Canceling Out Cocaine: Rewiring the Brain to Fight Addiction

By Emma Baltrusaitis

Addictive drugs profoundly alter brain circuits, triggering lasting changes that hijack the reward pathways of the brain. Drugs, such as cocaine, increase the release of dopamine, a chemical messenger associated with pleasure, mood, and attention span. This surge in dopamine reinforces the behavior of drug use, encouraging the brain to seek the drug repeatedly. As the initial high subsides, a portion of the brain called the amygdala is activated, spurring negative emotions, which create a cycle of seeking the drug for temporary relief from discomfort. 

As the brain begins to associate drugs with survival-level reward, cravings become increasingly impossible to resist. Because cocaine is not an opioid, there are no medications currently available to act as agonists, easing withdrawal. Therefore, scientists have developed a new approach: rather than blocking the drug craving characteristic of addiction, they have attempted to reprogram the brain’s initial response to the drug. Researchers Scott Sternson and Michael Michaelides, at the University of California, San Diego and the National Institute on Drug Abuse, respectively, have collaborated to engineer ion channels that reduce, and may even eliminate, the dopamine rush normally associated with cocaine consumption.

Sternson and Michaelides were inspired to engineer a drug-sensitive feedback process inspired by the loop systems that already monitor human physiology, such as temperature and appetite. Ion channels are proteins that act as gates in neuron membranes, letting charged particles in and out. Sternson and Michaelides’ research aims to develop artificial receptor proteins that respond to cocaine during drug-taking, but not to the molecules typically found in a normal biological system. Cocaine does not directly activate ion channels in nature, so the researchers had to engineer entirely new ones. These custom-designed proteins, or cocaine-activated ion channels, trigger an inhibitory signal in reward neurons. They can be placed in specific types of brain cells, allowing scientists to control exactly how those cells respond. Depending on the version, the channels can either stimulate neurons to fire (excite them) or quiet them down (inhibit them) when cocaine binds. Thus, cocaine would essentially “turn itself off.”

In their experimental approach, the researchers focused on the lateral habenula (LHb), a region in the brain that controls motivation and reward. Normally, the LHb suppresses the reinforcement of addictive drugs, inhibiting the effects of pleasure. When cocaine enters the brain, though, the LHb neurons are temporarily inhibited, strengthening cocaine’s addictive pull. Sternson and Michaelides targeted an excitatory version of their engineered ion channels to the LHb neurons in the brains of rats that had been trained to self-administer cocaine intravenously. They hoped to make the neurons more active, instead of silencing them, during cocaine use.

Sternson and Michaelides’ results demonstrated that rats with these excitatory cocaine-sensitive channels in their LHb showed weaker spikes in dopamine after taking cocaine, and a remarkable drop in cocaine self-administration when compared with the control group. Significantly, because the engineered ion channels only activated in response to cocaine, and only in the targeted neurons, the rats’ normal motivation for natural rewards like food remained unaffected.

Of course, there are limitations. The researchers have not been able to pinpoint the exact subtypes of LHb neurons that are usually inhibited by cocaine, so it’s possible that their engineered channels also activated some neurons that wouldn’t usually respond in that way. Still, the results suggest that this feedback-based strategy could be adapted to other drugs, such as opioids or nicotine, by designing ion channels that are selectively activated by those substances.