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Animal Study Reveals New Target for Antidepressants

University of Michigan scientists 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 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 can co-occur with anxiety disorders and substance abuse.

“There are big drawbacks in the current therapies for depression in that they can improve mood, but those benefits may be delayed, and it’s not unusual for depressive symptoms to return,” says senior author John Traynor, Ph.D., professor of pharmacology at the U-M Medical School and director of the U-M Substance Abuse Research Center.

Authors say the high relapse rate indicates a need for additional treatment options for the estimated 20.9 million Americans with depression.

The best current treatments for depression are selective serotonin reuptake inhibitors, or SSRIs. These drugs work by flooding the brain with a neurotransmitter than can trigger increased serotonin signaling through the more than 20 serotonin receptors in the brain.

The team of genomic and pharmacology researchers showed that one particular pathway, the serotonin 5HT1a 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 also details the complex action of a protein, Gai2, that is known to act as a brake on serotonin signaling.

Researchers created a mutant mouse to boost serotonin signaling in the 5HT1a receptor. This was done by genetically inhibiting the activity of the blocking proteins. Without the normal brake on serotonin signaling, these mutant mice showed antidepressive behavior even without being given antidepressant drugs. Their levels of serotonin were sufficient to give an antidepressant effect, according to the study. The mice were also more responsive to SSRIs.

Authors say that further research could lead to drugs capable of inhibiting the braking proteins and target the antidepressant signal where it is required on critical 5HT1a receptors.

Additional authors in the study are Jeffrey Talbot, Ph.D., Ohio Northern University, formerly of U-M, who continued parts of this work with Crystal Clemans, B.S., and Melanie Nicol, Pharm. D.  Other U-M authors are 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.

Funding: National Institute of General Medical Sciences; National Institute on Drug Abuse.

University of Michigan Health System -
Substance Abuse Research Center - 
Center for Chemical Genomics - 
National Institute of Mental Health - 

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