Involvement of organic cation transporter 2 inhibition in potential mechanisms of antidepressant action.

Novel antidepressants or treatment strategies that may offer a more rapid onset of action, improved efficacy, and greater tolerability are in desperate need. Because current clinically utilized antidepressants, which target high-affinity transporters for serotonin and norepinephrine, fail to provide satisfactory treatment outcomes for quite a portion of patients. In recent investigations, a low-affinity but high-capacity transporter organic cation transporter 2 (OCT2, SLC22A2) has been proposed as an important postsynaptic determinant of aminergic tonus and mood-related behaviors, a complementary system to the high-affinity transporters. In order to evaluate whether OCT2 inhibition may at least in part contribute to the pharmacological effects of antidepressants, several typical antidepressant compounds of various mechanism categories were employed to inhibit OCT2 activity in cells stably overexpressing OCT2. The tested antidepressant agents included selective serotonin reuptake inhibitors (SSRIs, fluoxetine, sertraline and paroxetine), tricyclic antidepressants (TCAs, amitriptyline, imipramine, desipramine), monoamine oxidase inhibitor (MAOI, moclobemide), serotonin-norepinephrine reuptake inhibitor (SNRI, venlafaxine) and reported antidepressant alkaloid piperine. Piperine was screened through synaptosomes before cell experiments, without the interference of monoamine oxidase. All of the nine antidepressant compounds showed moderate inhibitory effects on OCT2-mediated metformin, serotonin and/or norepinephrine uptake. Sertraline and desipramine tended to inhibit OCT2 activity via a competitive mechanism. The fact could be easily belied, since passive diffusion dominated the influx process. It remains to be seen whether OCT2 inhibition plays a role to the overall therapeutic effects in clinical practice.