Differential effects of the tricyclic antidepressant amoxapine on glycine uptake mediated by the recombinant GLYT1 and GLYT2 glycine transporters

1 We examined the effects of nine different tricyclic antidepressant drugs an the glycine uptake mediated by the glycine transporter Ib (GLYT1b) and g lycine transporter 2a (GLYT2a) stably expressed in human embryonic kidney 2 93 cells. Desipramine, imipramine, clomipramine, nomifensine and mianserin had no effect on the activity of the glycine transporters. Doxepin, amitrip tyline and nortriptyline inhibited the two transporter subtypes to a simila r extent. 2 Amoxapine displayed a selective inhibition of GLYT2a behaving as a 10 fol d more efficient inhibitor of this isoform than of GLYT1b. 3 Kinetic analysis of the initial rates of glycine uptake by GLYT2a as a fu nction of either glycine, chloride or sodium concentration, in the absence and presence of amoxapine indicated that amoxapine behaved as a competitive inhibitor of both glycine and chloride and a mixed-type inhibitor with res pect to sodium. 4 A kinetic model was developed which explains adequately these data, and g ives information about the order of binding of sodium and chloride ions to GLYT2a. 5 Our results may contribute to the development of the glycine transporter pharmacology. Additionally, the inhibition of the glycine uptake by GLYT2 i s suggested to pact-some role in the sedative and psychomotor side effects of amoxapine.