Down‐Regulation of Norepinephrine Transporters on PC12 Cells by Transporter Inhibitors

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Abstract
To investigate the regulation of norepinephrine transporters (NETs) in vitro, we measured the binding of the NET‐selective ligand [3H]nisoxetine in homogenates of PC12 cells after exposure of intact cells to the NET inhibitor desipramine (DMI). A 3‐day exposure of PC12 cells to DMI robustly reduced the Bmax, but not the KD, of [3H]nisoxetine binding to NETs. Reduction of the binding of [3H]nisoxetine was dependent on both the concentration of DMI and the time of exposure to DMI. Reduction of [3H]nisoxetine binding to NETs produced by a 1‐day exposure to DMI reverted to preexposure levels 48 h after cessation of DMI exposure. Similar down‐regulation of NETs was found when PC12 cells were exposed to another NET‐selective drug, nisoxetine, which is structurally unrelated to DMI. In contrast, exposure of cells to the serotonin transporter‐selective drug citalopram, or the NET substrate norepinephrine, had no effects on the binding of [3H]nisoxetine to NETs. The down‐regulation of NETs was paralleled by a DMI‐induced reduction in the uptake of [3H]norepinephrine in intact PC12 cells. It can be inferred from these data that inhibitors of the NET can down‐regulate NETs directly, and do so in the absence of changes in the synaptic concentration of norepinephrine.

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