Belviq®, an anti-obesity drug that acts on serotonin receptors in the brain, shows signs of dampening the rewarding and reinforcing effects of cocaine in rhesus macaques. Dr. Gregory Collins of the University of Texas Science Center at San Antonio and the South Texas Veterans Health Care System San Antonio is working with Dr. Charles France to determine if this drug could be safely repurposed for the treatment of cocaine addiction.
Belviq®, also known as lorcaserin, is an anti-obesity drug developed by Arena Pharmaceuticals that was approved by the FDA in 2013. It works by activating the serotonin receptor 5-HT2c in the brain hypothalamus to induce satiety. However, activation of the 5-HT2c receptor can also dampen dopaminergic neurotransmission, which has important implications for cocaine abuse. Cocaine leads to the increased release of dopamine in the brain, a neurotransmitter which activates the reward pathways of the brain. Drs. Collins, Lisa Gerak, and France are studying whether the activation of 5-HT2c receptors could counteract the increase in dopamine caused by cocaine, reducing the rewarding and reinforcing effects of the drug. “There have been a lot of preclinical studies looking at 2c receptor agonists and 2a receptor antagonists as phamacotherapies for cocaine abuse but since this one is actually in the clinic it should be pretty easy to repurpose it for a different indication if we can find effects in the lab,” stated Collins.
Drug repurposing, or the study of a drug currently used for one disease or condition for its use in other diseases, is a strategy which can speed the time it takes for a drug to travel from the lab to the clinic. By beginning with a drug which has already been proven safe for humans with one disease, the success rate is greatly increased for its use in another. The NIH National Center for Advancing Translational Sciences developed a program in 2012 to support drug repurposing, which can be read about here.
In order to repurpose lorcaserin, Collins needed to determine the effectiveness of the drug to reduce cocaine self-administration in animals, to confirm that the dose was still safe, and to determine that tolerance to lorcaserin didn’t develop. For his experiments, Collins used the rhesus macaque, a species of monkey with behavioral responses to cocaine very similar to that of humans.
In the first set of experiments, the possibility of negative behavioral effects was tested in monkeys. This allowed them to determine a safe and pharmacologically active range of lorcaserin doses. Importantly, they observed that lorcaserin treatment induced yawning in monkeys, a behavioral response that is characteristic of 5-HT2c activation, indicating that the scientists were maintaining receptor specificity with their treatment method. They also evaluated the effects of lorcaserin on food-maintained responding, a test that was used to confirm that the changes in animal response to cocaine were actually due to the lorcaserin treatment, and not just a general disruption of the animals’ behavior. This test showed only modest changes in food-maintained responding, allowing Collins to proceed to testing the effects of lorcaserin against cocaine.
In the next phase of research, Collins and colleagues measured blood levels of lorcaserin in monkeys to determine the point at which lorcaserin is highest in the body following treatment. This information is important for identifying the appropriate pretreatment time to study the effects of lorcaserin against cocaine. In behavioral treatments, Collins was then able to treat the monkeys with cocaine at a point in which lorcaserin levels were highest.
Finally, the key experiment for lorcaserin was performed. Would treatment with the drug decrease the monkeys’ interest in cocaine? To determine this, Collins and colleagues used a cocaine self-administration assay in which the monkeys were trained to press a lever to self-inject cocaine. Normally, monkeys will respond at high rates to earn injections of cocaine. However, if the rewarding and reinforcing effects of the drug are reduced by lorcaserin, the monkeys should start to reduce this cocaine-taking behavior.
Amazingly, when the monkeys were pre-treated with lorcaserin, their preference for the lever delivering cocaine was significantly reduced. In fact, this effect was consistent over 14 days, suggesting that the monkeys did not develop a tolerance to lorcaserin. In addition, the effects of lorcaserin treatment were also observed with larger doses of cocaine, suggesting that the monkeys were unable to surmount the effects of lorcaserin by taking more cocaine.
This is excellent news for Dr. Collins and the France lab, suggesting great promise for lorcaserin in the treatment of cocaine abuse. As investigations of the anti-cocaine effects of lorcaserin move into human cocaine-abusers, Drs. Collins, Gerak, and France are now beginning to assess the effectiveness of lorcaserin against other stimulants of abuse such as methamphetamine.
To learn more about the France Lab, click here.