Diabetes Drug May Be Effective in Treating Addiction

Pam Harrison

October 25, 2012

Exenatide (Ex-4), a glucagonlike peptide-1 (GLP-1) receptor agonist currently used in the management of type 2 diabetes, could effectively treat drug addiction, including cocaine dependence, new research shows.

Investigators at Vanderbilt University in Nashville, Tennessee, found that mice pretreated with the drug seemed to enjoy cocaine less, spending less time in the treatment chamber following cocaine introduction, compared with mice that were not pretreated with Ex-4.

"We know that the GLP-1 receptor affects the dopaminergic system and when dopamine neurotransmission is impaired, it leads to hedonic feeding and obesity," study investigator Aurelio Galli, PhD, professor of molecular physiology and biophysics and the Vanderbilt Brain Institute, told Medscape Medical News.

"So providing animals with a GLP-1 agonist activates the GLP-1 receptor and decreases interest in highly palatable food, and we found it also works to decrease the craving for cocaine."

The study was published online October 23 in a letter to the editor in Molecular Psychiatry.

Reduced Reward

GLP-1 is released in response to food intake and acts both peripherally and centrally to regulate feeding behavior.

Emerging data suggest that peptides such as GLP-1 may also be involved in drug reward and thus could serve as a therapeutic target for the treatment of psychostimulant addiction.

GLP-1 receptors are expressed in a number of regions in the brain that are part of the reward circuit that makes drugs like cocaine addictive, said Dr. Galli.

Because drug reward and hedonic feeding behavior use overlapping brain circuitry and mechanisms, "we hypothesized that the GLP-1R [GLP-1 receptor] agonist Ex-4 would reduce the rewarding effects of cocaine," the investigators write.

Using conditioned place preference, a test in which an animal is placed into 1 of 2 separate compartments of a test chamber, mice consistently migrated to the test chamber in which they received a pleasurable injection of cocaine.

However, when researchers pretreated mice with Ex-4, the animals appeared to enjoy the drug less, spending less time in the treatment chamber containing cocaine.

The rewarding effects of cocaine were attenuated in mice pretreated with Ex-4, regardless of the pretreatment dose. In addition, the researchers found no evidence of negative side effects or addiction to Ex-4 treatment.

The authors caution that additional research is needed to verify dosing structure and to determine whether these findings extend to other psychostimulants.

However, if results from future studies are positive, there may be significant clinical implications.

"What we have demonstrated is that a brain mechanism already known to be therapeutic for the treatment of diabetes also appears to be implicated in at least certain types of drug addiction," study coauthor Gregg Stanwood, PhD, assistant professor of pharmacology and an investigator within the Vanderbilt Kennedy Center and Vanderbilt Brain Institute, said in a release.

"We found that this drug...that is already used for the medical management of diabetes reduces the rewarding effects of cocaine in animals. We suspect that this is a general mechanism that will translate to additional drugs of abuse, especially other stimulants like amphetamine and methamphetamine."

Repurposing Drugs

Nigel Greig, PhD, from the National Institute on Aging in Baltimore, Maryland, told Medscape Medical News that he and his team have been working on the GLP-1 receptor drugs in the diabetes field for many years.

More recently, a number of investigators have been repurposing these drugs for neurological disorders, mostly notably Alzheimer's and Parkinson's disease. They are currently in clinical trials to assess the drugs' potential as neuroprotective and neurotrophic agents.

"This is the first strong scientific evidence that the same drugs may be repurposed for the treatment of drug abuse, and I think the findings are very intriguing and they are worth following up," said Dr. Greig.

The authors and Dr. Greig have disclosed no relevant financial relationships.

Mol Psychiatry. Published online October 23, 2012. Abstract