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Study Reveals New Target for Antidepressants
Ohio Northern University scientists with collaborators at the University of Michigan have provided the most detailed picture yet of a key receptor in the brain that influences the effectiveness of serotonin-related antidepressants, such as Prozac.
The findings, which appeared online Wednesday ahead of print in the journal, Proceedings of the National Academy of Sciences, open the door to providing a more targeted treatment of depression and anxiety with fewer side effects.
Depressive disorders change a person’s mood, emotions and physical well-being and often co-occur with anxiety disorders and substance abuse.
“Depression is a devastating illness that affects nearly every facet of a person’s life,” says lead author Dr. Jeffery Talbot, assistant professor of pharmacology at the ONU Raabe College of Pharmacy. “Yet, our best treatments continue to have a remarkably poor track record of effectively treating the disease.”
Current therapies for depression are plagued with drawbacks. Therapeutic benefits are often delayed by weeks or months, unwanted side effects are common and depressive symptoms frequently return after treatment. Authors say the high relapse rate indicates a need for additional treatment options for the estimated 21 million Americans with depression.
SSRIs, or selective serotonin reuptake inhibitors, are the most widely used treatments for depression. These drugs work by flooding the brain’s synapses with serotonin, a neurotransmitter linked with mood, leading to increased serotonin signaling through the more than 20 serotonin receptors in the brain.
The team of researchers discovered that one key pathway involving the serotonin 5-HT1a receptor is linked with antidepressive and antianxiety behavior in mice.
“Rather than activating all serotonin receptors as SSRIs do, one could increase signaling through the one critical serotonin receptor that our research shows is important for antidepressant behavior,” says co-author Richard R. Neubig, M.D., Ph.D., co-director of the U-M Center for Chemical Genomics and professor of pharmacology at the U-M Medical School.
The new research details the complex actions of a family of proteins, known as RGS proteins, that act as brakes on neurotransmitter signaling. Researchers discovered that genetically inhibiting these braking proteins dramatically and selectively enhanced serotonin signaling through the 5-HT1a receptor. Without the normal brake on serotonin signaling, the mice not only were more responsive to SSRIs, but also showed antidepressive behavior without being given antidepressant drugs.
Authors say that further research could lead to drugs capable of inhibiting RGS proteins, which would more selectively target the antidepressant signal produced by 5-HT1a receptors. Funding for the study was made possible by American Association of Colleges of Pharmacy; the Bower, Bennett & Bennett Research Endowment; National Institute of General Medical Sciences, and National Institute on Drug Abuse.
Additional authors in the study are: Senior author—John R. Traynor, Ph.D., professor of pharmacology and director of the University of Michigan Substance Abuse Research Center. ONU authors—Crystal Clemans and Melanie Nicol, Pharm. D. U-M authors—Emily Jutkiewicz, Ph.D., Steven Graves, B.S., and Xinyan Huang, Ph.D., from the Department of Pharmacology and Richard Mortensen, M.D., Ph.D., from the Department of Molecular and Integrative Physiology.
Reference: Proceedings of the National Academy of Sciences, "RGS inhibition at Gαi2 selectively potentiates 5-HT1A-mediated antidepressant effects,” doi 10.1073/pnas.1000003107