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).
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).
Authors: Frank P Bymaster; Wei Zhang; Petra A Carter; Janice Shaw; Eyassu Chernet; Lee Phebus; David T Wong; Kenneth W Perry Journal: Psychopharmacology (Berl) Date: 2002-01-29 Impact factor: 4.530
Authors: Katherine M Nautiyal; Laurent Tritschler; Susanne E Ahmari; Denis J David; Alain M Gardier; René Hen Journal: Neuropsychopharmacology Date: 2016-06-29 Impact factor: 7.853
Authors: Jacob P R Jacobsen; Per Plenge; Benjamin D Sachs; Alan L Pehrson; Manuel Cajina; Yunzhi Du; Wendy Roberts; Meghan L Rudder; Prachiti Dalvi; Taylor J Robinson; Sharon P O'Neill; King S Khoo; Connie Sanchez Morillo; Xiaodong Zhang; Marc G Caron Journal: Psychopharmacology (Berl) Date: 2014-05-09 Impact factor: 4.530
Authors: Kevin M Wood; Anisa Zeqja; H Frederik Nijhout; Michael C Reed; Janet Best; Parastoo Hashemi Journal: J Neurochem Date: 2014-04-26 Impact factor: 5.372