The Serotonin System and All that Goes With it

I’ve had some sturm und drang over this post. I’ve been wanting to do a basic post on serotonin, but I’ve also been wanting to do a post on the serotonin theory of depression (and why it is at the very least incomplete). The idea of a serotonin post is a significant challenge, but the idea of trying to explain the serotonin theory of depression WITHOUT a serotonin post is even worse. So my current compromise is to do a post on the serotonin system, and the serotonin theory of depression will be next up. Back to back will keep it all fresh in your minds.🙂
Hang on to your hats:
Serotonin
serotonin.jpg
Oh yeah, she went there. Photo courtesy of The Loom blog from Discover. Sci might have to get one of these…
To begin with, I will admit that I do not know everything there is to know about serotonin. I am able to readily admit this because NO ONE knows everything there is to know about serotonin. This is not just because we haven’t figured it all out yet, but also because the serotonin system is completely, insanely complicated. You perform a pubmed search for “serotonin system review” and you get 176 PAGES of citations, all of them on things like “the serotonin system and anxiety”, “the serotonin system and cardiovascular effects”, “the serotonin system and gastrointestinal effects”, and the list goes on. To do a complete review of all that is currently known about the serotonin system would take hundreds of pages and probably thousands of citations. This is partially because serotonin not only does tons of things, but it does lots of stuff that has very little relation to any of the other stuff that is also doing. You can’t really make any sweeping generalizations about serotonin, there are always exceptions to the rule.
So what I’m going to go into here will be what I know about serotonin, as general as I can make it, and not covering even a quarter of what there is out there. But it will hopefully give you an idea of what people are talking about when they talk about serotonin drugs, serotonin effects, etc.
So here we go.


Serotonin (otherwise known as 5-hydroxytryptamine, and abbreviated as 5-HT) is one of the monoamine neurotransmitters, and looks like this:
serotonin.png
Though most people now think of serotonin as something primarily in the brain and nervous system, in fact the serotonin system is widespread throughout the body. Dr. Erspamer first detected serotonin in the gastrointestinal tract in the 1930’s, and called it “enteramine”, but it wasn’t isolated until 1948, when Drs. Page, Green, and Rapport called it “serotonin”, identifying it as an agent that affected blood vessels. It wasn’t identified in the brain until the 1950’s, and though we now know it has far more implications than just effects of vasculature, “serotonin” was the name that stuck.
Serotonin is a pretty wild molecule for many reasons. First of all, it is formed form the amino acid L-tryptophan, which is one of the 20 standard amino acids required for life as we know it. Interestingly, tryptophan is also one of the few “essential” amino acids for humans, meaning that we don’t make it ourselves, and have to get it from the diet. But don’t worry, you’ve usually got plenty. The only way anyone could really suffer “tryptophan depletion” is if you’re in a lab and they give you tons of other amino acids, or if you’re starving. And if you’re starving, you’ve obviously got bigger problems.
To make serotonin, start out with some L-tryptophan. This gets transformed in cells by an enzyme known as tryptophan hydroxylase to 5-hydroxytryptophan, this then gets broken down using the enzyme amino acid decarboxylase to 5-hydroxytryptamine, or 5-HT. Then the 5-HT is ready to be stored in vesicles in preparation for release from the cell as a signaling molecule.
5-ht synthesis.gif
And that is what serotonin is, a signaling molecule. Sure, it found in the blood vessels, in the gut, and in most of the rest of your body, but it’s all coming from one place: the brain (ok, well, there’s some serotonin that may be manufactured by blood cells and platelets as well. Also, there is some that is endogenous in the vasculature, and…aw hell. Told you, you just can’t make generalizations.). The main production of serotonin in the brain takes place in little groups of neurons in the brainstem known as the raphe nuclei.
raphe.gif
The raphe nuclei then make connections all up and down the brain and spinal cord, releasing 5-HT pretty much everywhere, though in very low amounts. 5-HT is also what we like to call a modulatory chemical. It doesn’t really have direct control over something critical (like, say, acetylcholine or glutamate), but it wields some massive influence on things like:

  • mood
  • aging
  • anxiety
  • circadian rhythms
  • eating disorders
  • bowel problems
  • migraine
  • nausea
  • premature ejaculation
  • pain
  • drug abuse
  • vasodilation/.vasoconstriction
  • memory

…and the list goes on
5-HT Neurotransmission
If you’ve read this blog at all, you probably know what basic neurotransmission looks like right now, but if not, here’s a brief overview:
5-Ht transmission.gif
(Photo courtesy of NIDA)
What you can see above is your basic synapse, the space between two neurons (or a neuron and something else, like a muscle cell). The top big bulge is the pre-synaptic neuron, which is sending a signal to the bottom bulge, the post-synaptic neuron. Inside the pre-synaptic neuron you can see little bubbles, those represent vesicles, which are little pockets of membrane holding chemicals, in this case serotonin.
When an action potential comes down the pre-synaptic neuron and needs to jump the synapse, signaling within the cell will cause the vesicles containing serotonin to move to the membrane. When they hit the membrane, they will merge into it, spilling their 5-HT out of the cell and into the synapse (as a side note, usually they don’t spill ALL of the neurotransmitter into the synapse, they just let a little out, and then pull away from the membrane. Neuroscientists like to call this a ‘kiss and run’, which is about as cute as we generally get when we name things).
Once the 5-HT is out in the synapse, it bumps up against the little mushroom-like things on the other side, which represent serotonin receptors. And it does this VERY quickly. This picture doesn’t show it, but most synapses are surrounded by glia and carefully protected, so relatively little of the released neurotransmitter is able to escape. This saves a lot of energy (if the 5-HT stays close in, you need less to get the job done, and it also gives you a better chance of taking it back up into the neuron for recycling).
Once the 5-HT binds to the receptors on the opposite side, the signal can progress down the post-synaptic neuron. The 5-HT that has been released now has two options. If it stays in the synapse, an enzyme called monoamine oxidase, specifically monoamine oxidase A (the monoamine oxidase enzymes, btw, are the target of MAOIs, one of the first types of antidepressant) will break it down into 5-HIAA, a metabolite. Otherwise, it can get taken back up in to the pre-synaptic neuron by the serotonin transporter (usually called the SERT), which sucks up serotonin so it can be re-packaged and used again (the SERT is another major target of antidepressants such as Prozac).
But the effects of serotonin are not only where it’s released, but what receptors it hits on the other side. And here we come to probably the most complicated part.
5-HT Receptors
When I started as a grad student (not so very long ago) there were already 14 serotonin receptors. Now there are 17. Compared to the neat 5 for the dopamine system, or the 4 of the norepinephrine system, this is completely mind-boggling. And 5-HT receptors DO so many things. Right now, we can generally say that the serotonin system has strong influences on “anger, aggression, body temperature, mood, sleep, human sexuality, appetite, metabolism, and vomiting”, and that’s just in the central nervous system.
Not only that, 5-HT receptors defy any system to classify them in a general manner. Right now, they are classified by similarities in structure, and so you can have families like the 5-HT1 (broken down into 1A, 1B, 1D, 1E, and 1F). But even in that family, none of them do the same thing! It’s enough to make any physiologist tear her hair out just trying to keep them all straight. So what I’m going to go into here are the 5-HT receptors that a) I like to blog about, and b) are the most well known (usually because we have drugs that act on them).
5-HT1A receptor: This receptor is found in both the brain and the gut (where it has inhibitory effects of GI motility, stops stuff from moving along, if you know what I mean). In the brain, it’s got effects on things like appetite and temperature, but more importantly for most people is the 5-HT1A effects on anxiety. There are several anxiolytics out there that are 5-HT1A receptor agonists, including buspirone (known as Buspar and a bunch of other things) and trazodone (known by Deseryl and other names).
5-HT1B receptor: Ok, there aren’t any clinical drugs that are 5-HT1B drugs, but it’s one of my favorite receptors. Interestingly, mice without 5-HT1B receptors are highly aggressive and may have increased preference for alcohol, so there is some research on this receptor with regards to both aggression and drug addiction
5-HT2A receptor: This is the receptor that people want to hear about. Aside from its actions in your vasculature, the 5-HT2A receptor is best known for its trips. Hallucinogens such as LSD have their actions on the 5-HT2A receptor, and some of the ‘atypical’ antipsychotics inhibit this receptor.
5-HT2B receptor: This receptor hasn’t got any drugs out on the market yet, but it is known to function in relaxation of the smooth muscle in your blood vessels, and so some studies are looking at possible effects of 5-HT2B agonists in things like migraine. It’s also found in your heart, lungs, gut, and kidney.
5-HT3 receptor: These are actually a family of receptors, but they are very hard to prise apart pharmacologically. They are the only receptors in the 5-HT family that are ion-channels (as opposed to the others, which are coupled to G-proteins and work via second messengers). There are a couple of drugs that inhibit 5-HT3 which are being used to combat naudea induced by chemotherapy (such as ondansetron, which goes by the clinical name Zofran, ok, who the hell comes up with these names!?).
There are many more 5-HT receptors, most of which have been barely classified. We know that they exist, and sometimes where they are, but most of the time, we’re still working out what they DO. The 5-HT system plays such a modulatory role in so many things that 5-HT receptors may have a great deal to offer in terms of possible drugs. On the other hand, because 5-HT plays such a modulatory role, you can also get lots of side effects.
And that, is a VERY general overview of the serotonin system. Of course, this has given me all sorts of ideas. Now I want to do separate posts on serotonin and anxiety, serotonin and migraine, serotonin and LSD! Sigh…so much to blog. So little time. And of course, I didn’t even cover the SERT! We’re saving that for next time.
Next time: the 5-HT theory of depression.

21 Responses

  1. Thanks for this series of posts – very informative!

  2. Great post, looking forward to the next in the series. Been meaning to read up on the latest thinking on serotonin/depression but never got round to it, will let you bring me up to speed🙂

  3. you DID go there! i didn’t know if i’d see you take a crack at the insanity that is 5HT.
    though the tattoo… that’s a bit hardcore even for me.

  4. Great post, SciC!

  5. Is there really just one “serotonin system“? Given the number of different receptors, along with the fact that one receptor might well drive different processes in different post-synaptic neurons, isn’t it possible that one neurotransmitter is actually used by a number of independent systems?

  6. Cool post. I’ll definitely be back for more. After all, Scienceblogs is not all about Pharyngula (sorry PZ).

  7. Did you know the 2b receptor is expressed on Von Economo neurons?
    See Intuition and autism: a possible role for Von Economo neurons by John M. Allman, Karli K. Watson, Nicole A. Tetreault and Atiya Y. Hakeem TRENDS in Cognitive Sciences Vol.9 No.8 August 2005

    The serotonin 2b receptor is strongly expressed on the VENs (Figure 4c) and is rarely expressed elsewhere in the central nervous system [20]. However, the serotonin 2b receptor is also strongly expressed in the human stomach and intestines where it promotes contractions of the smooth muscles responsible for peristalsis [21].

  8. AK: I suppose you COULD break it up into pieces. But how would you break it up? Many of the receptors have jobs in more than one place, doing more than one thing, like the 5-HT1A which acts in the brain and the gut. So I’m not really sure how you’d break stuff up in that case.
    And also, there are other neurotransmitters, like acetylcholine, which have very different functions (in the case of ACh, acting in the brain and also at the neuromuscular junction, where it will do very different things), but it’s still classified as one major system.
    I suppose if you were to try and break it up, you’d do it the same way we break up dopamine, into neuroanatomical circuit segments (the nigrostriatal and the VTA-accumbal, for example) which control different things, but they are both still in the overarching dopamine system. Perhaps with more research into serotonin we would be able to do something like that.

  9. Great review of the insanely complicated 5-HT system. Sumatriptan (brand name Imitrex) is a 5-HT(1B) agonist available on the market … although it also hits the 1D receptor.

  10. Ross: thanks! I can’t believe I overlooked that one…I totally know about it, just didn’t even think of it last night.

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  12. @Scicurious:

    I suppose if you were to try and break it up, you’d do it the same way we break up dopamine, into neuroanatomical circuit segments (the nigrostriatal and the VTA-accumbal[sic, s/b mesolimbic], for example) which control different things, but they are both still in the overarching dopamine system.

    I’m not sure an “overarching dopamine system” should be regarded as a reality. “System” implies (IMO) some manner of mutual interaction among its parts, but the four circuits that use dopamine seem to be independent, related only by the fact that they all use dopamine. (Of course, each of these circuits seems to be part of a more general system that uses other neurotransmitters as well.)
    My suggestion is that there is a number (probably much more than four) of similarly independent systems containing one or more circuits that use serotonin. I just don’t see how grouping a bunch of otherwise unrelated circuits together just because they happen to use serotonin constitutes a “system”.

  13. I LOVE this post!

  14. I can’t believe you forgot the most interesting receptor: 5ht2c!

  15. anonais: no way! I totally did NOT forget. I happen to love the 2C receptor. It’s just not very in the public eye, though I think it should be, esp since fluoxetine (Prozac) can have actions at the 2C receptor at higher doses, resulting in some reductions in locomotor activity in some animal models. But I totally didn’t forget.🙂
    AK: you’re probably right. And I know I personally only worry about one aspect of the serotonin system. So probably people have already “broken up” the serotonin system. It just may take a while for nomemclature to follow.

  16. Am anxiously awaiting your promised article on Serotonin and Depression. Please post it as soon as you have it ready. Thanks.

  17. Came across this and had to show you…
    Serotonin necklace

  18. Dang HTML tags….can’t add an image, so go here ->
    http://blogs.nature.com/news/thegreatbeyond/GIFTSserotoninnecklacerocks.jpg

  19. I’ve been puzzling over the enteric nervous system for a while now with Gershon, and I wanted to check a point of fact that differs with the post above. In writing the history of his work on the ENS (prior to serotonin being accepted as a nuerotransmitter in the ENS), he writes: “Even in 1981, the gut was known to manufacture nearly all of the body’s serotonin. Since only 1 percent or so of the body’s serotonin is made in the brain, the brain’s output can thus be thought of a as a minor supplement (Gershon 1998, The Second Brain, p. 48).” Is there a distinction between the serotonin produced in the gut (restricted in distribution to those tissues only?) and that which is produced in the brain, and therefore you do not mention it in this post, or is Gershon incorrect? Can serotonin produced in the ENS affect the CNS and vice versa? If so, what are the mechanisms for this? I’ve just found your blog here, so perhaps you have written on this before. I appreciate your guidance.
    -a layman

  20. […] inhibitors (SIs) to treat this disease. Check out Scicuious’s excellent posts on the serotonin system and […]

  21. It is commonly believed that depression is linked to an imbalance of chemicals in the brain. An important chemical is serotonin as this influences mood. The amino acid tryptophan comprises one of the building blocks of DNA and is required by the body to produce serotonin. It is an essential amino acid, which means your body can not produce it and so it must be obtained through diet.`

    Most recent post produced by our personal web-site
    <.http://www.foodsupplementcenter.com/muira-puama-benefits/

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