Diabetes Medication May Help Curb Cocaine Use

Exendin-4, a glucagon-like peptide-1 (GLP-1) receptor agonist known for its effectiveness in the treatment of type 2 diabetes, may be able to reduce cocaine dependence, according to a study in Neuropsychopharmacology .

Previous research showed that activating the GLP-1 receptors in the ventral tegmental area (VTA)—a brain region known to be involved in reward—reduces intake of highly palatable food in animal models. To test if these receptors might also play a role in drug-taking behaviors, researchers at the University of Pennsylvania School of Nursing and Medicine injected exendin-4 directly into the ventral tegmental area (VTA) of rats trained to self-administer cocaine by pressing a lever. The animals treated with exendin-4 showed reduced cocaine self-administration compared with control animals.

Additional experiments revealed that cocaine taking was associated with higher corticosterone levels in the animals’ blood, and cocaine increased the activation of GLP-1-producing neurons in the hindbrain, which project to the VTA. Injecting corticosterone directly into the hindbrain caused the activation of GLP-1-producing neurons and resulted in reduced cocaine intake—an effect that was not seen in animals pretreated with a GLP-1-receptor antagonist.

These findings offer “direct evidence that the effect [of decreased cocaine intake] was through activating the GLP-1 pathway,” explained Heath Schmidt, Ph.D., an assistant professor of psychiatry at the School of Medicine and the lead author of the study. “We think corticosterone activates the circuit and serves as a ‘brake’ on cocaine intake,” he noted. Injecting the GLP-1 receptor agonist into the VTA may have the same downstream effect as increasing corticosterone in the hindbrain, he said.

It is not a coincidence that an antidiabetic drug is involved in the brain’s addiction circuits. The FDA-approved drug exenatide, a synthetic version of exendin-4, has been shown to cause weight loss in patients with type 2 diabetes. Animal studies have also revealed that GLP-1 receptor activation suppresses the pleasure from eating tasty food without affecting the consumption of bland food.

The GLP-1 signaling system “regulates the palatable, hedonic, and highly rewarding aspects” of eating as well as cocaine addiction, Schmidt said. It may be involved in a whole host of “addiction-like behaviors such as compulsive eating” but not normal, hunger-driven eating. Thus, the GLP-1 receptor in the brain may present a desirable target for treating multiple addictions while leaving normal functions intact.

Since exenatide has already been used in human patients, the safety profile of the drug, which is given through injection, is well known. Nevertheless, Schmidt cautioned that clinical testing of GLP-1 receptor agonists for the treatment of addiction will have to consider potential adverse effects, particularly those on the central nervous system. “We know that it has the propensity to cause nausea and vomiting in humans.”

This research was supported by grants from National Institutes of Health. ■