Effect of concurrent organic cation transporter blockade on norepinephrine clearance inhibiting- and antidepressant-like actions of desipramine and venlafaxine

Abstract

Depression is a major health problem for which most patients are not effectively treated. This underscores a need to identify new targets for the development of antidepressants with improved efficacy. Studies have shown that blockade of low-affinity/high-capacity transporters, such as organic cation transporters (OCTs) and the plasma membrane monoamine transporter (PMAT), with decynium-22 can produce antidepressant-like effects and inhibit serotonin clearance in brain when the serotonin transporter is pharmacologically or genetically compromised. In vitro studies show that OCTs/PMAT are also capable of norepinephrine transport, raising the possibility that decynium-22 might enhance the antidepressant-like effects of norepinephrine transporter inhibitors. Using in vivo electrochemistry, we show that local administration of decynium-22 into dentate gyrus of hippocampus enhanced the ability of the norepinephrine transporter blocker, desipramine, but not the dual norepinephrine/serotonin transporter blocker venlafaxine, to inhibit norepinephrine clearance. In parallel, systemic administration of decynium-22 (0.32 mg/kg) enhanced the antidepressant-like effects of desipramine (32 mg/kg), but not those of venlafaxine, in the tail suspension test, underscoring the heterogeneous response of mice to antidepressants, including those that share similar mechanisms of action. Systemic administration of normetanephrine, a potent blocker of OCT3, failed to potentiate the antidepressant-like effects of desipramine, suggesting that the actions of decynium-22 to augment the antidepressant-like effects of desipramine are likely mediated by another OCT isoform and/or PMAT. Taken together with existing literature, concurrent blockade of OCTs and/or PMAT merits further investigation as an adjunctive therapeutic for desipramine-like antidepressant drugs.

Keywords: Antidepressant; Decynium-22; Desipramine; Norepinephrine transporter; Serotonin transporter; Venlafaxine.

Fig. 1.

Decynium-22 enhances the ability of desipramine to inhibit norepinephrine clearance in dentate gyrus. (A and C) Representative oxidation currents produced by pressure-ejecting norepinephrine into dentate gyrus before (grey) and 7 min after (black) local application of vehicle (PBS), desipramine (DMI; 54 pmol and 108 pmol), venlafaxine (VEN; 54 pmol), decynium-22 (D22; 1.4 pmol), or decynium-22 given with desipramine or venflafaxine. Traces are superimposed for ease of comparison. (B and D) Change in norepinephrine clearance time (T₈₀). Tukey’s multiple comparison tests following 2-way ANOVA show that (B) 54 pmol desipramine given with decynium-22 significantly inhibits norepinephrine clearance and (D) 108 pmol desipramine given with decynium-22 significantly inhibits norepinephrine clearance compared to vehicle, decynium-22, and 108 pmol desipramine; 108 pmol desipramine also significantly inhibits norepinephrine clearance compared to vehicle and decynium-22. *P < 0.05. **P < 0.01. Data are mean ± S.E.M.; n = 6–13 as depicted in the bars for each treatment group. Note the different scales on y-axis of B and D.

Fig. 2.

Antidepressant-like effects of desipramine, but not venlafaxine, were enhanced by co-administration of decynium-22. (A) Immobility time (s) in the tail suspension test after acutely administered venlafaxine in combination with 0.1 or 0.32 mg/kg decynium-22 (D22) or saline. Solid symbols represent a significant difference from saline with Tukey’s post hoc multiple comparisons test after a two-factor ANOVA (venlafaxine, decynium-22). *P < 0.05 represents 0.1 mg/kg decynium-22 significantly different from 0.32 mg/kg decynium-22; Tukey’s post hoc test for multiple comparisons. (B) Immobility time (s) in the tail suspension test after acute administration of vehicle, 0.1 or 0.32 mg/kg decynium-22. Decynium-22 does not affect immobility time when administered alone. (C) Immobility time (s) in the tail suspension test after acutely administered desipramine in combination with 0.1 mg/kg decynium-22 or saline. Solid circles and squares represent a significant difference from saline with Tukey’s post hoc multiple comparisons test after a two-factor ANOVA (desipramine, decynium-22). In separate experiments (results represented by triangles), immobility time in the tail suspension test was examined after acutely administered desipramine (32 mg/kg) in combination with 0.32 mg/kg decynium-22. *P < 0.05 represents 0.32 mg/kg decynium + 32 mg/kg desipramine significantly different from saline + 32 mg/kg desipramine, as determined by student’s t-test. (D) There is no difference in immobility time between mice given normetanephrine (normet) or vehicle in conjunction with desipramine. Data are mean ± S.E.M.; n = 8–12 per group.