Mechanism of action of serotonin selective reuptake inhibitors - Serotoninreceptors and pathways mediate therapeutic effects and side effects

Serotonin selective reuptake inhibitors (SSRIs) are currently among the mos t frequently prescribed therapeutic agents in all of medicine. Their therap eutic actions are diverse, ranging from efficacy in depression to obsessive -compulsive disorder, panic disorder, bulimia and other conditions as well. The plethora of biological substrates, receptors and pathways for serotoni n are candidates to mediate not only the therapeutic actions of SSRIs, but also their side effects. Specifically, the immediate actions of SSRIs are m ostly side effects, and may be mediated by the initiating actions of SSRIs, namely negative allosteric modulation of the serotonin transporter. A lead ing hypothesis to explain these immediate side effects is that serotonin is increased at specific serotonin receptor subtypes in discrete regions of t he body where the relevant physiologic processes are regulated. Desensitiza tion of post-synaptic receptors in these same discrete brain regions may ex plain the development of tolerance to these same side effects. The explanat ion for therapeutic effects characteristic of SSRIs may be found in delayed neurochemical adaptations. A leading hypothesis for this action is desensi tization of somatodendritic serotonin 1A autoreceptors in the: midbrain rap he. The hypothesis to explain why SSRIs have such diverse therapeutic actio ns is that somatodendritic 5HT1A autoreceptor desensitization increases ser otonin in those critical brain regions and at those key serotonin receptor subtype(s) which may mediate the pathophysiologies of the various disorders . Understanding the topography of serotonin receptor subtypes in discrete a natomical pathways may enhance our understanding of both the therapeutic ac tions and side effects of these important pharmaceutical agents. (C) 1998 E lsevier Science B.V. All rights reserved.