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Researchers have found that activating certain acetylcholine receptors in the brain reduces the use of cocaine in rodents.

A ball-and-stick model of the dopamine molecule, a neurotransmitter that affects the rewards of the brain and the center of pleasure. Credit: Jynto / Wikipedia

Cocaine, opioids, and other substances of abuse disrupt the brain’s reward system and often shift the user’s priority to getting more drugs than anything else. For those who fight addiction, this persistent craving is notorious for being difficult to overcome, but new research by scientists and collaborators at MIT’s McGovern Institute for Brain Research shows useful treatment strategies.


Researchers in the laboratory of Professor Anne Gravier of the MIT Institute and collaborators at the University of Copenhagen and the University of Vanderbilt report in an online publication of the journal on January 25. Addiction biology Activation of signaling molecules in the brain known as muscarinic receptors 4 (M4) reduces rodents cocaine Choose a treat over cocaine at the same time as self-administration.

M4 receptors are found on the surface of neurons in the brain and alter signal transduction in response to neurotransmitters. acetylcholine.. They are abundant in the striatum and are areas of the brain that have shown that Graybiel’s lab is deeply involved in habit formation. They are of interest to addiction researchers because they often appear to act against the neurotransmitter dopamine, along with a related receptor called M1, which is also abundant in the striatum.

Substances of abuse stimulate the habitual circuits of the brain by allowing dopamine to accumulate in the brain. When used chronically, the circuit can become less sensitive to dopamine, which makes the once rewarding experience unpleasant and encourages users to look for higher doses of the drug.Try to block directly Dopamine Researchers have an alternative strategy to restore balance within the brain’s reward circuit, as the system has not been found to be an effective method of treating addiction and can cause unpleasant or dangerous side effects. I’m looking for. “Another way to fine-tune the system is to activate these muscarinic receptors,” explains Jill Critenden, a research scientist at the Gray Beer Institute.

At the University of Copenhagen, neuroscientist Morgan Thomsen discovered that activation of the M1 receptor causes rodents to choose food over cocaine. In the new work, we have shown that drugs that selectively activate M4 receptors have similar effects.

When rats trained to self-administer cocaine are given M4 activating compounds, they immediately reduce substance use and actively choose food instead. Thomsen found that this effect became stronger during the 7-day treatment process and that cocaine use decreased day by day. Upon discontinuation of M4 activation therapy, the rats immediately resumed their previous cocaine-seeking behavior.

Thomsen’s experiments have shown that activation of either M1 or M4 can reduce cocaine use in animals, but it is clear that the two muscarinic receptors do not regulate cocaine use in the same way. am. Activation of M1 works on different time scales and takes some time to begin, but some lasting effects remain even after treatment is discontinued.

In an experiment with genetically modified mice developed in Gray Beer’s lab, two Receptor It affects drug-seeking behavior through various molecular pathways. Earlier, the team discovered that activation of M1 did not affect the search for cocaine in mice lacking a signaling molecule called CalDAG-GEFI. However, activation of M4 reduces cocaine consumption regardless of the presence of CalDAG-GEFI. “CalDAG-GEFI is completely essential for the M1 effect to occur, but it doesn’t seem to play any role in the M4 effect,” says Thomsen. “It really isolates the pathway. In both behavior and neurobiology, there are two different ways in which cocaine effects can be regulated.” The findings show that M4 activation is a substance abuse disorder in people. May help overcome addiction, suggesting that such a strategy may be even more effective when combined with M1 receptor activation.

Gray Beer’s lab was first interested in CalDAG-GEFI in the late 1990s and discovered that it was unusually abundant in the main compartment of the striatum of the brain. Their research reveals that proteins are important for controlling movement and even their important role in blood coagulation, but the behavioral effects of CalDAG-GEFI remain elusive for a long time. did. Gray Beer says it’s good to see this long-standing interest shed light on potential treatment strategies for substance abuse disorders. Her lab continues to explore the underlying molecular pathways of addiction as part of a new addiction initiative at the McGovern Institute for Brain Research.


New research may lead to therapeutic interventions to treat cocaine addiction


For more information:
Effect of Acute and Repeated Administration of Selective M 4 PAM VU0152099 on Cocaine vs. Food Selection in Male Rats, Morgane Thomsen et al, Addiction biology (2022). DOI: 10.1111 / adb.13145

Quote: Researchers have found that activating certain acetylcholine receptors in the brain reduces the use of cocaine in rodents (February 16, 2022). .html

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Researchers have found that activating certain acetylcholine receptors in the brain reduces the use of cocaine in rodents.

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