Israeli discovery could help brain block urge for highly addictive fentanyl

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Research conducted at the Hebrew University of Jerusalem’s Edmond and Lily Safra Center for Brain Sciences and published Monday has unveiled insights into the brain’s potential ability to regulate the urge to consume the highly addictive opioid fentanyl and could provide a path to treatment.

The timely discovery comes as countries around the world struggle with public health crises caused by addiction to fentanyl and other synthetic opioids. Fentanyl is the main contributor to more than 100,000 annual drug overdose deaths in the US alone.

Israel also faces an opioid crisis fueled in recent years by fentanyl, which is at least 50 times stronger than heroin and highly addictive. The country leads the world in per capita prescriptions of opioids as a result of many physicians having seen them as a magic bullet for treating pain without knowing enough about the potential for abuse, dependency, and addiction.

The Hebrew University study, published in the peer-reviewed Current Biology journal, highlights the role that the claustrum plays in the brain’s response to fentanyl consumption.

The study was conducted on mice in neuroscientist Prof. Ami Citri‘s lab, where work is focused on how the little-understood claustrum supports the selection of relevant sensory information, and then how the brain encodes experiences that form the basis of habits, compulsions, and drug addiction. Dr. Anna Terem and Yonatan Fatal also contributed to the research.

“The claustrum is a thin sheet, or curtain, of neurons that sit under the cortex. It is very thin and communicates with almost all of the cortex, but mostly with the frontal regions, which have to do with rationalization, decision making, and self-control,” Citri said.

Prof. Ami Citri of Hebrew University of Jerusalem’s Edmond and Lily Safra Center for Brain Sciences (Yoram Aschheim)

“What we’ve learned in recent years from my lab and others is that the claustrum is a region that communicates very strongly with these frontal regions and largely defines their activity,” he said.

In the past, Citri studied the claustrum’s role in modulating how mice develop an appetite for cocaine. With the fentanyl crisis making headlines, Citri’s group decided to look into claustral neurons’ possible role in self-control regarding the consumption of opioids.

As in the past, they worked with mice. Studying human brains through scans was not possible in this case.

“It’s very challenging to study this in humans. If you do MRIs, [the claustrum] is very hard to tell apart from the region of cortex that’s next to it, which is called the insular cortex. That region has to do with inner motivations and how we motivate ourselves in terms of behaviors like eating and sexual appetite,” Citri said.

“The imaging resolution is just not good enough for us to be able to tease apart what should be attributed to the insular cortex and what to the claustrum,” he explained.

Illustrative: A research assistant holding a mouse used to study autism, December 15, 2021. (Jeff Roberson/AP)

When the mice in Citri’s lab were given fentanyl, it was observed that their claustrum was activated.

“This motivated us to study this further,” Citri said.

The scientists learned that the claustrum acts as a regulator of fentanyl intake. First, the team shut down the mice’s claustrum using genetic tools that can access specific neurons in mouse brains. This led to hyper-activation of the frontal cortex when the mice consumed fentanyl.

“The mice not only drank more fentanyl, but they were doing so in binges,” Citri noted.

The team interpreted this as the mice having given in to the drug and having lost their ability to stop its consumption. They drank repeatedly until they were “totally stoned,” and then stopped. But soon they came back to start the process again.

Then the scientists used laser pulses to turn on the claustrum and make it very active. This resulted in the mice immediately losing interest in the fentanyl when it was introduced to them.

“It was if we turned on their self-control, and they chose not to consume it anymore,” Citri said.

Dr. Anna Terem (left) and Yonatan Fatal (Hebrew University)

The team measured the level of claustrum activity when the mice were binging on the fentanyl and found that it was nonexistent. Just knowing that they were going to get the fentanyl shut down the mice’s neurons even before the drugged kicked in. Then, when the binge ended and they moved away from the drug, their claustrum activity rose.

The Times of Israel asked Citri whether it was possible to extrapolate any conclusions that could be applied to humans.

Citri said that there were two hypotheses. The first would be that people who are more susceptible to addiction or have an issue with impulse control are more likely to ingest larger amounts of the drug and therefore find themselves more easily on the path to addiction.

“These people might have a deficit in the function of the claustrum for whatever reason. Either it’s nonresponsive to neural control from other brain structures or it’s smaller or it has less impact on the cortex. This is worth investigating in the future because it might help us identify susceptible people versus people that are less likely to form addiction,” Citri said.

Another option to explore is how drug compounds that are already available might be able to bump up the activity of the claustrum to help certain people become more resistant to the over-consumption of fentanyl.

A Drug Enforcement Administration (DEA) chemist pours 2,500 packs of confirmed fentanyl onto a counter for testing at the DEA Northeast Regional Laboratory on October 8, 2019 in New York. (Don EMMERT / AFP)

“We have a good understanding of a small population of neurons in the claustrum that are unique in the sense that they express very specific receptors that are enriched for the expression of receptors for which there are drugs already available. This means that we could start thinking of drugs or drug combinations as pharmaceutical therapies,” Citri said.

He said it might even be worth looking at fentanyl itself and whether there is something inherent in it that causes diminished activity in the claustrum in all people. This could make sense given how quickly fentanyl dependency develops.

Although Citri studies the claustrum in general, he plans to continue investigating its relationship to fentanyl to address the urgency of the global public health crisis.

“One hope is that we can identify drugs that will modulate consumption and contribute that way,” he said.

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