Hexbyte Glen Cove Researchers find activating a specific acetylcholine receptor in the brain reduces cocaine use in rodents

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Ball-and-stick model of the dopamine molecule, a neurotransmitter that affects the brain’s reward and pleasure centers. Credit: Jynto/Wikipedia

Cocaine, opioids, and other drugs of abuse disrupt the brain’s reward system, often shifting users’ priorities to obtaining more drug above all else. For people battling addiction, this persistent craving is notoriously difficult to overcome—but new research from scientists at MIT’s McGovern Institute for Brain Research and collaborators points toward a therapeutic strategy that could help.

Researchers in MIT Institute Professor Ann Graybiel’s lab and collaborators at the University of Copenhagen and Vanderbilt University report in a Jan. 25 online publication in the journal Addiction Biology that activating a signaling molecule in the brain known as muscarinic receptor 4 (M4) causes rodents to reduce self-administration and simultaneously choose a food treat over cocaine.

M4 receptors are found on the surface of neurons in the brain, where they alter signaling in response to the neurotransmitter . They are plentiful in the striatum, a brain region that Graybiel’s lab has shown is deeply involved in habit formation. They are of interest to addiction researchers, because along with a related receptor called M1, which is also abundant in the striatum, they often seem to act in opposition to the neurotransmitter dopamine.

Drugs of abuse stimulate the brain’s habit circuits by allowing dopamine to build up in the brain. With chronic use, that circuitry can become less sensitive to dopamine, so experiences that were once rewarding become less pleasurable and users are driven to seek higher doses of their drug. Attempts to directly block the system have not been found to be an effective way of treating addiction and can have unpleasant or dangerous side effects, so researchers are seeking an alternative strategy to restore balance within the brain’s reward circuitry. “Another way to tweak that system is to activate these muscarinic receptors,” explains Jill Crittenden, a research scientist in the Graybiel lab.

At the University of Copenhagen, neuroscientist Morgane Thomsen has found that activating the M1 receptor causes rodents to choose a food treat over cocaine. In the new work, she showed that a drug that selectively activates the M4 receptor has a similar effect.

When rats that have been trained to self-administer cocaine are given an M4-activating compound, they immediately reduce their drug use, actively choosing food instead. Thomsen found that this effect grew stronger over a seven-day course of treatment, with cocaine use declining day by day. When the M4-activating treatment was stopped, rats quickly resumed their prior cocaine-seeking behavior.

While Thomsen’s experiments have now shown that animals’ cocaine use can be reduced by activating either M1 or M4, it’s clear that the two muscarinic receptors don’t modulate cocaine use in the same way. M1 activation works on a different time scale, taking some time to kick in, but leaving some lasting effects even after the treatment has been discontinued.

Experiments with genetically modified mice developed in Graybiel’s lab confirm that the two influence drug-seeking behavior via different molecular pathways. Previously, the team discovered that activating M1 has no effect on cocaine-seeking in mice that lack a signaling molecule called CalDAG-GEFI. M4 activation, however, reduces cocaine consumption regardless of whether CalDAG-GEFI is present. “The CalDAG-GEFI is completely essential for the M1 effect to happen, but doesn’t appear to play any role in the M4 effect,” Thomsen says. “So that really separates the pathways. In both the behavior and the neurobiology, it’s two different ways that we can modulate the cocaine effects.” The findings suggest that activating M4 could help people with substance abuse disorders overcome their addiction, and that such a strategy might be even more effective if combined with activation of the M1 receptor.

Graybiel’s lab first became interested in CalDAG-GEFI in the late 1990s, when they discovered that it was unusually abundant in the main compartment of the brain’s striatum. Their research revealed the protein to be important for controlling movement and even uncovered an essential role in blood clotting—but CalDAG-GEFI’s impacts on behavior remained elusive for a long time. Graybiel says it’s gratifying that this long-standing interest has now shed light on a potential therapeutic strategy for substance abuse disorder. Her lab will continue investigating the molecular pathways that underlie addiction as part of the McGovern Institute’s new addiction initiative.



More information:
Morgane Thomsen et al, Effects of acute and repeated administration of the selective M 4 PAM VU0152099 on cocaine versus food choice in male rats, Addiction Biology (2022). DOI: 10.1111/adb.13145

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Hexbyte Glen Cove Two Russian cosmonauts, NASA astronaut return from ISS thumbnail

Hexbyte Glen Cove Two Russian cosmonauts, NASA astronaut return from ISS

Hexbyte Glen Cove

For the last decade, the space station’s population has varied between three and six as crews that blasted off from Russia’s Baikonur cosmodrome in Kazakhstan came and went. 

Two Russian cosmonauts and a NASA astronaut touched down Saturday on the steppe of Kazakhstan following a half-year mission on the International Space Station, footage broadcast by the Russian space agency showed.

Russia’s Sergei Ryzhikov and Sergei Kud-Sverchkov as well as NASA’s Kate Rubins landed on barren land at 0455 GMT around 150 kilometres (90 miles) southeast of the town of Zhezkazgan.

The Soyuz descent module carring the trio landed upright after descending through a cloudless sky on a fine spring day in central Kazakhstan, a Roscosmos TV commentator confirmed.

Molecular biologist Rubins, 42, and former military pilot Ryzhikov, 46, were rounding off their second missions in space having both made their ISS debuts following launches in July and October of 2016 respectively.

Kud’-Sverchkov, 39, another ex-military man, was completing his first mission.

Footage from the landing site showed Rubins smiling as she received a bouquet of flowers from retired cosmonaut Yuri Malenchenko, who was there to greet the crew.

“It is great to be on this side of things,” Rubins said.

She will return to NASA’s hub in Houston while colleagues Ryzhikov and Kud-Sverchkov are bound for Moscow as they wind down their missions.

During her debut mission in 2016, Rubins became the first person to sequence DNA in space.

In her second mission she continued her sequencing activities, worked on cariovascular experiments and oversaw a small patch of radishes “as they grew in orbit… harvesting them for analysis back on Earth”, according to NASA.

Busy orbital lab

For the last decade, the space station’s population has typically varied between three and six as crews that blasted off from Russia’s Baikonur cosmodrome in Kazakhstan came and went.

Entrepreneur Elon Musk’s SpaceX last year broke the monopoly that Russia and Baikonur had held on manned launches since the mothballing of the US shuttle programme in 2011, beginning a new chapter of spaceflight from US soil.

As a result the number of crew on board will reach 11 next week with the arrival of NASA’s SpaceX Crew-2 mission.

NASA’s Shane Kimbrough and Megan McArthur, Japanese astronaut Akihiko Hoshide, and Thomas Pesquet of the European Space Agency are expected to dock with the ISS next Friday, with the four-person crew they are replacing scheduled to return to Earth on April 28.

The absolute record for people aboard the ISS was set in 2009, when an arriving crew took the orbital lab’s population to 13.

That is also the joint all-time record for the most people in space at any one time after seven astronauts were aboard the NASA space shuttle Endeavour and a six-man crew was aboard the Mir space station simultaneously in March 1995.

Continuously occupied for more than 20 years, the ISS is expected to be retired before the end of the decade, raising questions about future cooperation between Russia and the West in space.

NASA on Friday said it had selected SpaceX to develop a spacecraft to land the first astronauts on the surface of the Moon since 1972—a huge victory for Elon Musk’s company.

April 12 marked the sixtieth anniversary of Soviet cosmonaut Yuri Gagarin’s historic marking the beginning of human spaceflight and a key moment in the race between Moscow and the West.

Since the fall of the Soviet Union there has been more cooperation than competition, although it is difficult to disguise the appearance that Roscosmos and NASA are going their separate ways as the ISS winds down.



© 2021 AFP

Citation:
Two Russian cosmonauts, NASA astronaut return from ISS (2021, April 17)
retrieved 18 April 2021
from https://phys.org/news/2021-04-russian-cosmonauts-nasa-astronaut-iss.html

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