Adaptive dynamics of the 5‐HT systems following chronic administration of selective serotonin reuptake inhibitors: a meta‐analysis

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 subchronic 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 2 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.

Intracerebral microdialysis of adenosine and adenosine monophosphate – a systematic review and meta‐regression analysis of baseline concentrations

“…Furthermore, according to the metaanalyses by Fliegel et al (2013), dialysate glutamate and GABA concentrations change with exposure to and withdrawal from ethanol. Moreover, meta-regression has shown a relationship between serotonin and duration of selective serotonin reuptake inhibitor treatment in the frontal cortex in rats (Fritze et al 2017). Combined, these results show the power of meta-analysis as an alternative to performing new animal experiments in answering various research questions in the field of neurochemistry.…”

“…Moreover, meta‐regression has shown a relationship between serotonin and duration of selective serotonin reuptake inhibitor treatment in the frontal cortex in rats (Fritze et al . ). Combined, these results show the power of meta‐analysis as an alternative to performing new animal experiments in answering various research questions in the field of neurochemistry.…”

“…While many interesting narrative reviews on microdialysis are available (refer to the microdialysis handbook by Westerink and Cremers (2007) for an excellent selection), only few SRs of the microdialysis technique have been performed to date. Examples comprise cocaine-induced dopamine increases in the nucleus accumbens (Frank et al 2008); ethanol-induced alterations in glutamate and GABA ) and monoamines ; and serotonin neurotransmission after selective serotonin reuptake inhibitors (Fritze et al 2017).…”

No basal or drug‐induced sex differences in striatal dopaminergic levels: a cluster and meta‐analysis of rat microdialysis studies

“…A previously reported (Noori, et al, 2012a; Brand, et al, ; Fliegel, et al, ; Hirth, et al, ; Fritze, et al, ; Noori, et al, ), we have established a robust pipeline for standardized data mining, database creation and integrative analysis of pre‐clinical neuropsychopharmacology experiments. This approach allows accurate extraction of maximum amount of data with a minimized chance for missing critical information and was therefore applied here to characterize basal dopamine concentrations as well as overlapping and distinct features of striatal dopaminergic response to systemically administered drugs of abuse in female rats.…”

“…A previously reported (Noori, et al, 2012a; Brand, et al, ; Fliegel, et al, ; Hirth, et al, ; Fritze, et al, ; Noori, et al, ), three categories (i.e. biological, experimental procedure and outcome) of study variables and parameters were extracted using a structured template.…”