Zinc modulation of serotonin uptake in the adult rat corpus callosum

Antidepressants partially inhibit the uptake of 5-hydroxytryptamine (5-HT; serotonin) in the rat corpus callosum (CC), a white matter commissure involved in interhemispheric brain communication. It is also known that zinc modulates many proteins, including neurotransmitter transporters. We examined the effects of zinc on the uptake of 5-HT into slices of the adult rat CC, in the absence or presence of some antidepressants. Zinc increased 5-HT uptake in a concentration-dependent manner when the CC slices were incubated in a solution buffered with sodium bicarbonate; however, zinc exerted no effect on 5-HT transport when HEPES was the buffer. Potentiation of 5-HT uptake by zinc was maximal with 1 microM (45% over the control uptake). Moreover, 1 microM zinc potentiated 5-HT uptake in the cingulate cortex by 58% and in the Raphe nucleus by 65%. The antidepressants fluoxetine and imipramine inhibited 5-HT uptake in the CC by approximately 50%, whereas 6-nitroquipazine, a potent 5-HT uptake blocker, inhibited uptake by only 23%. Interestingly, inhibition of 5-HT uptake by all three substances, fluoxetine, imipramine, and 6-nitroquipazine, was counteracted by the presence of 1 microM zinc. Free zinc may thus contribute to modulation of extracellular levels of 5-HT and its removal. These actions should be considered in the treatment of mental depression with antidepressants.