French researchers have linked abnormal activity in a specific part of the brain to compulsive cocaine seeking in rats, identifying a potential biomarker for addiction and method of treatment through deep brain stimulation.
A paper published April 6 in Proceedings of the National Academy of Sciences demonstrates that unusual patterns in the subthalamic nucleus (STN) — a structure belonging to the basal ganglia that plays a role in motor function and decision-making — could be used to predict which individuals are vulnerable to drug-escalating behavior.
Understanding why some people can use drugs recreationally with little consequence and others spiral out of control is a major challenge for addiction researchers, said Christelle Baunez, a researcher with the Institut de Neurosciences de la Timone in Marseille, France, and a co-lead author of the study.
"We don't know why we are so different from one person from the next, why some are so vulnerable and some have this amazing capacity to get drunk every Saturday and get clean for the entire week with no addiction issues," she said in an interview with The Academic Times. "Same thing with cocaine or any kind of addiction — it's totally unequal."
Baunez and her colleagues have been researching the STN for many years. In 2009, she co-authored a paper concluding that deep brain stimulation surgery in the STN — a treatment originally developed for neurodegenerative disorders like Parkinson's disease and obsessive-compulsive disorder — reduces motivation for cocaine in rats without affecting their drive for food.
"That was absolutely puzzling," she said. "We were all surprised that, somewhere in the brain, you could disassociate motivation for drugs from rewards like sweet food. That's what you want to do for an addict: Reduce motivation for the drug while restoring motivation for natural activities and substances."
Baunez's subsequent research has examined the progressive nature of addiction, in which users become willing to expend more and more effort for the same high. Using rat models in which the animals press levers to be administered drugs, she showed that stimulating the STN can prevent escalation of drug use.
But until now she hadn't addressed the "most robust criterion" for addiction — continuing to chase the high despite negative consequences, as with cigarette smokers who maintain daily habits despite the overwhelming evidence that it could kill them. "To mimic that in rodents, what we did in this paper was not to associate the drug intake with punishment, but to punish the seeking of the drug," she said.
The rats in the experiment pressed on a lever to seek the drug; half gained access to a second lever, which administered an injection of cocaine, and the other half were given a mild electric shock. About 80% of the rats stopped seeking the drug after receiving the shock, but most of the rest remained willing to seek cocaine by pressing a second lever despite the risk of pain.
"When we had that percentage of rats compulsively seeking the drug, we thought we should look at the stage before," Baunez explained. "To obtain this resistance to punishment, you need to have animals that have escalated their drug intake already. If they had limited access to the drug before going on to the task with the punishment, all animals extinguished the [addictive] behavior."
The researchers were unable to predict which rats would exhibit compulsive drug-seeking based on behavior or the number of injections. During the escalation phase of the experiment, the researchers recorded activity in the STN via implanted electrodes, seeking an early telltale sign.
"What we observed was a strong increase in the very low frequencies in the [alpha/theta and low-beta frequency bands] only in those individuals that are later resistant to the electric shock," Baunez said. "We thought, 'Wow, that's amazing. We have a biomarker.' And then all my friends told me, 'Yes, it's very interesting, but you need to prove causality.'"
To this end, the researchers took the rats that modified their behavior after receiving an electric shock and put them through another escalation — this time while applying deep brain stimulation that mimicked the brain wave patterns observed in the drug-seeking rats. At the end of the second escalation of drug use, the rats were again given the choice to seek cocaine despite the risk of an electric shock.
"They were resistant to punishment," Baunez said. "So, you can induce this compulsive drug-seeking just by mimicking this abnormal activity in the STN. That validates causality, and we really have this signature that is predictive of which individuals will be vulnerable to addiction."
In the second half of the study, the team members sought to determine whether they could treat drug-seeking rats by applying deep brain stimulation to the STN. They found that high-frequency stimulation at 130Hz did not have a positive effect, but a lower frequency of 30Hz was beneficial.
There is a standard frequency for deep brain stimulation of Parkinson's patients, but Baunez believes the procedure might not be so straightforward for people with substance use disorders. A different frequency may be required for each person. But the findings are promising because deep brain stimulation has been used for decades and is "highly transferable" to addiction medicine, she said.
Baunez's research is still ongoing. In a yet-to-be published paper, she and her colleagues show similarly beneficial effects in macaques. She hopes that her decades of research will eventually help people suffering from substance use disorders.
"Finding a different path we haven't investigated yet, a new idea to help people — that's my goal," she said.
The study, "Subthalamic low-frequency oscillations predict vulnerability to cocaine addiction," published April 6 in Proceedings of the National Academy of Sciences of the United States of America, was authored by Mickael Degoulet, Alix Tiran-Cappello, Etienne Combrisson, Christelle Baunez and Yann Pelloux, Institut de Neurosciences de la Timone.