Discovery may represent a future target for treating substance use disorders

Discovery may represent a future target for treating substance use disorders

In a rat model of impulsive behavior, researchers discovered that inhibiting certain acetylcholine receptors in the lateral habenula (LHb), a region of the brain that balances reward and aversion, made it more difficult to resist the urge to seek cocaine.

These findings point to a novel function for these receptors that might serve as a future target for the creation of cocaine use disorder treatments. There are no approved drugs to treat cocaine use disorder at the moment.

The National Institute on Drug Abuse (NIDA), a division of the National Institutes of Health, provided funding for the study, which was published in the Journal of Neuroscience.

Including cocaine and methamphetamine, drug overdoses involving stimulants claimed the lives of approximately 41,000 individuals in 2020. It is essential to increase the options available to those seeking treatment and support long-term recovery by creating safe and effective drugs that help treat addictions to cocaine and other stimulants.

The NIDA Director, Nora Volkow, M.D., stated that “this discovery gives researchers a fresh, precise target toward solving a problem that has long proved difficult – discovering treatments for cocaine addiction.”

“Adding this tool to clinical care could save lives from overdose and significantly enhance health and quality of life, as we have seen with drugs to treat opioid use disorder.”

Because the LHb serves as an interface between brain areas mediating emotion and reward and those involved with reasoning and other higher order thought processes, factors known to be associated with substance use disorders and major depressive disorders, addiction science researchers are particularly interested in the LHb as a target for the development of future treatments.

These areas, for instance, are engaged in controlling actions like refraining from a reward when it is assessed that it is not “helpful.”

This study further describes the molecular processes by which LHb neurons control impulsive cocaine-seeking, building on earlier research that demonstrated the significance of the LHb and cholinergic receptor signaling in this behavior.

Researchers employed a rat behavioral paradigm known as the Go/NoGo model.

In this experiment, rats were taught to inject themselves with cocaine by pressing a lever.

The Go/NoGo assignment, in which cocaine was available when the lights were on (Go), but not when they were off, was then specifically practiced (NoGo). Animals rapidly picked up that when cocaine wasn’t there, they should stop responding.

The LHb was then chemically altered by the researchers to see how it affected the rats’ capacity to suppress their reaction to cocaine.

They discovered that blocking a particular class of muscarinic acetylcholine receptors, known as M2Rs, with an experimental drug called AFDX-116 decreased response inhibition for cocaine, but not with a substance called pirenzepine, which blocks other muscarinic acetylcholine receptors known as M1Rs.

As a result, despite training, the rodents were no longer able to quit reacting for cocaine even in the absence of the drug (the “NoGo” condition) when M2Rs were blocked in the LHb.

This suggests that improving LHb M2R function may be a possible treatment goal for illnesses characterized by compulsive drug seeking and substance abuse.

The electrical activity of these neurons in response to acetylcholine-like medications was monitored by the researchers in order to study changes in LHb neuronal activity and the biological mechanisms by which M2Rs influence LHb neuronal activity.

Although both excitatory and inhibitory inputs onto LHb neurons were decreased by these medications, there was a net increase in inhibition, which would explain why cholinergic can prevent impulsive cocaine seeking.

According to Carl Lupica, Ph.D., head of the Electrophysiology Research Section of the Computational and Systems Neuroscience Branch of NIDA, “the LHb acts as an interface between rational thought in the forebrain and the modulation of neurotransmitters like dopamine and serotonin that originate in the midbrain, which are important in regulating decision processes and emotions.”

While the study’s immediate findings are connected to cocaine use, its larger implications for impulsivity in relation to other drugs and mental illnesses like obsessive-compulsive disorder are also worth noting.

Future research by our team will examine the connection between LHb activity and impulsive behavior brought on by other drugs like cannabis and opiates like heroin.

The muscarinic acetylcholine system is involved in several processes, including controlling vasodilation, regulating heart rate, and impacting motion sickness, among others.

This presents hurdles even though targeting M2Rs appears promising. Additionally, the body contains these receptors in many other parts of the brain.

As a first step, these researchers are attempting to pinpoint the location in the brain where the acetylcholine released in the LHb originates.

More research is required to create strategies to target the M­2Rs in the LHb without resulting in a cascade of negative effects.

The NIDA Intramural Research Program financed the study.

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