Brain-Modifying Drugs

By Neuroskeptic | August 4, 2011 8:25 am

What if there was a drug that didn’t just affect the levels of chemicals in your brain, it turned off genes in your brain? That possibility – either exciting or sinister depending on how you look at it – could be remarkably close, according to a report just out from a Spanish group.

The authors took an antidepressant, sertraline, and chemically welded it to a small interfering RNA (siRNA). A siRNA is kind of like a pair of genetic handcuffs. It selectively blocks the expression of a particular gene, by binding to and interfering with RNA messengers. In this case, the target was the serotonin 5HT1A receptor.

The authors injected their molecule into the brains of some mice. The sertraline was there to target the siRNA at specific cell types. Sertraline works by binding to and blocking the serotonin transporter (SERT), and this is only expressed on cells that release serotonin; so only these cells were subject to the 5HT1A silencing.

The idea is that this receptor acts as a kind of automatic off-switch for these cells, making them reduce their firing in response to their own output, to keep them from firing too fast. There’s a theory that this feedback can be a bad thing, because it stops antidepressants from being able to boost serotonin levels very much, although this is debated.

Anyway, it worked. The treated mice showed a strong and selective reduction in the density of the 5HT1A receptor in the target area (the Raphe nuclei containing serotonin cells), but not in the rest of the brain.

Note that this isn’t genetic modification as such. The gene wasn’t deleted, it was just silenced, temporarily one hopes; the effect persisted for at least 3 days, but they didn’t investigate just how long it lasted.

That’s remarkable enough, but what’s more, it also worked when they administered the drug via the intranasal route. In many siRNA experiments, the payload is injected directly into the brain. That’s fine for lab mice, but not very practical for humans. Intranasal administration, however, is popular and easy.

So siRNA-sertraline, and who knows what other drugs built along these lines, may be closer to being ready for human consumption than anyone would have predicted. However… the mouse’s brain is a lot closer to its nose than the human brain is, so it might not go quite as smoothly.

The mind boggles at the potential. If you could selectively alter the gene expression of selective neurons, you could do things to the brain that are currently impossible. Existing drugs hit the whole brain, yet there are many reasons why you’d prefer to only affect certain areas. And editing gene expression would allow much more detailed control over those cells than is currently possible.

Currently available drugs are shotguns and sledgehammers. These approaches could provide sniper rifles and scalpels. But whether it will prove to be safe remains to be seen. I certainly wouldn’t want to be first one to snort this particular drug.

ResearchBlogging.orgBortolozzi, A., Castañé, A., Semakova, J., Santana, N., Alvarado, G., Cortés, R., Ferrés-Coy, A., Fernández, G., Carmona, M., Toth, M., Perales, J., Montefeltro, A., & Artigas, F. (2011). Selective siRNA-mediated suppression of 5-HT1A autoreceptors evokes strong anti-depressant-like effects Molecular Psychiatry DOI: 10.1038/mp.2011.92

  • Anonymous

    How would this affect those who need nasal sprays for allergies (steroidal, ipatroprium, etc.)? Might there be a possibility to expand this research to older anti-seizure medications (e.g. lamotrigine) for we bipolar disorder sufferers? Please keep us posted!

  • Iatrogenia

    What a truly horrible idea, boosting serotonin still higher in the brain.

    Increased serotonin from antidepressants already interferes with feedback loops of neurohormones and other hormones all over the body. One element of fallout from this dysregulation is the common side effect of sexual dysfunction.

    Our nervous systems thrive on a normal homeostasis. Disruptive mechanisms of greater strength are not a promising development.

  • Anonymous

    I'm trying to understand how the drug selectively gains entry through cell wall (self-educated layman here). Is it that the sertraline binds to the SERT receptor, the combination is internalized, and the siRNA gets 'pulled through' as part of the internalization?

  • Zachary Tong

    Iatrogenia: Well, first of all, SSRIs are excellent treatments for many people.

    Secondly, the dysregulation you mention is the exact reason studies like this are so critical. To use Neuroskeptic's analogy, our current usage of SSRIs is like shooting the brain with a shotgun. Instead of blasting SSRIs everywhere, this technique allows precise and accurate application of drugs.

    The goal is to remove side effects through precision targeting.

    Anonymous: The authors don't investigate the exact mechanism, but they suspect it works through internalization of the receptor like you mentioned. Their rationale for this includes:

    1) They find C-1A-siRNA in the dendrite and cell body of neurons far from the injection site (meaning it was internalized and transported back to the cell body)

    2) They can block the action of C-1A-siRNA by first infusing with sertraline, showing that c-1A-siRNA requires functional SERT sites to operate

    Now, how it gets out of the endosome and into the nucleus is anyone's guess…

  • Diana Lee

    Wow, what a cool possibility! This holds potential for so many disorders and diseases. Very exciting.

  • Pseudonymoniae

    This is definitely an interesting development. Nasal inhalation of siRNAs… now that's cool. Still, the idea of chronically administering siRNAs to humans is a whole other ball park. I kind of wonder what the long-term efficacy of this sort of treatment will be like.

    Also, if, as this paper suggests, SSRIs inhibit the mechanism of siRNA uptake, then it's difficult to judge how this technology would be used in combination with traditional SSRIs. I suppose a combination of autoreceptor knockdown and 5HT1A agonists might work?

    Well, anyways, there's lots of interesting ideas that could come out of this.

  • Ralfo

    I really wonder what the side effects of this will be. It seems very plausible that this injection method might yield much less side effects than current methods but one can't know for sure just yet.

    I'm looking forward for an experiment comparing both injection methods checking for physiological differences especially on mid- and longterm.

    Also @ Neurosceptic: Is there anything known how the brain and body will deal with this method when substances are overdosed? To me, it sounds like longterm damages are more likely to occur with this new method if overdosed.

  • petrossa

    It's still debatable if it's the specific suppression of a neurotransmitter subtype that directly causes the curative (if any) effect, or the cascading of the alteration of the neurotransmitter balance caused by suppressing one of them.

    As such anything that might cause permanent changes is not going to find it's way into my brain. But good luck to someone who does, he'll need it.

  • Neuroskeptic

    Anonymous #2: “I'm trying to understand how the drug selectively gains entry through cell wall”

    Good question. The authors say

    “[binding to sertraline] was intended to direct C-1A-siRNA molecules to 5-HT axons, extremely rich in axonal varicosities (>106 per mm3),29 expressing SERT, for which sertraline shows very high affinity”

    However this doesn't explain how the siRNA actually gets inside the cells. I don't know. It would seem like it would be hard because they're large molecules. I don't think siRNAs existed back when I was studying molecular biology. I assume there must be a known pathway.

  • Zoloft Birth Defect

    Too bad you can't measure side-effects like suicidal tendencies in mice? Or can you?

  • Neuroskeptic

    Sadly not…

  • Michelle

    Changing the make of SSRI's would still have the same makeup the has caused the birth defects would it not?

  • Fred

    I'm have the same question as Michelle.The changes to the SSRI's Would still have the same makeup. The drug companies are going nuts with all of the lawsuits.



No brain. No gain.

About Neuroskeptic

Neuroskeptic is a British neuroscientist who takes a skeptical look at his own field, and beyond. His blog offers a look at the latest developments in neuroscience, psychiatry and psychology through a critical lens.


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