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01.12.2015 | Research article | Ausgabe 1/2015 Open Access

BMC Anesthesiology 1/2015

Doxepin and imipramine but not fluoxetine reduce the activity of the rat glutamate transporter EAAT3 expressed in Xenopus oocytes

Zeitschrift:
BMC Anesthesiology > Ausgabe 1/2015
Autoren:
Hye Jin Park, Hee Jung Baik, Dong Yeon Kim, Guie Yong Lee, Jae Hee Woo, Zhiyi Zuo, Rack Kyung Chung
Wichtige Hinweise
Hye Jin Park, Hee Jung Baik, Dong Yeon Kim, Guie Yong Lee, Jae Hee Woo, and Zhiyi Zuo contributed equally to this work.

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

HP and HB contributed study design and data analysis and made critical revisions of the manuscript. HB also wrote the first draft of the manuscript. DK and GL contributed to revisions, and approved the final draft of the manuscript. JW and ZZ carried out the design and coordination of the study. RC contributed study design. All authors read and approved the final analysis of the manuscript.

Abstract

Background

Many researchers have suggested that the glutamatergic system may be involved in the effects of antidepressant therapies. We investigated the effects of doxepin, imipramine, and fluoxetine on the excitatory amino acid transporter type 3 (EAAT3).

Methods

EAAT3 was expressed in Xenopus oocytes by injection of EAAT3 mRNA. Membrane currents were recorded after application of L-glutamate (30 μM) in the presence or absence of various concentrations of doxepin, imipramine, and fluoxetine. To study the effects of protein kinase C (PKC) activation on EAAT3 activity, oocytes were pre-incubated with phorbol 12-myristate-13-acetate (PMA) before application of imipramine and doxepin.

Results

Doxepin at 0.063–1.58 μM significantly decreased EAAT3 activity. Imipramine reduced EAAT3 activity in a concentration-dependent manner at 0.16–0.95 μM. However, fluoxetine did not affect EAAT3 activity, and PMA increased EAAT3 activity. At 0.32 μM, imipramine caused an equivalent decrease in EAAT3 activity in the presence or absence of PMA. However, 0.79 μM doxepin did not abolish the enhancement of EAAT3 activity by PMA.

Conclusions

We showed that doxepin and imipramine, but not fluoxetine, inhibited EAAT3 activity at clinically relevant concentrations. This reveals a novel mechanism of action for doxepin and imipramine; that they increase glutamatergic neurotransmission. PKC may be involved in the effects of doxepin on EAAT3, but is not involved in the effects of imipramine at the concentrations studied.
Literatur
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