Speaker 1: Francesc Artigas, Spain

Major depression is a severe and heterogeneous psychiatric disease with high, increasing prevalence and socio-economic impact.1 The serotonergic system is implicated in the etiology and treatment of mood disorders.2 Most prescribed antidepressants, the selective serotonin (5-HT) reuptake inhibitors (SSRI) and the dual 5-HT and norepinephrine reuptake inhibitors block physiological reuptake mechanisms in serotonergic axons and thereby increase extracellular 5-HT concentration to activate postsynaptic 5-HT receptors required for clinical effects3. However, this process is severely compromised by the simultaneous activation of somatodendritic 5-HT1A-autoreceptors in the midbrain raphe nuclei after serotonin transporter (SERT) blockade or MAO inhibition4,5. 5-HT1A-autoreceptor activation reduces serotonergic activity and forebrain 5-HT release, an effect contrary to that required for the therapeutic response.3–6 Hence, the limited clinical efficacy of 5-HT-enhancing drugs and their delayed action are partly due to this negative feedback mechanism. Upon chronic treatment, 5-HT1A-autoreceptors desensitize, leading to the recovery of serotonergic activity and 5-HT release.3,6 Individuals with elevated density or activity of 5-HT1A-autoreceptors are more susceptible to mood disorders and respond poorly to antidepressants.7–9 5-HT1AR antagonists might thus be useful to improve antidepressant therapy by preventing the 5-HT1A-autoreceptor-mediated negative feedback. However, the activation of postsynaptic 5-HT1AR is a necessary step for antidepressant effects 6 which limits the usefulness of this strategy. Thus, unlike the non-selective 5-HT1AR/ß-adrenoceptor antagonist pindolol 10-12 (with a preferential action at 5-HT1A-autoreceptors), the selective 5-HT1AR antagonist DU-125530 does not enhance clinical fluoxetine effects despite augmenting the presynaptic effects of SSRI.13 Overall, these observations have led to the development of antidepressant drugs combining SERT inhibition with partial agonist effects on 5-HT1A-R, such as vilazodone 14 or vortioxetine (the latter compound is also antagonist at other 5-HT receptors15). In recent years we have used a new antidepressant strategy, based on the use of small interfering RNA (siRNA) targeted to serotonin neurons, to selectively reduce the expression and function of presynaptic (but not postsynaptic) 5-HT1AR. Local siRNA application in the raphe nuclei of mice reduced the expression and function of 5-HT1A autoreceptors locally, without affecting postsynaptic 5-HT1AR. This resulted in an antidepressant-like effect in the forced-swim and tail suspension tests, associated to an enhanced forebrain 5-HT release.16 We also developed a conjugated 5-HT1AR siRNA (C-1A-siRNA) directed to serotonin neurons, by covalently binding 5-HT1AR siRNA molecules to the SSRI sertraline. The intracerebroventricular or intranasal application of the C-1A-siRNA produced a selective reduction of 5-HT1A autoreceptor expression/function without affecting postsynaptic 5-HT1AR. This effect was associated to an antidepressant-like effect. Likewise, SSRI administration to C-1A-siRNA-treated mice produced a greater elevation of extracellular 5-HT than in control mice.17 Overall, existing evidence indicates that preand postsynaptic 5-HT1A-R play a major role in antidepressant action, either by limiting (presynaptic 5-HT1A autorecepors) or facilitating their effects (postsynaptic 5-HYT1A-R).