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

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.

Figure 1

Regulation of 5-HT1A receptors in depression. Shown figuratively are 5-HT1A-expressing presynaptic raphe neuron and post-synaptic prefrontal cortical neuron. The 5-HT1A gene and its regulators (Deaf1, Freud-1, Freud-2, REST, Hes) are shown; 5-HT1A receptors (circle/triangle) and serotonin (triangles) are shown to indicate expected changes in their levels in depression. In depression, 5-HT1A receptor RNA and protein levels are increased presynaptically, leading to inhibition of 5-HT neurons (red-) and reduced firing. Paradoxically, the presynaptic levels of repressors REST and Deaf1 are increased, and there is also a trend for increase in Freud-1, perhaps to compensate for 5-HT1A overexpression due to the G(−1019) allele, for example. Post-synaptically, 5-HT1A receptors appear reduced, and levels of Deaf1 are also lower, although Freud-1 and Freud-2 (trend) increase. See text for details and references.