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Front Neurosci. 2010 Jun 17;4:35. doi: 10.3389/fnins.2010.00035. eCollection 2010.

Modifying 5-HT1A Receptor Gene Expression as a New Target for Antidepressant Therapy.

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1
Department of Neuroscience, Ottawa Hospital Research Institute, University of Ottawa Ottawa, ON, Canada.

Abstract

Major depression is the most common form of mental illness, and is treated with antidepressant compounds that increase serotonin (5-HT) neurotransmission. Increased 5-HT1A autoreceptor levels in the raphe nuclei act as a "brake" to inhibit the 5-HT system, leading to depression and resistance to antidepressants. Several 5-HT1A receptor agonists (buspirone, flesinoxan, ipsapirone) that preferentially desensitize 5-HT1A autoreceptors have been tested for augmentation of antidepressant drugs with mixed results. One explanation could be the presence of the C(-1019)G 5-HT1A promoter polymorphism that prevents gene repression of the 5-HT1A autoreceptor. Furthermore, down-regulation of 5-HT1A autoreceptor expression, not simply desensitization of receptor signaling, appears to be required to enhance and accelerate antidepressant action. The current review focuses on the transcriptional regulators of 5-HT1A autoreceptor expression, their roles in permitting response to 5-HT1A-targeted treatments and their potential as targets for new antidepressant compounds for treatment-resistant depression.

KEYWORDS:

5-HT1A receptor; autoreceptor; major depressive disorder; raphe nuclei; serotonin receptors; transcription

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