Blockade of the high-affinity noradrenaline transporter (NET) by the selective 5-HT reuptake inhibitor escitalopram: an in vivo microdialysis study in mice.

BACKGROUND AND PURPOSE Escitalopram, the S(+)-enantiomer of citalopram is the most selective 5-HT reuptake inhibitor approved. Although all 5-HT selective reuptake inhibitors (SSRIs) increase extracellular levels of 5-HT ([5-HT](ext)). some also enhance, to a lesser extent, extracellular levels of noradrenaline ([NA](ext)). However, the mechanisms by which SSRIs activate noradrenergic transmission in the brain remain to be determined. EXPERIMENTAL APPROACH This study examined the effects of escitalopram, on both [5-HT](ext) and [NA](ext) in the frontal cortex (FCx) of freely moving wild-type (WT) and mutant mice lacking the 5-HT transporter (SERT(-/-)) by using intracerebral microdialysis. We explored the possibilities that escitalopram enhances [NA](ext), either by a direct mechanism involving the inhibition of the low- or high-affinity noradrenaline transporters, or by an indirect mechanism promoted by [5-HT](ext) elevation. The forced swim test (FST) was used to investigate whether enhancing cortical [5-HT](ext) and/or [NA](ext) affected the antidepressant-like activity of escitalopram. KEY RESULTS In WT mice, a single systemic administration of escitalopram produced a significant increase in cortical [5-HT](ext) and [NA](ext). As expected, escitalopram failed to increase cortical [5-HT](ext) in SERT(-/-) mice, whereas its neurochemical effects on [NA](ext) persisted in these mutants. In WT mice subjected to the FST, escitalopram increased swimming parameters without affecting climbing behaviour. Finally, escitalopram, at relevant concentrations, failed to inhibit cortical noradrenaline and 5-HT uptake mediated by low-affinity monoamine transporters. CONCLUSIONS AND IMPLICATIONS These experiments suggest that escitalopram enhances, although moderately, cortical [NA](ext) in vivo by a direct mechanism involving the inhibition of the high-affinity noradrenaline transporter (NET).