping to govern our advanced evolutionary gifts, such as our executive functions, our working memory, our goal setting, our ability to have deep thoughts, our social awareness, how we interpret sensory stimuli and associate senses with memories or memories with other memories, how we have awareness of the significance of our context, and even how we build our sense of self.  That was a long run-on sentence with a lot of things.

5HT2A receptors are also frequently located intracellularly, which means that serotonin in the synapse is not stimulating it, but it could be interacting with serotonin or other compounds within the cell on endosomes and still regulating cellular activity.  Many of the psychedelic drugs that hit this receptor are lipophilic, which is why they can cross the blood brain barrier and get into cells.  They could be exerting their effects primarily via intracellular signaling, but this is a hard thing to observe.  One might over-generalize and say that while 5TH1A helps ensure our survival, 5TH2A helps to make us uniquely human and promotes flexibility in thinking.  Also, I have failed to mention that while 5HT1A is generally inhibitory because it hyperpolarizes a neuron by reducing cAMP production and opening K+ channels, 5HT2A, when active, is excitatory because it results in closing of K+ channels which results in less hyperpolarization and an increased firing rate.

You may remember from my last few episodes that many antipsychotics block the 5HT2A receptor and this is thought to be one of their mechanisms of action.  The antipsychotic pimavanserin in the US likely acts primarily as an inverse agonist or antagonist at 5HT2A.  While most antipsychotics still antagonize the Dopamine 2 receptor, the stronger D2 is blocked, the more likely someone is to develop a drug induced movement disorder.  That is why pimavanserin is given in Parkinson's disease, because dopamine is already very low, so messing with D-receptors puts the patient at a very high risk of movement side effects.

One of the more studied functions of 5HT2A is as a modulator of pyramidal neurons in the cortex, especially in layer 5.   There, 5HT2A receptors are primarily located on the apical dendrites of pyramidal neurons.

There are many serotonin receptors in the cortex, but I am going to focus on 5HT1A and 2A for the moment with some honorable mentions.  In the cortex there are neurons that release glutamate, for example they may extend into the dorsal striatum and release glutamate into the direct pathways.  These glutamatergic neurons send projections all over the brain in order to make associations, coordinate responses, and regulate other neurotransmitter systems.  When serotonin is released into cortex synapses, it will stimulate both 5HT1A (or 5HT5) and 5HT2A (or 2C, 4,6 and 7 which do similar things, but I’m ignoring them for now).  5HT1A and friends have opposite effects from 5HT2A and friends, but 5HT1A in particular has a 2-6 fold higher affinity for serotonin.  Therefore the location and density of each receptor relative to where serotonin is released will determine how it affects the target cell.  High volume transmission, overall probably favors 2A transmission.

Around the pyramidal glutamatergic neurons are populations of GABA-ergic interneurons that also have 5HT1A and 2A receptors and indirectly regulate the glutamate release of the pyramidal neurons.  So here is a little run-down.  Dumping some serotonin into the cortex can result in 2A activation, which directlys increases glutamate release from pyramidal neurons, but it also results in 1A action, which will decrease glutamate release, and 1A autoreceptors also decrease serotonin release overall.  In the neighborhood, there are other serotonin responsive cells.  Stimulating 2A receptors on GABA-ergic interneurons will suppress glutamate release from the pyramidal neurons, but stimulating 5HT1A on these same GABA releasing neurons can reduce the release of GABA and disinhibit the glutamate releasing pyramidal neuron.  Also some of these GABA-interneurons also have 5HT3 receptors, which are those ion carriers that can increase excitability.  5HT3 has a lower affinity for serotonin than 1A or 2A, so it will come into play especially when large amounts of serotonin are released.

To get slightly more complicated, there are two primary populations of GABA interneurons, called parvalbumin neurons and non-parvalbumin neurons due to how they looked when they were stained with a dye.  It probably would have been better to name them fast spiking and not-so-fast spiking neurons instead, because that is more important for their function.  The parvalbumin GABA interneurons can fire quickly and repeatedly, and in doing this they tend to regulate the frequency that the glutamatergic neuron fires.  The non-parvalbumin gaba neurons fire less frequently and so, they tend to regulate more the volume of glutamate that is delivered.  Both the frequency and the magnitude of transmission of a neuron are different ways of sending encoded information to the receiving neuron, that has little receptor antennae on them that are tuned to detect these variations.

Maybe you can understand better why we have not been able to find single genes that cause depression or schizophrenia or anxiety or OCD, but they still can have high heritability.  Anything that disrupts the elegant balance of this system can result in poorly regulated or deranged cognitive or emotional states.  This can also help to explain why environmental factors are so important.  By changing our sensory inputs, associating our present with memories or emotional states, ingesting certain substances, exercising more than we previously did, the functioning of various parts of this system can be affected either in the short term or chronically.

Before I end today, I want to mention one way that disrupting our CNS serotonergic system has been used deep into our evolutionary history to intentionally change the way that we think.  Compounds like psilocybin that occur naturally and more modern synthetic compounds like LSD, when ingested, can wreak a special kind of havoc on our brains.  It’s a kind of havoc that many people seek out.

Our brain's main job is to predict reality.  It needs to tell us the value of our sensory information and very basically whether to move toward or away from something or whether it is inconsequential.  We also are able to brood, create internal experiences, pull up our prior mental states in the form of memories and at times spontaneously create novel mental states, some of which are highly valuable to use.  We call these states “good ideas,” but good ideas are not always as good as they feel.

Our cortex takes sensory information and our own thoughts and associates it with other things.  If the only red thing you had ever seen in your life was a cardinal, then the first time you saw a red scarf on someones neck you would immediately think that they were wearing a cardinal.  When your expectation was violated, an error signal would be processed and the brain would update its predictions about what red means.  However, we can have biased cognition.  In depressive or anxious states we often brood on negative thoughts or potential threats and give biased salience toward sensory information that appears to validate those thoughts (e.g. she frowned at me, she must be able to tell that I am a terrible person, or he is walking toward me, he must be going to attack).

Psychedelic substances like psilocin and LSD, temporarily mess with our ability to interpret our thoughts and senses and cause us to violate our normal assumptions about reality.  They do this primarily by hyper-activation of 5HT2A receptors in the cortex, which result in a flood of odd or improbable thoughts, strange sensations, unlikely associations.  Some people describe ego-dissolution or a loss of sense of self.

With 5HT2A agonists, there are especially frequent distortions of visual perception. This is why people like to drop acid (LSD) and then watch laser light shows.  There can be frank hallucinations but often people describe hyper-esthesia, when senses feel enhanced, colors are brighter, sounds are sharper.  They may also describe synesthesia, when one sensation, let’s say the sound of water, results in experiencing a different sensation simultaneously, such as the taste of pears.  Often people will say that colors have sounds.

People experience mystical experiences and often say they have deep, meaningful insights or feel extraordinarily connected to others or the world around them.  They may even lose a sense of where their own body ends and their chair begins. These spiritual insights, if written down and reread when sober, often appear to make no sense like “if the chair were to promulgate its effective self, the universe would give pause,” or are just vague nearly meaningless aphorisms like “love is the answer.”  

Not everyone has such rosy connected experiences.  Horrendous, frightening experiences have also been described.  Someone might describe having died over and over again or been stolen from their body.  There seems to be a strong bias for positive experiences, though.

But even though it is unlikely that anyone is going to figure out the answer to world peace while on a trip, it can have enduring positive effects for individuals.  It seems that massive activation of 5HT2A has enduring effects on the brain.  I am not going to get into the details here, but most of the proposed mechanism of how these substances can treat things like PTSD or depression is by promoting neuroplasticity and flexibility of thought, which is evident in neurogenesis and arborization of neurons (which means new neurons are formed and old ones make new connections).  However they do it, psychedelics have a way of unsticking our thoughts from very sticky places and they do this by massively and selectively activating 5HT2A serotonin receptors.


Thank you for listening.  I hope everyone has a great new year.  Until next time, I am Dr. O and this has been an episode of psydactic residency edition.


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https://en.wikipedia.org/wiki/5-HT2A_receptor
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