Can anti-diabetes drugs be repurposed to treat cocaine addiction?
or technically,
Glucagon-like peptide-1 receptor activation in the ventral tegmental area attenuates cocaine seeking in rats.
[See Original Abstract on Pubmed]
Authors of the study: Nicole S. Hernandez, Kelsey Y. Ige, Elizabeth G. Mietlicki-Baase, Gian Carlo Molina-Castro, Christopher A. Turner, Matthew R. Hayes, & Heath D. Schmidt
Addiction is a disease affecting the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals., and neuroscientists have been trying to figure out how to best treat it. Cocaine addiction is a major problem in the United States. Cocaine is the second deadliest illicit drug following opioids and actually claims more lives than opioids in certain racial groups.1 Unfortunately, people facing cocaine addiction today have very few treatment options. Nicole Hernandez, a graduate student in Heath Schmidt’s lab, studies cocaine addiction using rats as a model to try to find effective treatments. In 2015, Dr. Schmidt’s lab discovered a drug already used to treat diabetes actually reduces the amount of cocaine rats will consume.2 These experiments were done when the rats had free access to cocaine. The major hurdle in the treatment of cocaine addiction, however, is preventing relapse after quitting because of drug cravings. Nicole wondered how this drug might affect the amount rats will work to obtain cocaine when it is not readily available. Seeking to answer this question, she tested if the drug could potentially reduce cocaine craving and relapse.
So what is this drug, and how does it work? In the last decade, the FDA approved several drugs for the treatment of Type II Diabetes. One of these drugs, Exendin-4, works by acting like a hormoneA substance produced in the body that controls or regulates the activity of certain cells or organs. Many hormones are produced by special glands and travel through the blood to reach the location in the body where they act. that is released by cells in the intestine and neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles in the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals., called glucagon-like peptide-1 (GLP-1). In the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals., GLP-1 binds to GLP-1 receptorsA molecule that binds to a chemical signal and causes a change inside a cell. For example, a receptor on the outside of a neuron can bind to a neurotransmitter released from a different neuron. and activates them, which stimulates neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles that reduce food intake. Exendin-4, the drug used in Nicole’s study, also activates GLP-1 receptorsA molecule that binds to a chemical signal and causes a change inside a cell. For example, a receptor on the outside of a neuron can bind to a neurotransmitter released from a different neuron. and therefore has the same effect as GLP-1 itself. GLP-1, aside from reducing food intake, also affects the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals.'s reward system. Since drugs of abuse act on this system, Dr. Schmidt’s lab tested whether Exendin-4 would affect the rewarding properties of cocaine. Indeed, Exendin-4 decreased the amount of cocaine rats took when given free access to the drug. However, it still wasn’t clear how Exendin-4 would affect cocaine craving. Craving can be measured by determining how hard rats are willing to work to get more cocaine, which they call cocaine seeking behavior. Specifically, they tested how many times rats would press a lever that was previously paired with cocaine but was no longer. Nicole found that treating rats given Exendin-4 did not work as hard to seek out cocaine: there was a decrease in cocaine seeking. This suggested that rats did not crave cocaine as much after receiving Exendin-4. Interestingly, this was the case even when given doses of Exendin-4 that were too low to affect food intake and body weight, suggesting that this medication may be used in cocaine addicts without any adverse effects such as weight loss or changes in appetite. As such, maybe Exendin-4 could be a first step in curbing drug relapse!
Armed with this interesting finding, Nicole tried to understand where this drug might be acting in the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals.. She thought it might be acting in the ventral tegmental area (VTA). The VTA is a region of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. rich in GLP-1 receptorsA molecule that binds to a chemical signal and causes a change inside a cell. For example, a receptor on the outside of a neuron can bind to a neurotransmitter released from a different neuron. and part of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals.’s reward system that is very active in response to cocaine. To see if Exendin-4 might be acting in the VTA to reduce cocaine seeking, she blocked GLP-1 receptorsA molecule that binds to a chemical signal and causes a change inside a cell. For example, a receptor on the outside of a neuron can bind to a neurotransmitter released from a different neuron. in the VTA and repeated the experiment. When GLP-1 receptorsA molecule that binds to a chemical signal and causes a change inside a cell. For example, a receptor on the outside of a neuron can bind to a neurotransmitter released from a different neuron. in the VTA were blocked, Exendin-4 no longer reduced cocaine seeking. Remember, Exendin-4 normally activates GLP-1 receptorsA molecule that binds to a chemical signal and causes a change inside a cell. For example, a receptor on the outside of a neuron can bind to a neurotransmitter released from a different neuron., so this result suggests that in order for Exendin-4 to reduce cocaine seeking, it needs to be able to activate GLP-1 receptorsA molecule that binds to a chemical signal and causes a change inside a cell. For example, a receptor on the outside of a neuron can bind to a neurotransmitter released from a different neuron. in the VTA. This is very strong evidence that Exendin-4 reduces cocaine seeking by activating GLP-1 receptorsA molecule that binds to a chemical signal and causes a change inside a cell. For example, a receptor on the outside of a neuron can bind to a neurotransmitter released from a different neuron. in brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. regions involved in reward.
This study uncovered a possible new use for drugs that activate GLP-1 receptorsA molecule that binds to a chemical signal and causes a change inside a cell. For example, a receptor on the outside of a neuron can bind to a neurotransmitter released from a different neuron., like Exendin-4. It also opens the door to several future experiments. For example, while Nicole showed that activating GLP-1 receptorsA molecule that binds to a chemical signal and causes a change inside a cell. For example, a receptor on the outside of a neuron can bind to a neurotransmitter released from a different neuron. in the VTA might reduce cocaine seeking, it is still not clear how this happens. The VTA is a region of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. that produces dopamineA neurotransmitter produced by neurons in the brain that regulates movement and emotion.. DopamineA neurotransmitter produced by neurons in the brain that regulates movement and emotion. is a chemical typically released during pleasurable experiences, such as food consumption and social interactions. Cocaine and other drugs of abuse hijack this system, increasing dopamineA neurotransmitter produced by neurons in the brain that regulates movement and emotion. signalling, which promotes addiction. It is possible that GLP-1 receptorA molecule that binds to a chemical signal and causes a change inside a cell. For example, a receptor on the outside of a neuron can bind to a neurotransmitter released from a different neuron. activation decreases the amount of dopamineA neurotransmitter produced by neurons in the brain that regulates movement and emotion. that is released to the rest of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. , which might blunt the addictive property of cocaine. While more research is needed to support this hypothesis, Nicole’s study sheds light on a possible new use for GLP-1 receptorA molecule that binds to a chemical signal and causes a change inside a cell. For example, a receptor on the outside of a neuron can bind to a neurotransmitter released from a different neuron. activators such as Exendin-4, already on the market to treat diabetes, in the treatment of cocaine addiction.
So what is this drug, and how does it work? In the last decade, the FDA approved several drugs for the treatment of Type II Diabetes. One of these drugs, Exendin-4, works by acting like a hormoneA substance produced in the body that controls or regulates the activity of certain cells or organs. Many hormones are produced by special glands and travel through the blood to reach the location in the body where they act. that is released by cells in the intestine and neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles in the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals., called glucagon-like peptide-1 (GLP-1). In the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals., GLP-1 binds to GLP-1 receptorsA molecule that binds to a chemical signal and causes a change inside a cell. For example, a receptor on the outside of a neuron can bind to a neurotransmitter released from a different neuron. and activates them, which stimulates neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles that reduce food intake. Exendin-4, the drug used in Nicole’s study, also activates GLP-1 receptorsA molecule that binds to a chemical signal and causes a change inside a cell. For example, a receptor on the outside of a neuron can bind to a neurotransmitter released from a different neuron. and therefore has the same effect as GLP-1 itself. GLP-1, aside from reducing food intake, also affects the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals.'s reward system. Since drugs of abuse act on this system, Dr. Schmidt’s lab tested whether Exendin-4 would affect the rewarding properties of cocaine. Indeed, Exendin-4 decreased the amount of cocaine rats took when given free access to the drug. However, it still wasn’t clear how Exendin-4 would affect cocaine craving. Craving can be measured by determining how hard rats are willing to work to get more cocaine, which they call cocaine seeking behavior. Specifically, they tested how many times rats would press a lever that was previously paired with cocaine but was no longer. Nicole found that treating rats given Exendin-4 did not work as hard to seek out cocaine: there was a decrease in cocaine seeking. This suggested that rats did not crave cocaine as much after receiving Exendin-4. Interestingly, this was the case even when given doses of Exendin-4 that were too low to affect food intake and body weight, suggesting that this medication may be used in cocaine addicts without any adverse effects such as weight loss or changes in appetite. As such, maybe Exendin-4 could be a first step in curbing drug relapse!
Armed with this interesting finding, Nicole tried to understand where this drug might be acting in the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals.. She thought it might be acting in the ventral tegmental area (VTA). The VTA is a region of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. rich in GLP-1 receptorsA molecule that binds to a chemical signal and causes a change inside a cell. For example, a receptor on the outside of a neuron can bind to a neurotransmitter released from a different neuron. and part of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals.’s reward system that is very active in response to cocaine. To see if Exendin-4 might be acting in the VTA to reduce cocaine seeking, she blocked GLP-1 receptorsA molecule that binds to a chemical signal and causes a change inside a cell. For example, a receptor on the outside of a neuron can bind to a neurotransmitter released from a different neuron. in the VTA and repeated the experiment. When GLP-1 receptorsA molecule that binds to a chemical signal and causes a change inside a cell. For example, a receptor on the outside of a neuron can bind to a neurotransmitter released from a different neuron. in the VTA were blocked, Exendin-4 no longer reduced cocaine seeking. Remember, Exendin-4 normally activates GLP-1 receptorsA molecule that binds to a chemical signal and causes a change inside a cell. For example, a receptor on the outside of a neuron can bind to a neurotransmitter released from a different neuron., so this result suggests that in order for Exendin-4 to reduce cocaine seeking, it needs to be able to activate GLP-1 receptorsA molecule that binds to a chemical signal and causes a change inside a cell. For example, a receptor on the outside of a neuron can bind to a neurotransmitter released from a different neuron. in the VTA. This is very strong evidence that Exendin-4 reduces cocaine seeking by activating GLP-1 receptorsA molecule that binds to a chemical signal and causes a change inside a cell. For example, a receptor on the outside of a neuron can bind to a neurotransmitter released from a different neuron. in brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. regions involved in reward.
This study uncovered a possible new use for drugs that activate GLP-1 receptorsA molecule that binds to a chemical signal and causes a change inside a cell. For example, a receptor on the outside of a neuron can bind to a neurotransmitter released from a different neuron., like Exendin-4. It also opens the door to several future experiments. For example, while Nicole showed that activating GLP-1 receptorsA molecule that binds to a chemical signal and causes a change inside a cell. For example, a receptor on the outside of a neuron can bind to a neurotransmitter released from a different neuron. in the VTA might reduce cocaine seeking, it is still not clear how this happens. The VTA is a region of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. that produces dopamineA neurotransmitter produced by neurons in the brain that regulates movement and emotion.. DopamineA neurotransmitter produced by neurons in the brain that regulates movement and emotion. is a chemical typically released during pleasurable experiences, such as food consumption and social interactions. Cocaine and other drugs of abuse hijack this system, increasing dopamineA neurotransmitter produced by neurons in the brain that regulates movement and emotion. signalling, which promotes addiction. It is possible that GLP-1 receptorA molecule that binds to a chemical signal and causes a change inside a cell. For example, a receptor on the outside of a neuron can bind to a neurotransmitter released from a different neuron. activation decreases the amount of dopamineA neurotransmitter produced by neurons in the brain that regulates movement and emotion. that is released to the rest of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. , which might blunt the addictive property of cocaine. While more research is needed to support this hypothesis, Nicole’s study sheds light on a possible new use for GLP-1 receptorA molecule that binds to a chemical signal and causes a change inside a cell. For example, a receptor on the outside of a neuron can bind to a neurotransmitter released from a different neuron. activators such as Exendin-4, already on the market to treat diabetes, in the treatment of cocaine addiction.
About the brief writer: Nitsan Goldstein
Nitsan is a third year graduate student in Nick Betley’s lab. She is interested in how the brain senses the energy needs of the body and coordinates appropriate behaviors
Citations:
Warner M, Trinidad JP, Bastian BA, et al. Drugs most frequently involved in drug overdose deaths: United States, 2010–2014. National vital statistics reports; vol 65 no 10. Hyattsville, MD: National Center for Health Statistics. 2016.
Schmidt HD, Mietlicki-Baase EG, Ige KY, Maurer JJ, Reiner DJ, Zimmer DJ, et al. Glucagon-like peptide-1 receptor activation in the ventral tegmental area decreases the reinforcing efficacy of cocaine. Neuropsychopharmacology. 2016;41:1917–1928.