Back to Basics 3: Depression post 4, the SEROTONIN SYSTEM

Yeah, today's a big day, there's a LOT I've written on depression, but do not fret, we will get through it all!!!

You can't get through a whole day on depression without talking about some serotonin a little!

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.

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