Using rat models, researchers find that an existing drug could help to reduce cocaine relapse.
Researchers at the University of Pennsylvania in Philadelphia found that a drug called exendin-4 decreased cocaine-seeking behavior in addicted rats during withdrawal.
They report their findings in a paper that is now published in Neuropsychopharmacology.
According to a 2014 survey, around 913,000 users of cocaine now meet the criteria for dependence or abuse in the United States.
One of the biggest challenges that cocaine users face in kicking the habit is relapse, which occurs in 40–60 percent of cases.
Cocaine relapse is a “significant public health concern,” note the study authors, and as yet, there are no effective approved treatments.
“Our goal as basic scientists,” explains senior study author Heath D. Schmidt, a research assistant professor of psychiatry working in the University of Pennsylvania, “is to use animal models of relapse to identify novel medications to treat cocaine addiction.”
Repurposing GLP-1 receptor agonists?
Exendin-4 mimics a hormone that reduces blood sugar and food consumption and is approved for the treatment of type 2 diabetes and obesity. It is also being piloted as a treatment for Alzheimer’s disease.
The drug belongs to a class called glucagon-like peptide 1 (GLP-1) agonists. These drugs work by stimulating GLP-1 receptors, which are particular signal-receiving proteins that are present in the brain and the gut.
Using a rat model of cocaine relapse, the researchers identified a previously unknown and “critical role for GLP-1 receptors in cocaine-seeking behavior.”
“Moreover,” they note, “we have identified doses of the GLP-1 receptor agonist exendin-4 that selectively reduced cocaine seeking and did not produce adverse effects in rats.”
They suggest that their findings make a case for repurposing exendin-4 “as an anti-relapse medication.”
The study is also significant because the team located a low dose of exendin-4 that kept the medication effective without producing side effects. High rates of nausea and vomiting are common in people who take GLP-1 receptor agonists for type 2 diabetes and obesity.
In their experiments, the scientists showed that the reduction in cocaine-seeking behavior in the treated rats was not a consequence of the animals falling sick because of the drug.
Exendin-4 reduced drug-seeking behavior
The study was done in stages. First, the team tested blood from rats that had been taking cocaine for 21 days. This showed that the rats had reduced levels of GLP-1 hormone.
Although the main source of GLP-1 hormone in the body is cells in the small intestine, the nucleus tractus solitarius in the brainstem also produces it.
That result got the scientists interested in GLP-1 and wondering whether it may influence cocaine-seeking behaviour.
In the next step, the team tested the effect of GLP-1 receptor agonists in a “rat model of relapse.”
After allowing the rats to freely dose themselves intravenously with cocaine for a period of 3 weeks, the researchers induced a withdrawal period by replacing the cocaine with saline.
They also paired the cocaine dosing with cues, such as a light coming on when the rodents pressed the levers to give themselves a shot of cocaine.
During the withdrawal period, cocaine-seeking behavior reduced significantly from the 28 self-administered daily doses of the early phase.
Then, the researchers brought back the drug-seeking behavior in two ways: either by reintroducing cocaine, or by leaving saline in the dose but switching on the cue (the light that was paired with cocaine doses originally) when the rats pressed the lever to get a shot.
In both cases, the rodents went back to pressing the lever at a high rate, suggesting that they were “seeking the drug.” This is similar to what happens in addicted humans during relapse — they seek people, places, and things associated with the habit.
Then, the researchers carried out the experiments again, but this time, with rats that had been pretreated with exendin-4.
They discovered that the animals’ drug-seeking behavior did not shoot up when they sought to reintroduce it during withdrawal — neither after receiving an acute dose of cocaine, nor when exposed to the paired cues.
In the final part of the study, the team used a fluorescent marker to track where the GLP-1 receptor agonist went in the brain and found exactly which molecular pathway boosted the GLP-1 signaling.
“We’ve shown for the first time that central GLP-1 signaling plays an important role in cocaine-seeking.”
Prof. Heath D. Schmidt