Potential new drug target for depression identified

April 28, 2009

An acid-sensitive protein in the brain may represent a new target for the treatment of depression, according to animal research in the April 29 issue of The Journal of Neuroscience. The study shows that disrupting acid-sensitive ion channel-1a (ASIC1a) produces antidepressant-like effects in mice. The findings may one day benefit people who do not respond to traditional antidepressants or who cannot tolerate their side effects.

"Depression is one of the most devastating and difficult-to-treat disorders known to man," said John F. Cryan, PhD, at University College Cork in Ireland, who was not affiliated with the study. "Despite much research, all antidepressant medications that are currently prescribed work in much the same way and are of limited efficacy in more than a third of all patients. The development of antidepressants that act on other molecular targets in the brain would be a major breakthrough," Cryan said.

Although animal models cannot reproduce all of the symptoms of human depression, several behavioral tests in rodents are sensitive to antidepressant treatment, suggesting that they address important aspects of the disease. For example, chronically stressed mice lose their normal preference for sugary drinks, and mice repeatedly placed in a pool of water tend to give up and float rather than swim in the hopes of escaping. These mouse behaviors are thought to reflect loss of interest in pleasurable activities and hopelessness or despair. But traditional antidepressants are able to restore the mouse preference for sweet treats and reduce the amount of time that they float rather than swim.

The researchers, led by Matthew Coryell, PhD and senior researcher John Wemmie, MD, PhD, at the University of Iowa, found that mice lacking the ASIC1a gene and normal mice treated with drugs that inhibit ASIC1a showed reduced depression-like behaviors. These mice showed increased sweet taste preference and reduced immobility, consistent with antidepressant treatment.

Mice lacking the ASIC1a gene also failed to show a known biomarker for depression. Chronic stress normally decreases the amount of the BDNF gene in the brain, but mice lacking ASIC1a failed to show this change.

The researchers found that ASIC1a-based treatment works through a different biological pathway than traditional antidepressants, suggesting that it may benefit people who do not respond to traditional therapies.

ASIC1a is located in brain structures associated with mood, including the amygdala, which is critical for so-called negative emotions such as anger, anxiety, and fear. The researchers previously showed reduced amygdala activity in animals that lacked the ASIC1a gene. In the current study, they reversed the antidepressant effect of ASIC1a gene deletion by turning the ASIC1a gene back on only in the amygdala. These findings support the idea that depression could be caused, at least in part, by hyperactivity of the amygdala.

"ASIC1a inhibitors may combat depression by reducing amygdala activity. Because of the importance of the amygdala in negative emotions and fear, we speculate that ASIC1a inhibition increases the brain's resistance to the negative effects of stress, perhaps reducing the likelihood of developing depression," said study author Wemmie.
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The research was supported by the National Institute of Mental Health, the National Alliance for Research on Schizophrenia and Depression, and the Department of Veteran Affairs.

The Journal of Neuroscience is published by the Society for Neuroscience, an organization of more than 38,000 basic scientists and clinicians who study the brain and nervous system. Wemmie can be reached at john-wemmie@uiowa.edu.

Society for Neuroscience

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