Background: Many researchers have suggested that the glutamatergic system may be involved in the effects of\nantidepressant therapies. We investigated the effects of doxepin, imipramine, and fluoxetine on the excitatory\namino acid transporter type 3 (EAAT3).\nMethods: EAAT3 was expressed in Xenopus oocytes by injection of EAAT3 mRNA. Membrane currents were recorded\nafter application of L-glutamate (30 Ã?¼M) in the presence or absence of various concentrations of doxepin, imipramine,\nand fluoxetine. To study the effects of protein kinase C (PKC) activation on EAAT3 activity, oocytes were pre-incubated\nwith phorbol 12-myristate-13-acetate (PMA) before application of imipramine and doxepin.\nResults: Doxepin at 0.063ââ?¬â??1.58 Ã?¼M significantly decreased EAAT3 activity. Imipramine reduced EAAT3 activity in\na concentration-dependent manner at 0.16ââ?¬â??0.95 Ã?¼M. However, fluoxetine did not affect EAAT3 activity, and PMA\nincreased EAAT3 activity. At 0.32 Ã?¼M, imipramine caused an equivalent decrease in EAAT3 activity in the presence\nor absence of PMA. However, 0.79 Ã?¼M doxepin did not abolish the enhancement of EAAT3 activity by PMA.\nConclusions: We showed that doxepin and imipramine, but not fluoxetine, inhibited EAAT3 activity at clinically\nrelevant concentrations. This reveals a novel mechanism of action for doxepin and imipramine; that they increase\nglutamatergic neurotransmission. PKC may be involved in the effects of doxepin on EAAT3, but is not involved in\nthe effects of imipramine at the concentrations studied.
Loading....