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Knocking 5-HT1A down to bring mood up

Most current treatments for depression target the serotonin system, a chemical messenger that plays a role in mood (though it also plays a role in many, many other things).

This article was published in Scientific American’s former blog network and reflects the views of the author, not necessarily those of Scientific American


Most current treatments for depression target the serotonin system, a chemical messenger that plays a role in mood (though it also plays a role in many, many other things). Most of the antidepressant drugs on the market (such as Prozac, Celexa, and Zoloft) that target serotonin do it by blocking the recycling of serotonin, keeping it in the spaces between neurons and allowing it to be active for far longer than it might otherwise.

The problem is, these drugs take a long time to work. Often many weeks. In that time, patients may grow frustrated as side effects happen and the needed effects don't. Patients may be in very desperate straights when they first go on medication, and any extra time before the drugs work becomes that much more dangerous. The drugs may not work at all, causing doctors and patients to have to go through the entire, weeks long process over and over again.

Scientists are looking for new antidepressant mechanisms, and trying to create more effective drugs. But there are various ways to go about it. You can go looking for an entirely new way of working, but you can also look at ways to make the current drugs work faster.


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One target that might help antidepressant drugs work faster is one of the many receptors for serotonin, the 5-HT1A receptor. Receptors are proteins that sit on cell surfaces, and bind chemicals. When they bind a chemical, they cause change, maybe by opening a channel, or starting a signal to make a neuron fire more, or less. What a receptor does depends on its type, but also where in the brain it is located and on what type of cell.

The 5-HT1A receptor is a case in point. It's found throughout the brain, sometimes as an autoreceptor on a serotonin neuron (such as in the dorsal raphe region of the brain) to provide feedback to the cell. Sometimes it's on other neurons in the cortex, where it has different effects. But its role as an autoreceptor could be an important one for antidepressants.

Most antidepressants increase levels of serotonin available in the brain. That means it hits receptors more often. In the dorsal raphe, which produces a lot of the serotonin in the brain, 5-HT1A receptors are there to provide feedback. When serotonin hits them, they signal that there is enough serotonin and the raphe them lighten up a bit on the release. That's great in a normal state, but in a depressed brain being treated with antidepressants, it fights against the antidepressants. More serotonin stays around, yes, but less is released as well, as the 5-HT1A receptors provide feedback. This makes the antidepressant less effective than it could be. Over the long run, the 5-HT1A receptors, hit too hard by all the extra serotonin around due to the antidepressants, will desensitize, and the raphe serotonin cells will fire at more normal rates. This further increases the serotonin levels, once the 5-HT1A receptors are no longer "working against" the antidepressant. So if you could artificially desensitize 5-HT1A receptors immediately, in theory it could help antidepressants work faster, increasing the levels of serotonin even further by stopping the usually feedback from taking place.

There are a couple of drugs on the market that hit 5-HT1A receptors (such as buspirone and vilazodone). But these aren't 5-HT1A drugs alone, they have many other effects. Could hitting 5-HT1A alone, and only in the raphe, be enough to create antidepressant like effects? It's hard to say. In a traditional knockout mouse, you have to knockout the receptor all over the brain. You can't narrow it down to a brain region.

But there's more than one way to get things done. And if you use a small interfering RNA, you can limiting the brain region, and find out just what 5-HT1A in the raphe will do.

Ferres-Coy et al. "Acute 5-HT1A autoreceptor knockdown increases antidepressant

responses and serotonin release in stressful conditions" Psychopharmacology, 2013.

The authors of this study wanted to look specifically at the role of the 5-HT1A receptor in the raphe, to see if knocking just the raphe 5-HT1A receptors down might produce antidepressant effects. To do this, they used something called a small interfering RNA. These short RNA sequences can stop the expression of genes, including genes for things like receptor proteins. If you give them locally to a mouse, say, in a viral vector aimed at a specific region of the brain, you could restrict the effects of the interference to a small area, allowing only the receptors in that area to be knocked down.

You can see the effects in the photo above. On the top two rows are the vehicle injection, and the injection with random RNA. The 5-HT1A receptor expression (shown in the color plot), looked the same for both. But for the bottom row, you can see a blank spot (with the arrow pointing to it). That is the group that got the small interfering RNA. You can see that in the tiny area where the virus was spread, the dorsal raphe, there is a big decrease in "glow", indicating a decrease in 5-HT1A receptors. And it occurs quickly, about a day after the injection.

But what effects does it have? In theory, if the 5-HT1A receptors in this area control serotonin release, the mice shouldn't response to 5-HT1A drugs. There will be no receptors to hit. No feedback to give.

It does appear to the work that way. Above (Figure 4 A from the paper), you can see levels of serotonin in normal mice (white circles), mice that got nonsense RNA (white squares), mice that got small interfering RNA (black squares), and mice that have 5-HT1A receptors knocked out all over (black circles). You can see that when control mice get a 5-HT1A agonist, their serotonin levels decrease, the 5-HT1A agonist is promoting feedback and the raphe is ceasing serotonin production. But in the 5-HT1A knockout and the ones getting the small interfering RNA, serotonin levels stayed normal. There's no feedback to give, no 5-HT1A receptors to give it.

But does this impact behavior? To find this out, the authors looked at anxiety tests and antidepressant tests. While the small interfering RNA had no effect on anxiety tests, in antidepressant tests (including the forced swim and tail suspension), the small interfering RNA made a big difference.

Above you can see the tail suspension test for antidepressant efficacy. You can see that both the 5-HT1A knockout all over and the one specific for the raphe (with the small interfering RNA) spent less time immobile than the control, which indicates that decreasing 5-HT1A expression in the raphe produces antidepressant-like effects in mice. They also had a stronger serotonin response to antidepressants. Without feedback, the antidepressants let serotonin reign.

And this happened FAST. The 5-HT1A receptor expression was down in 1 day! If we can get the small interfering RNA mechanisms ready to be used in humans, they could be a way to help make antidepressants work faster and better than they currently do. It'd be using an RNA, knocking a receptor down, to bring mood up.

Obviously this is a long way from the clinic, but it's an interesting angle, a direct attack on the 5-HT1A receptor to get the current antidepressants to work. And when looking for a good antidepressants, we will take whatever we can get.

Scicurious has a PhD in Physiology from a Southern institution. She has a Bachelor of Arts in Philosophy and a Bachelor of Science in Biology from another respected Southern institution. She is currently a post-doctoral researcher at a celebrated institution that is very fancy and somewhere else. Her professional interests are in neurophysiology and psychiatric disorders. She recently obtained her PhD and is pursuing her love of science and writing at the same time. She often blogs in the third person. For more information about Scicurious and to view her recent award and activities, please see her CV ( http://scientopia.org/blogs/scicurious/a-scicurious-cv/)

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