Scientists at the NIH have discovered 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 rat model of impulsive behavior. These findings identify a new role for these receptors that may represent a future target for the development of treatments for cocaine use disorder, according to the researchers.

The team, which published its study “Muscarinic Acetylcholine M2 Receptors Regulate Lateral Habenula Neuron Activity and Control Cocaine Seeking Behavior” in the Journal of Neuroscience, notes that are currently no approved medications to treat cocaine use disorder. In 2020, over 41,000 people died from drug overdoses involving stimulants, including cocaine and methamphetamine.

“The lateral habenula (LHb) balances reward and aversion by opposing activation of brain reward nuclei and is involved the inhibition of responding for cocaine in a model of impulsive behavior. Previously, we reported that the suppression of cocaine seeking was prevented by LHb inactivation or nonselective antagonism of LHb mAChRs,” write the investigators.

“Here, we investigate mAChR subtypes mediating the effects of endogenous acetylcholine in this model of impulsive drug seeking and define cellular mechanisms in which mAChRs alter LHb neuron activity. Using in vitro electrophysiology, we find that LHb neurons are depolarized or hyperpolarized by the cholinergic agonists oxotremorine-M (Oxo-M) and carbachol (CCh), and that mAChRs inhibit synaptic GABA and glutamatergic inputs to these cells similarly in male and female rats.

“Synaptic effects of CCh were blocked by the M2-mAChR (M2R) antagonist AFDX-116 and not by pirenzepine, an M1-mAChR (M1R) antagonist. Oxo-M-mediated depolarizing currents were also blocked by AFDX-116. Although M2R activation inhibited excitatory and inhibitory inputs to LHb neurons, the effect on excitation was greater, suggesting a shift in excitatory-inhibitory balance toward net inhibition. Activation of VTA inhibitory inputs to LHb neurons, via channelrhodopsin-2 expression, evoked IPSCs that were inhibited by M2Rs.

“Finally, we measured LHb-dependent operant response inhibition for cocaine and found it impaired by antagonism of M2Rs, and not M1Rs. In summary, we show that a cholinergic signal to LHb and activation of M2Rs are critical to enable inhibition of responding for cocaine, and we define cellular mechanisms through which this may occur.”

Discovery gives researchers a new, specific target

“This discovery gives researchers a new, specific target toward solving a problem that has long been elusive–developing treatments for cocaine addiction,” says Nora Volkow, MD, director of the National Institute on Drug Abuse (NIDA). “As we have seen with medications to treat opioid use disorder, adding this tool to clinical care could save lives from overdose and drastically improve health and quality of life.”

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

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

The researchers then chemically manipulated the LHb, to assess the impact on the rats’ ability to withhold their response to cocaine. They found that response inhibition for cocaine was impaired by blocking a specific type of muscarinic acetylcholine receptor, known as M2Rs, with an experimental drug called AFDX-116, and not with a drug called pirenzepine that blocks other muscarinic acetylcholine receptors known as M1Rs. Thus, when M2Rs were blocked in the LHb the rodents were no longer able to stop responding for cocaine even when it was not available (the “NoGo” condition), despite the training. This indicates that increasing LHb M2R function may represent a potential target for treating impulsive drug seeking and substance use disorders.

“While the immediate results of this study are related to cocaine seeking, there are also greater implications for impulsivity as it relates to other drugs as well as to psychiatric conditions like obsessive-compulsive disorder,” said Carl Lupica, PhD, chief of the Electrophysiology Research Section of the Computational and Systems Neuroscience Branch of NIDA. “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 muscarinic acetylcholine system is involved in everything from regulating heart rate, affecting motion sickness, and 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 the 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 the LHb originates.

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