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BMC Anesthesiol
2015 Aug 08;15:116. doi: 10.1186/s12871-015-0098-5.
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Doxepin and imipramine but not fluoxetine reduce the activity of the rat glutamate transporter EAAT3 expressed in Xenopus oocytes.
Park HJ
,
Baik HJ
,
Kim DY
,
Lee GY
,
Woo JH
,
Zuo Z
,
Chung RK
.
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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). 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. 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. 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.
Fig. 1. Dose–response of doxepin inhibition of excitatory amino acid transporter type 3 (EAAT3) responses to L-glutamate (30 μM). Data are means ± S.E.M. (n = 25 or 26 for each data point). *p < 0.05 vs. control
Fig. 2. Dose–response of imipramine inhibition of EAAT3 responses to L-glutamate (30 μM). Data are means ± S.E.M. (n = 17–24 for each data point). *p < 0.05 vs. control
Fig. 3. Dose–response of fluoxetine on EAAT3 responses to L-glutamate (30 μM). Data are means ± S.E.M. (n = 17–26 for each data point). *p < 0.05 vs. control
Fig. 4. Effects of protein kinase C activation and doxepin on EAAT3 activity. EAAT3 activity was observed in the presence or absence of 0.79 μM doxepin. Data are means ± S.E.M., n = 25–29 in each group. *p < 0.05 vs. control, †
p < 0.05 vs. phorbol 12-myristate-13-acetate (PMA) alone, ‡
p < 0.05, vs. doxepin alone
Fig. 5. Effects of protein kinase C activation and imipramine on EAAT3 activity. EAAT3 activity was observed in the presence or absence of 0.32 μM imipramine. Data are means ± S.E.M., n = 19–29 in each group. *p < 0.05 vs. control, †
p < 0.05 vs. PMA alone, ‡
p < 0.05 vs. imipramine alone
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