Combined actions of zinc and fluoxetine on nicotinic acetylcholine receptors

Abstract

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 a4b4 and muscle a1b1gd nAChRs, expressing in oocytes, by the combined action of zinc and fluoxetine. At a holding potential of -60 mV, 200 mM zinc increased by 361% the currents elicited by acetylcholine (ACh currents) for a4b4 and by 182% for a1b1gd nAChRs. In contrast, 5 mM fluoxetine reduced the ACh currents to 31% for a4b4 and to 45% for a1b1gd nAChRs. Additionally, fluoxetine reduced more the ACh currents in the presence of zinc: to 17% for a4b4 and to 19% for a1b1gd 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.

Positive and negative modulation of nicotinic receptors

“…In this regard, antidepressants normalize Zn 2þ levels in depressed patients. The evidence indicating that Zn 2þ potentiates the inhibitory action of fluoxetine on a4b4 and a1b1gd AChRs (García-Colunga et al, 2004) concurs with the results from animal and depressed patient studies (Cunha et al, 2008;Siwek et al, 2009;reviewed in Szewczyk et al, 2008). Considering the hypothesis that hyperstimulation of the cholinergic system over the noradrenergic system results in depressed states (Shytle et al, 2002b;Arias, 2009Arias, , 2010b, the observed inhibitory synergism by Zn 2þ and antidepressants could be of clinical significance.…”

The antidepressant fluoxetine but not citalopram suppresses synapse formation and synaptic transmission between Lymnaea neurons by perturbing presynaptic and postsynaptic machinery

“…, 2004; Yeung et al. , 1999), and numerous neurotransmitter receptor targets, including the nicotinic ACh receptor (García‐Colunga et al. , 2004).…”

The GABAergic deficit hypothesis of major depressive disorder

“…For example, fluoxetine (1–10 μM) has direct off-target effects at nicotinic acetylcholine 212,213 and 5-HT3 receptors 214–216 as well as diverse Cl − 217 , voltage-gated Ca 2+ and K + channels 218–223 . Importantly, therapeutically relevant concentrations of fluoxetine and its metabolite norfluoxetine act as potent positive allosteric modulators of GABA A Rs in vitro when tested on receptors expressed in heterologous cells 224 and in cultured neurons 225 .…”