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

BMC Anesthesiology

Research Article

Hye Jin Park¹  Zhiyi Zuo²  Hee Jung Baik³  Guie Yong Lee³  Jae Hee Woo³  Rack Kyung Chung³  Dong Yeon Kim³ 

[1] Dasom anesthesia and analgesia practice association, Seoul, Republic of Korea;Department of Anesthesiology, University of Virginia Health System, Charlottesville, VA, USA;Department of anesthesiology and pain medicine, School of Medicine, Ewha Womans University, Seoul, Republic of Korea;

关键词: Major Depressive Disorder;    Fluoxetine;    Imipramine;    Xenopus Oocyte;    Doxepin;   

DOI  :  10.1186/s12871-015-0098-5

 received in 2015-03-02, accepted in 2015-07-28,  发布年份 2015

来源: Springer

【 摘 要 】

BackgroundMany 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).MethodsEAAT3 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.ResultsDoxepin 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.ConclusionsWe 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.

【 授权许可】

CC BY   
© Park et al. 2015