Star-shaped brain cells can turn off” neurons involved in heroin relapse

Star-shaped brain cells can turn off” neurons involved in heroin relapse

Neuroscientists at the Medical University of South Carolina (MUSC) report in Science Advances that star-shaped brain cells called astrocytes can "turn off" neurons involved in a heroin relapse. Drug-related cues in the environment can increase the urge to seek drugs and lead to relapse. In this article, a team led by Peter Kalivas, Ph.D., and Anna Kruyer, Ph.D., both of the Department of Neuroscience, examined how astrocytes interact with neurons and whether astrocytes play an important role in regulating the response to drug cues.

When we learn to ride a bike or solve a math problem, the messenger cells in our brain called neurons make connections that allow them to communicate better, making it easier for us to complete the same task next time. The same thing happens when we learn to associate pleasure with harmful substances like drugs. Neurons send powerful messages to each other, motivating us to keep coming back to them.

Communication between neurons is controlled by a variety of cells, particularly a group of star-shaped cells called astrocytes. Astrocytes surround our neurons and act as traffic lights, regulating communication between cells, particularly in addictive behavior.

Another important factor in addiction and relapse is the chemical messenger glutamate. Glutamate stimulates neurons, causing them to send out electrical signals to communicate with each other. The Kalivas laboratory was instrumental in establishing the importance of glutamate. Through decades of research, Kalivas has developed the “glutamate hypothesis of addiction,” Kruyer said.

According to this hypothesis, too much glutamate can cause our neurons to constantly fire in response to drug-induced environmental stimuli. This constant fire pushes communication between cells into overdrive and promotes drug-addictive behavior and relapse.

Kalivas and Kruyer found that astrocytes can slow down overactive communication.

Astrocytes are like a brake in a car and you apply them to stop the glutamate signal.”

Anna Kruyer, Ph.D., Department of Neuroscience, MUSC

But how exactly do they do that?

To answer this question, the researchers used an established model of heroin relapse. In the model, rats first learn to self-administer heroin by pressing a lever. After pressing the lever, they receive the drug along with light and sound signals so that the rats can associate the signals with the drug. Then the signal and drug are removed, mimicking withdrawal. Eventually the animals are given access to the signal again, and pressing the lever is a measure of drug addiction and relapse.

Using this approach, Kruyer and Kalivas found that astrocytes adapt in two ways to reduce drug addiction during withdrawal. A family of astrocytes move closer to neurons and divert glutamate away from the synapse, reducing communication between neurons. Another family increases the expression of the glutamate transporter GLT-1, which takes up excess glutamate. In both cases, astrocytes slow down neuronal communication during withdrawal.

However, fewer astrocytes were available for this braking function during the relapse phase and they were located further away from the neurons. Using special chemical technology, Kruyer and Kalivas were able to turn astrocytes on and off to change their behavior, showing that these star-shaped cells play an important role.

“When astrocytes surround neurons,” Kruyer explained, “they essentially suck up the glutamate and close that synapse,” she said. “But when they withdraw from neurons, it’s like you’ve lost the brakes.”

These findings could provide new insights into how to prevent relapses.

“Because astrocytes undergo two adaptations in the normal brain to suppress relapse, we believe they could be a valuable cellular target for developing therapeutics to combat relapse in substance use disorders,” Kruyer said.

Previous clinical studies have shown that reducing glutamate alone is not enough to prevent relapse in humans. These results suggest the possibility that combination therapy that not only lowers glutamate levels but also enhances the braking effect of astrocytes may be more successful and warrants further investigation.

“Historically, neurons have received the most attention when it comes to behavioral pathology,” Kruyer said. “Our results show that we need to look at the nervous system more holistically and consider that cell types other than neurons can influence behavior and may be key to treating relapse.”

To set the stage for new astrocyte-based therapies, the Kalivas Lab is trying to identify potential gene targets.

“Many genes are expressed in astrocytes that are not expressed in other brain cells, including neurons,” Kalivas said. "If we understand which of these genes are critical for astrocyte regulation of relapse, we can develop drugs that selectively increase the ability of astrocytes to inhibit relapse. This is a branch of active research in our laboratory, and we have identified a few astrocyte-selective gene products that could serve as targets in the treatment of substance use disorders."

Source:

Medical University of South Carolina

Reference:

Kruyer, A., et al. (2022) Plasticity in astrocyte subpopulations regulates heroin relapse. Scientific advances. doi.org/10.1126/sciadv.abo7044.

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