Combined actions of zinc and fluoxetine on nicotinic acetylcholine receptors

Zinc and nicotinic acetylcholine receptors (nAChRs) seem to be associated with major depression, and some antidepressants, including fluoxetine (Prozac), antagonize nAChRs. Therefore, a study was made of the modulation of neuronal α4β4 and muscle α1β1γδ nAChRs, expressing in oocytes, by the combined action of zinc and fluoxetine. At a holding potential of –60 mV, 200 μM zinc increased by 361% the currents elicited by acetylcholine (ACh currents) for α4β4 and by 182% for α1β1γδ nAChRs. In contrast, 5 μM fluoxetine reduced the ACh currents to 31% for α4β4 and to 45% for α1β1γδ nAChRs. Additionally, fluoxetine reduced more the ACh currents in the presence of zinc: to 17% for α4β4 and to 19% for α1β1γδ nAChRs, and after washing out the fluoxetine the ACh current did not recover its zinc-potentiated value. Moreover, when ACh-activated nAChRs were exposed first to fluoxetine and then zinc was added, the potentiating effect of zinc was very small for muscle nAChRs and was nil for neuronal receptors. Thus, the inhibiting effect of fluoxetine prevails over the potentiating action of zinc. Finally, the effects of both zinc and fluoxetine were voltage independent, indicating that these substances interact outside the ion channel. As fluoxetine nullifies the effects of zinc, it appears that both substances interact in the same site. These results should help understand better the roles played by zinc, antidepressants, nAChRs and their combination in brain functions and in the treatment of depression.