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). some also enhance, to a lesser extent, extracellular levels of noradrenaline (NA). 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 and NA 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, 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 elevation. The forced swim test (FST) was used to investigate whether enhancing cortical 5-HT and/or NA 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 and NA. As expected, escitalopram failed to increase cortical 5-HT in SERT(-/-) mice, whereas its neurochemical effects on NA 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 in vivo by a direct mechanism involving the inhibition of the high-affinity noradrenaline transporter (NET).