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Do selective serotonin reuptake inhibitors acutely increase frontal cortex levels of serotonin?

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Abstract

Selective serotonin uptake inhibitors (SSRIs) exert their effects by inhibiting serotonin (5-HT) re-uptake. Although blockade occurs almost immediately, the neurochemical effects on 5-HT, as measured by in vivo microdialysis, have been a matter of considerable debate. In particular, literature reports yield conflicting neurochemical results in the rat frontal cortex. Thus, while some groups consistently find increases in extracellular 5-HT levels following acute SSRI administration, others reproducibly report an absence of these acute serotonergic effects. In an attempt to unravel this apparent discrepancy, we combined published literature with in-house microdialysis experiments. When we plotted the lateral stereotaxic coordinate of the dialysis probe against published reports on the acute effects of fluoxetine a clear correlation was revealed. Whereas pronounced increases in SSRI-induced 5-HT were observed when the dialysis probe was placed 0 to 1 mm from the midline, effects diminished when the lateral probe placement was greater than 3 mm from the midline. In-house microdialysis studies corroborated these reports. Overall, these results illustrate – for the first time – that the midline stereotaxic coordinate is critical for interpreting the acute serotonergic effects of SSRIs within the frontal cortex. Moreover, the common observation that the clinical efficacy of SSRIs is not evident following acute administration complements preclinical microdialysis results in the lateral frontal cortex. The significance of this observation, along with potential explanations for the disparate neurochemical findings in the medial versus lateral cortices, will be discussed.

Introduction

Selective serotonin reuptake inhibitors (SSRIs) represent the most widely prescribed class of antidepressants available on the market today. As inferred from their name, SSRIs selectively block the re-uptake of serotonin (5-hydroxytryptamine or 5-HT) resulting in elevated levels of 5-HT in the extracellullar environment. Despite their clinical success, a common theme among all marketed SSRIs is the two to six week delay in onset of therapeutic activity (Artigas et al., 1996, Schechter et al., 2005). Consistent with this lag time, preclinical microdialysis studies reveal that central 5-HT levels are increased following chronic treatment with SSRIs such as fluoxetine, paroxetine, and citalopram (Dawson et al., 2002). What may be surprising, however, are the equivocal reports in the literature describing the serotonergic effects of acute SSRI treatment (reviewed in Table 1).

One brain region that is notorious for yielding disparate 5-HT effects following acute SSRI administration is the rat frontal cortex (see Table 1). Thus, while several laboratories routinely describe increases in the extracellular levels of 5-HT, others reproducibly report a lack of these serotonergic effects following acute SSRI treatment. Several explanations of these neurochemical differences include the type and dose of SSRI tested, route of administration and/or other methodological issues.

It is also reasonable to suggest that the differential responses to SSRIs are due to variations in the subregion of the prefrontal cortex investigated. A Medline® search on microdialysis and the acute serotonergic effects of the SSRI, fluoxetine, reveals that when the dialysis probe is placed in the medial prefrontal cortex (median PFC; ± 0.8 mm from the midline), a pronounced increase in 5-HT is observed (see Table 1). In contrast, this serotonergic increase faded and was indistinguishable from vehicle treatment when the dialysis probe is placed in the dorsal lateral frontal cortex (> 3 mm from the midline). These apparent differences have yet to be fully explored, but likely reflect important cellular and/or molecular differences between these two subregions of the rat frontal cortex.

To date, no studies have exclusively investigated the acute neurochemical effects of SSRIs within subregions of the rat frontal cortex. In the present study, literature resources, along with additional in-house microdialysis experiments, were used to evaluate whether the differential neurochemical effects of fluoxetine are related to variations in microdialysis probe placement within the median PFC vs. lateral prefrontal cortex.

Section snippets

Literature search

Medline® searches were performed using the search string “microdialysis” and “serotonin” and “fluoxetine” and “cortex”. Studies were selected on the use of rats and all studies subsequently found to include SSRIs in the perfusion medium were excluded. In addition, studies utilizing high concentrations of calcium (> 2 mM) in the artificial cerebrospinal fluid (aCSF) were omitted, since the elevated basal levels of neurotransmitter might skew the overall response/effect of the SSRI.

Microdialysis surgery

All

Literature search

Our literature search yielded 26 results that are shown in Table 1 (studies utilizing high concentrations of calcium (> 2 mM) in the aCSF were omitted). Although the data differ in routes of administration and other experimental/methodological conditions, uniformity was found to exist at the highest dose of fluoxetine tested (between 10 and 30 mg/kg). Plotting the maximal increase in SSRI-induced 5-HT against the lateral coordinate of the microdialysis probe revealed significantly lower

Discussion

Varying reports on the ability of SSRIs to acutely elevate 5-HT in the rat frontal cortex have been a source of much debate over recent years. For example, in the last decade, 26 studies have been published investigating the effect of fluoxetine on 5-HT levels in the rodent prefrontal cortex. A careful review of these experiments demonstrates that when probes are 0 to 1 mm lateral to the midline (i.e., median PFC), a mean increase of approximately 185% above baseline is found in 10 studies.

Acknowledgements

The authors would like to thank Drs Sharon Rosenzweig-Lipson, Zoë Hughes and Lee Schechter for their helpful editorial comments and candid discussions during the preparation of this manuscript. Additionally, we would like to acknowledge Qian Lin and Juan Mercado for their respective technical contributions.

Financial disclosure statement: the authors declare that, except for income received from primary employer, no financial compensation has been received from any individual or corporation over

References (13)

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