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Using Cryo-EM Tech, Scientists Discover New Anti-Addiction Option

Posted August 6, 2019

There is still a lot researchers don’t know about how the brain works and what characteristics about it make people more or less likely to develop problems like depression and substance abuse. But, they have learned something called the serotonin transport gene plays a key role in the latter question.

Recently, scientists depended on a technology called cryo-electron microscopy (cryo-EM) to study the three major shapes of the serotonin transport gene (5-HTT).

Image credit: Julie Viken via Pexels (Free Pexels licence)

Image credit: Julie Viken via Pexels (Free Pexels licence)

A Bit About Cryo-EM

Cryo-EM allows seeing how biomolecules move and interact while functioning. One of the scientists who helped develop cryo-EM came up with a method of freezing transmission electron microscope (TEM) samples so rapidly that the result is a glass-like surface, rather than a crystallized one.

That kind of freezing is instrumental because it does not cause severe diffraction of the TEM’s electron beam. Then, it’s easier to maintain a clear view of the electrons for study. Moreover, the traditional preparation for TEM samples is complex and time-intensive. Cryo-EM eliminates the need for those measures and allows mere freezing instead.

Cryo-EM is also advantageous because it allows performing assessments at a near-molecular level. Scientists usually use it to study large proteins. However, when these researchers discovered the serotonin gene shapes, they showed how the technique could work well for much smaller molecules.

How Did Scientists Reach Their Conclusion?

First, their research involved targeting a psychoactive alkaloid called ibogaine. It’s in iboga, an African shrub. Alkaloids are a class of naturally occurring compounds that primarily contain basic nitrogen atoms. In some plants, they serve functions that prevent animals and plants from eating them.

The researchers depended on cryo-EM to look at how the serotonin transporter bound to ibogaine. Doing that allowed them to study the three shapes of the transporter’s structure: closed, inward-open and outward-open.

When examining how ibogaine interacted with the serotonin transporter, the team found it behaved differently from most antidepressants. They usually bind to the outward-open formation. But, ibogaine can attach to the serotonin transporter’s inward state.

The study’s senior author, Eric Goulaux, Ph.D., is no stranger to researching the serotonin transporter. In 2019, he was the leading member of a research team that was the first to show its structure. Those findings gave new details about how citalopram and paroxetine, two widely prescribed antidepressants, interact with and inhibit serotonin transport.

Serotonin affects virtually all behaviors humans display, in addition to impacting biological and neurological processes ranging from digestion to sleep. So, it’s easy to see how these findings could span beyond substance abuse treatment and answer other pressing questions scientists have.

What Does This Mean for the Future of Addiction Treatment Research?

Some people overlook how those who struggle with addiction didn’t necessarily get hooked when they encountered dealers willing to set them up with continual supplies of street drugs. Millions of people become addicted after their doctors prescribe highly addictive opioids to help with pain relief. Many individuals understandably believe prescription drugs are safe because they come from physicians.

This latest research could help avoid severe consequences of prescription drug addiction. It’s significant because it gives information scientists could use to target the serotonin transporter in different states and alter its activity. Moreover, researchers envision this newly gained knowledge could facilitate creating new molecules to bind to the serotonin transporter.

Ibogaine Is Far From an Ideal Option

The effects of ibogaine differ depending on the amount ingested. In small doses, it’s a mild stimulant. But, large doses cause people to go into psychedelic states or suffer unpleasant and harmful side effects. It can even be fatal, as more than 30 deaths in peer-reviewed literature indicate.

However, people with substance abuse report that taking significant amounts of ibogaine can reduce their opiate withdrawal symptoms and cravings. Ibogaine is illegal in the U.S. and several other countries. Some Americans, desperate for relief from their long-term addictions, cross the border into Mexico for treatment.

Thanks to this new research made possible through cryo-EM technology, scientists may devise ways to create new medications to help fight substance abuse without the hallucinogenic and dangerous side effects of ibogaine.

Hope for Improvements in Addiction Treatment

Substance abuse wreaks havoc on those who directly suffer from it, as well as their loved ones. Some reach such low points that they’ll try anything — even ibogaine, which is a Schedule I drug in the U.S. Their view is often that if their addiction may kill them anyway, it’s still worth pursuing a treatment that may also be fatal, but could break the addictive cycle.

But, this work by the team that used cryo-EM technology could offer a different option. It could give patients a choice to pursue legal pharmaceutical interventions that are highly effective and safe.

Written by Kayla Matthews, Productivity Bytes.

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