Serotonin receptors involved in antidepressant effects

Open Access

Abstract

El pdf del artículo es la versión manuscrita de autor. ; The neurotransmitter serotonin (5-hdroxytryptamine; 5-HT) has been implicated in the pathophysiology and treatment of major depression since the serendipitous discovery of antidepressant drugs in the 1950s. However, despite the generalised use of serotonin-enhancing drugs, such as the selective serotonin reuptake inhibitors (SSRIs) and the dual serotonin and norepinephrine reuptake inhibitors (SNRIs), the exact neurobiological mechanisms involved in the therapeutic action of these drugs are poorly understood. Better knowledge of these mechanisms may help to identify new therapeutic targets and to overcome the two main limitations of current treatments: reduced efficacy and slowness of action. Here I review the preclinical and clinical evidence supporting the involvement of different 5-HT receptors in the therapeutic action of antidepressant drugs. Presynaptic 5-HT1A and 5-HT1B autoreceptors play a major detrimental role in antidepressant treatments, as their activation by the excess of the active (extracellular) 5-HT fraction produced by serotonin transporter (SERT) blockade reduces presynaptic serotonergic function. Conversely, stimulation of postsynaptic 5-HT1A receptors in corticolimbic networks appears beneficial for the antidepressant action. The 5-HT2 receptor family is also involved as 5-HT2A/2C receptor blockade improves the antidepressant action of SSRIs, and recent data suggest that 5-HT2B receptor activation enhances serotonergic activity. Less is known from the rest of postsynaptic 5-HT receptors. However, 5-HT3 receptor blockade augments the 5-HT increase evoked by SERT inhibition, and 5-HT4 receptor activation may have antidepressant effects on its own. Finally, blockade of 5-HT6 and 5-HT7 receptors appears also to augment the antidepressant effects of SERT inhibition. ; Supported by the Innovative Medicine Initiative Joint Undertaking under grant agreement no. 115008, of which resources are composed of EFPIA in-kind contribution and financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and by grant SAF 2012–35183 from the Ministerio de Economía y Competitividad. Support from the Generalitat de Catalunya (2009-SGR220) and the Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM) is also acknowledged. ; Peer Reviewed