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Multiple serotonergic paths to antidepressant efficacy
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Edité par CCSD ; American Physiological Society -
International audience. Lutz P.-E. Multiple serotonergic paths to antidepressant efficacy.Depression is a leading cause of disability worldwide. Brain mechanisms underlying the clinical anti-depressant efficacy of selective serotonin reuptake inhibitors (SSRI), currently the first-line treatment, remain poorly understood. Recent animal studies have implicated multiple serotonin receptor subtypes in SSRI response, opening new therapeutic perspectives. serotonin receptor; selective serotonin reuptake inhibitor; depression; neurogenesis DEPRESSION, DEFINED MAINLY by depressed mood and anhedonia, is a leading cause of disability worldwide. The serendipitous discovery 60 years ago of the antidepressant properties of tricyclics, and later of selective serotonin reuptake inhibitors (SSRI), has prompted scientists to investigate the role of the serotonergic system in antidepressant medication and depression pathophysiology. Here, we summarize recent findings from rodent models indicating that different subtypes of sero-tonin (5-HT) receptors regulate the activity of 5-HT neurons, and mediate the antidepressant-like efficacy of SSRI. Serotonergic neurons are mainly located in the midbrain dorsal raphe nucleus (DRN) and send axonal projections throughout the whole brain, where released 5-HT targets 14 different receptor types (Hannon and Hoyer 2008). Serotoner-gic neurons can be identified by their typical pattern of elec-trophysiological activity (a slow and regular firing rate, with long-duration positive action potentials). These neurons express the molecular target of SSRI, the 5-HT transporter (SERT), in both their somato-dendritic compartment and axon terminals (Fig. 1A). At both levels, acute SSRI treatment inhibits SERT and increases 5-HT concentration in the extra-cellular space. In the DRN, increased release of 5-HT activates the inhibitory G i-coupled 5-HT 1A receptor (5-HT 1A R), which is expressed by 5-HT neurons as an autoreceptor. 5-HT 1A R activation in turn decreases the firing rate of 5-HT neurons and their neurotransmitter release, thus opposing the effect of SSRI on axon terminals. Therefore, due to DRN 5-HT 1A R negative feedback, acute SSRI treatment only slightly increases the endogenous serotonergic tone in projection regions (Blier and de Montigny 1994). SSRI typically require 4-6 wk to achieve antidepressant efficacy in the clinic, and neuroadaptations responsible for this delayed onset-of-action are extensively studied. One of the earliest proposed mechanisms was the desensitization of 5-HT 1A R in the DRN (Blier and de Montigny 1994). Upon chronic SSRI treatment, 5-HT neurons return to a normal firing rate through 5-HT 1A R desensitization, thereby potentiating the serotonergic tone in virtually all DRN projection regions (Fig. 1B). Accordingly, decreased 5-HT 1A R function would be expected to result in decreased autoinhibition and faster SSRI response. However, combining SSRI and a specific 5-HT 1A R antagonist (such as WAY100635) has failed to produce fast antidepressant response in animal models. Additional complexity comes from the fact that the 5-HT 1A R is also expressed as a heteroreceptor by forebrain non-serotonergic neurons. During chronic SSRI treatment, the serotonergic tone acting at every postsynaptic 5-HT receptor, including 5-HT 1A heteroreceptor, is potentiated. Activation of these heteroreceptors, notably in the hippocampus, has been implicated in SSRI antidepressant efficacy, and may be blocked during combined therapy with a 5HT 1A R antagonist (Lucas et al. 2007). Moreover, 5-HT 1A heteroreceptors indirectly regulate the activity of 5-HT neurons. Activation of 5-HT 1A R expressed by layer 5 pyramidal neurons in the prefrontal cortex (PFC) was shown to decrease the firing rate of 5-HT neurons, a negative long-feedback loop that mimics activation of DRN autoreceptors (Celada et al. 2001). How this cortical receptor pool adapts during chronic SSRI treatment, and its behavioral relevance for antidepressant efficacy, remains poorly understood. To manipulate specifically 5-HT 1A autoreceptors and determine their role in SSRI behavioral effects, Richardson-Jones et al. (2010) recently used a conditional genetic approach. They compared adult mice showing normal levels (Auto1A-High) or a 30% genetic deletion (Auto1A-Low) of 5-HT 1A autorecep-tors, while expression of 5-HT 1A heteroreceptors was unchanged. Surprisingly, this modest decreased autoinhibition in Auto1A-Low mice had strong effects on 5-HT neurons and emotional responses, and was sufficient to increase the spontaneous firing activity of 5-HT neurons. Upon acute SSRI exposure, reduced autoinhibition led to increased 5-HT release in the two projection regions examined (PFC and hippocam-pus). Importantly, Auto1A-Low mice showed enhanced behav-ioral response to SSRI in the novelty suppressed feeding test, a measure of hyponeophagia classically responsive to chronic but not acute treatment. Eight or 26 days of treatment with the SSRI fluoxetine had antidepressant-like effects in Auto1A-Low mice, whereas Auto1A-High mice showed no response for either treatment duration. These results therefore suggest that the level of 5-HT 1A R expression in the DRN partly determines the onset of SSRI antidepressant-like effects. The 5-HT 1B receptor (5-HT 1B R) is another G i-coupled receptor , expressed both as an auto-and heteroreceptor. In contrast to the somato-dendritic 5-HT 1A R autoreceptor, the 5-HT 1B R is localized in axon terminals of 5-HT neurons (Fig. 1A), thereby controlling 5-HT release in projection regions. Chronic SSRI treatment was shown to induce desensitization and reduced expression of 5-HT 1B autoreceptors, likely con
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