Personal care treatments

Study reveals specific new target for development of treatments for cocaine addiction

Researchers found that blocking certain acetylcholine receptors in the lateral habenula (LHb), an area of ​​the brain that balances reward and aversion, made it harder to resist seeking cocaine in a model of rat with impulsive behavior. These findings identify a new role for these receptors that could represent a future target for the development of treatments for cocaine use disorders. There are currently no drugs approved to treat cocaine use disorders.

Posted in the Journal of Neuroscience, the study was supported by the National Institute on Drug Abuse (NIDA), part of the National Institutes of Health. In 2020, more than 41,000 people died from drug overdoses involving stimulants, including cocaine and methamphetamine. Developing safe and effective drugs that help treat addictions to cocaine and other stimulants is essential to expanding the choices available to people seeking treatment and to help support recovery.

This discovery gives researchers a specific new target to solve a problem that has long been elusive – developing treatments for cocaine addiction. As we have seen with drugs to treat opioid use disorder, adding this tool to clinical care could save lives from overdose and dramatically improve health and quality of life. “

Nora Volkow, MD, Director of NIDA

Addiction science researchers are particularly interested in LHb as a target for the development of future treatments because of its position as an interface between brain regions involved in reasoning and other order thought processes. higher and those that mediate emotion and reward – factors known to be associated with substance use. disorders as well as major depressive disorders. For example, these domains are involved in regulating behaviors such as abstaining from a reward when it is determined not to be “beneficial.”

Building on previous work that established the importance of LHb and acetylcholine receptor signaling in impulsive cocaine seeking, this study further defines the cellular mechanisms by which LHb neurons regulate this behavior. The researchers used a behavioral paradigm called the Go/NoGo model in rats. In this model, rats were trained to self-administer cocaine, where pressing the lever led to an injection of the drug. This was followed by Go/NoGo task-specific training where cocaine was available when the lights were on (Go), but not when the lights were off (NoGo). The animals quickly learned to stop responding when cocaine was not available.

The researchers then chemically manipulated LHb, to assess the impact on the rats’ ability to hold back their response to cocaine. They found that inhibition of the cocaine response was impaired by blocking a specific type of muscarinic acetylcholine receptor, known as M2Rs, with an experimental drug called AFDX-116, not with a drug called pirenzepine that blocks other muscarinic acetylcholine receptors known as M1Rs. Thus, when M2Rs were locked into LHb, rodents were no longer able to stop responding to cocaine even when it was unavailable (the “NoGo” condition), despite training. This indicates that the increase in LHb M2The R function may represent a potential target for the treatment of impulsive drug seeking and substance use disorders.

The researchers also studied the cellular mechanisms by which M2Rs alter neuronal LHb activity by measuring changes in the electrical activity of these neurons in response to acetylcholine drugs. Although these drugs reduced both excitatory and inhibitory inputs to LHb neurons, there was a marked increase in inhibition, which may explain acetylcholine’s ability to limit impulsive cocaine seeking.

“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-making processes and emotions,” said Carl Lupica. , Ph.D., Chief of the Electrophysiology Research Section of NIDA’s Computational and Systems Neuroscience Branch. “While the immediate findings of this study relate to cocaine seeking, there are also broader implications for impulsivity with respect to other drugs as well as psychiatric conditions like obsessive-compulsive disorder. Our Future studies will explore the relationship between LHb activity and impulsive behavior related to other drugs such as cannabis and opioids such as heroin.”

Although targeting M2Rs is promising, there are challenges because the acetylcholine muscarinic system is involved in everything from regulating heart rate to motion sickness to controlling vasodilation, for example. These receptors are also located throughout the body, including many other regions of the brain. Further research is needed to develop ways to target the M2Rs in LHb without causing a cascade of side effects, and as a first step, these researchers are now trying to identify where in the brain the acetylcholine released in LHb comes from.

The study was funded by the NIDA Intramural Research Program.


Journal reference:

Wolfe, CIC, et al. (2022) Muscarinic acetylcholine M2 receptors regulate the lateral activity of Habenula neurons and control cocaine-seeking behavior. The Journal of Neuroscience.