New Evidence for Metabotropic Glutamate Receptors As Targets for Alcoholism Therapy

Volume 20, Number 3, September 2009


Joyce Besheer, Ph.D.

      All drugs of abuse produce distinct interoceptive/subjective effects that are perceived by the individual and can be distinguished from a non-drug state. For example, after drinking a glass of wine you may feel lightheaded, dizzy, sleepy or relaxed. These subjective effects represent a major controlling process that regulates drug-seeking behavior. Understanding the processes in the brain that affect these subjective effects is key to understanding how alcohol and other substances of abuse gain control over behavior in addiction.
The neurobiological mechanisms that regulate how the brain perceives alcohol are not yet fully understood. For decades, researchers have examined the glutamatergic system in the brain to better understand the effects of alcohol. Recently, a specific subtype of metabotropic glutamate receptors (mGlu5) has been identified as a potential target for new therapies for alcoholism and other drugs of abuse.

    Joyce Besheer, Ph.D., assistant professor at the UNC Bowles Center for Alcohol Studies and the Department of Psychiatry, and colleagues have recently discovered that mGlu5 receptors in the nucleus accumbens (a brain region known to modulate drug reward) regulates the subjective effects of alcohol. Using a well characterized drug discrimination procedure, rats were trained to discriminate the subjective effects of a moderate dose of alcohol from water. Besheer examined how the subjective effects of alcohol were changed by compounds that are known to block or enhance mGlu5 receptor function. These studies, recently published in the Journal of Neuroscience, show for the first time that blocking mGlu5 receptors within the nucleus accumbens blunts the subjective effects of alcohol and activation of these receptors enhances the subjective effects of alcohol. “We are excited about these findings, because they show that mGlu5 receptor activity in the nucleus accumbens is critical for the perception of alcohol,” said Besheer.

      While it is still unclear exactly how the interoceptive effects affect drug-seeking or addiction, the results of this research suggest that mGlu5 receptors could play a significant role. “The nucleus accumbens is a central component of the brain’s reward circuitry, so our results suggest the potential for overlap between drug reward processes and the interoceptive effects of drugs, especially in relation to the role of mGlu5 receptors,” said Besheer. “We believe this work also highlights the importance of understanding the mechanisms that underlie the interceptive effects of drugs.”