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Glutamate and its role in addiction
BLOOMINGTON, Ind.—A study, published in early January and led by Indiana University on neurochemical changes associated with alcohol addiction, found that the neurotransmitter glutamate plays a role in some alcohol cravings. Alcohol dependence and alcohol use disorders occur in about 30 percent of all Americans, taking a severe toll on peoples’ lives, as well as the healthcare system and economy. Ninety percent of all attempts to cure the dependence on or abuse of alcohol result in relapse within four years. These relapses are primarily triggered by sights, sounds and situations associated with past drinking experiences.
“This is the first study to document changes in glutamate levels during exposure to alcohol cues in people with alcohol use disorders, and shines a spotlight on glutamate levels as an important target for new therapies to treat the condition,” says Dr. Sharlene Newman, cognitive neuroscientist and director of the Imaging Research Facility in the Department of Psychological and Brain Sciences at Indiana University Bloomington.
The study, recently published in the Journal of Alcohol and Alcoholism, builds upon research by scientists such as George Rebec, a professor emeritus in the Department of Psychological and Brain Sciences, who previously found that sights and sounds associated with addictive substances such as cocaine or alcohol affect glutamate levels in the brains of rats addicted to these substances. These sights and sounds are called “cues” because they elicit a craving for the previously abused substance.
According to Rebec, “Glutamate is an excitory signaling chemical that allows nerve cells to communicate. It is the most abundant neurotransmitter. We focused on glutamate for two reasons. The first is due to previous work in animal models that showed it plays a role in drug relapse/reinstatement. Animal research shows that cues associated with drug-taking activate glutamate neurons in brain circuits involved in motivated behavior. The second is because it is one of the neurotransmitters that we can measure with MRS [magnetic resonance spectroscopy] using our MRI scanner. Therefore we are able to measure glutamate levels in humans non-invasively, allowing us to compare the findings in animal models to those in humans.”
“Glutamate is the real workhorse of all transmitters in the brain,” Rebec continues. “Dopamine is the more popularly known neurotransmitter, a lack of which contributes to depression, anxiety, attention deficit hyperactivity disorder and Parkinson’s disease, but it actually accounts for less than 5 percent of all synaptic activity. By contrast, glutamate accounts for about 50 percent of this activity and is especially involved in the reward-motivation circuits integral to addiction.”
To conduct the new study, researchers enlisted 35 subjects, 17 with alcohol use disorder and 18 without the disorder. Then they measured concentrations of glutamate using magnetic resonance spectroscopy. The study found a decrease of the chemical in the brain of people with alcohol abuse disorder after they were shown cues associated with drinking—such as a photo of alcohol in a glass—compared to when they viewed neutral photos. Individuals without the disorder showed no change in glutamate levels when viewing the same images.
“Scientists can now confidently target glutamate levels in the brain as they develop new treatments for alcoholism and other forms of addiction,” reports Newman, who led the collaboration between her department’s addiction researchers to build upon Rebec’s previous work in animals.
“In animal models glutamate levels are measured by inserting a probe into the brain region of interest. That isn’t practical in human studies. MRS allows us to do it non-invasively,” Newman explains. “We again focus on a region of interest and exploit the chemical and magnetic properties of the chemical measure the concentration of a number of chemicals and luckily glutamate is one of them. The ability to both measure glutamate and measure it in a particular brain region is something only MRS can do.
“Insight into the neurochemical changes induced by abused substances allows researchers to focus on those changes in the search for potential treatments. Evidence of glutamate involvement suggests multiple potential drug targets, ranging from the receptors that respond to glutamate to the proteins that clear it from the synapse. But because glutamate is so abundant in the brain, the challenge is to find ways to focus on the circuits involved in drug craving without interfering with normal functioning.
“The most exciting aspect of this research is that it does demonstrate that there is a potential pharmaceutical treatment for drug addiction. Being able to translate the preclinical research conducted in this area to humans is an important step,” Newman concludes. “MRS is one way to do that.”
Technical expertise on the use of magnetic resonance spectroscopy to measure glutamate levels was provided by Newman, director of the IU Imaging Research Facility; Hu Cheng, a senior scientist in the Department of Psychological and Brain Sciences; and Ulrike Dydak, a professor in the School of Health Sciences at Purdue University. IU professor Peter Finn, a clinical psychologist who studies decision-making behavior in the early stages of alcohol use disorders, assisted in the recruitment of participants in the study.
Additional authors of the study were Rebec; undergraduate research assistant Derek Kellar and graduate student Allison Lake in the Department of Psychological and Brain Sciences; and Shalmali Dharmadhikari, a former graduate student in Dydak’s lab at Purdue. Newman is also the associate vice provost for undergraduate education at IU Bloomington.
This study was funded in part by the National Institutes of Health’s National Institute on Alcohol Abuse and Alcoholism and the Indiana Clinical and Translational Sciences Institute.