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Abstract

Selective serotonin reuptake inhibitors (SSRIs) are the most frequently prescribed antidepressants. However, a major concern is their delayed onset of action, which is hypothesized to be associated with the time required for serotonin (5-HT) autoreceptors to desensitize, which should be reflected by actual neurochemical changes. Numerous in vivo microdialysis studies have been published that report on 5-HT levels in different brain sites following SSRI administration. Here we performed a meta-analysis on dynamic changes of 5-HT neurotransmission during the course of chronic SSRI treatment. We conducted a meta-analysis on research articles of 5-HT neurotransmission measured by in vivo microdialysis in rat brain after sub-chronic and chronic SSRI administrations. In total, data from 42 microdialysis studies (798 rats) were analyzed. Within the first week of SSRI treatment, extracellular 5-HT concentrations drop in frontal cortex. Over the next two weeks of treatment a linear increase in extracellular 5-HT levels up to 350 of prior treatment baseline is evident (n=269). However, in hippocampus, prefrontal cortex, nucleus accumbens and ventral tegmental area we found increased 5-HT levels within the first 3 days of SSRI administration. The time course of 5-HT dynamics in frontal cortex is in line with the hypothesis that 5-HT autoreceptors desensitize over 2-3 weeks of SSRI treatment and thereby enhanced extracellular 5-HT levels ensue. Yet, in other regions we did not find evidence supporting the traditional autoreceptor-mediated feedback loops hypothesis and thus other neurobiological adaptation mechanisms may also play a role in the delayed onset of SSRI action.