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Selective Mitochondrial Targeting Exerts Anxiolytic Effects In Vivo

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Nussbaumer,  Markus
Max Planck Institute of Psychiatry, Max Planck Society;

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Teplytska,  Larysa
Max Planck Institute of Psychiatry, Max Planck Society;

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Turck,  Christoph W.
Max Planck Institute of Psychiatry, Max Planck Society;

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Filiou,  Michaela D.
Max Planck Institute of Psychiatry, Max Planck Society;

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Citation

Nussbaumer, M., Asara, J. M., Teplytska, L., Murphy, M. P., Logan, A., Turck, C. W., et al. (2016). Selective Mitochondrial Targeting Exerts Anxiolytic Effects In Vivo. NEUROPSYCHOPHARMACOLOGY, 41(7), 1751-1758. doi:10.1038/npp.2015.341.


Cite as: http://hdl.handle.net/11858/00-001M-0000-002B-5F4F-E
Abstract
Current treatment strategies for anxiety disorders are predominantly symptom-based. However, a third of anxiety patients remain unresponsive to anxiolytics highlighting the need for more effective, mechanism-based therapeutic approaches. We have previously compared high vs low anxiety mice and identified changes in mitochondria' pathways, including oxidative phosphorylation and oxidative stress. In this work, we show that selective pharmacological targeting of these mitochondria! pathways exerts anxiolytic effects in vivo. We treated high anxiety-related behavior (HAB) mice with MitoQ, an antioxidant that selectively targets mitochondria. MitoQ administration resulted in decreased anxiety-related behavior in HAB mice. This anxiolytic effect was specific for high anxiety as MitoQ treatment did not affect the anxiety phenotype of C57BL/6N and DBA/2J mouse strains. We furthermore investigated the molecular underpinnings of the MitoQ-driven anxiolytic effect and found that MitoQ treatment alters the brain metabolome and that the response to MitoQ treatment is characterized by distinct molecular signatures. These results indicate that a mechanism-driven approach based on selective mitochondria' targeting has the potential to attenuate the high anxiety phenotype in vivo, thus paving the way for translational implementation as long-term MitoQ administration is well-tolerated with no reported side effects in mice and humans.