Antagonism of nicotinic acetylcholine receptors by inhibitors of monoamine uptake

Abstract

A study was made of the effects of several monoamine-uptake inhibitors on membrane currents elicited by acetylcholine (ACh-currents) generated by rat neuronal ␣2␤4 and mouse muscle nicotinic acetylcholine receptors (AChRs) expressed in Xenopus laevis oocytes. For the two types of receptors the monoamine-uptake inhibitors reduced the ACh-currents albeit to different degrees. The order of inhibitory potency was norfluoxetine Ͼ clomipramine Ͼ indatraline Ͼ fluoxetine Ͼ imipramine Ͼ zimelidine Ͼ 6-nitro-quipazine Ͼ trazodone for neuronal ␣2␤4 AChRs, and norfluoxetine Ͼ fluoxetine Ͼ imipramine Ͼ clomipramine Ͼ indatraline Ͼ zimelidine Ͼ trazodone Ͼ 6-nitro-quipazine for muscle AChRs. Thus, the most potent inhibitor was norfluoxetine, whilst the weakest ones were trazodone, 6-nitro-quipazine and zimelidine. Effects of the tricyclic antidepressant imipramine were studied in more detail. Imipramine inhibited reversibly and non-competitively the ACh-current with a similar inhibiting potency for both neuronal ␣2␤4 and muscle AChRs. The half-inhibitory concentrations of imipramine were 3.65 ± 0.30 M for neuronal ␣2␤4 and 5.57 ± 0.19 M for muscle receptors. The corresponding Hill coefficients were 0.73 and 1.2 respectively. The inhibition of imipramine was slightly voltage-dependent, with electric distances of ෂ0.10 and ෂ0.12 for neuronal ␣2␤4 and muscle AChRs respectively. Moreover, imipramine accelerated the rate of decay of AChcurrents of both muscle and neuronal AChRs. The ACh-current inhibition was stronger when oocytes, expressing neuronal ␣2␤4 or muscle receptors, were preincubated with imipramine alone than when it was applied after the ACh-current had been generated, suggesting that imipramine acts also on non-activated or closed AChRs. We conclude that monoamine-uptake inhibitors reduce ACh-currents and that imipramine regulates reversibly and noncompetitively neuronal ␣2␤4 and muscle AChRs through similar mechanisms, perhaps by interacting externally on a non-conducting state of the AChR and by blocking the open receptor-channel complex close to the vestibule of the channel. These studies may be important for understanding the regulation of AChRs as well as for understanding antidepressant-and side-effects of monoamine-uptake inhibitors. Molecular Psychiatry (2001) 6, 511-519.

Dual Antidepressant Duloxetine Blocks Nicotinic Receptor Currents, Calcium Signals and Exocytosis in Chromaffin Cells Stimulated with Acetylcholine

“…In this line is the reported association between depression and smoking, likely due to desensitization by nicotine of nAChRs (Mineur & Picciotto, 2010;Philip et al, 2010;Shytle et al, 2002). Also, consistent with this cholinergic hypothesis is the observation that a number of key antidepressants such as the selective serotonin reuptake inhibitors (SRIs) fluoxetine, sertraline, paroxetine and citalopram, the selective noradrenaline reuptake inhibitor (NRI) reboxetine, the noradrenaline-dopamine reuptake inhibitor bupropion, and tricyclics amitriptyline, imipramine, and nortriptyline have all been shown to possess antagonistic activities at nAChRs Arias et al, 2010a;Arias et al, 2010b;Bianchi, 2008;Fryer & Lukas, 1999a;Hennings et al, 1997;López-Valdés & García-Colunga, 2001;Shytle et al, 2002). On the other hand, nicotine itself and some nicotinic agonists or antagonists, can potentiate the antidepressant-like effects of SRIs and NRIs in rodent models of depression (Andreasen et al, 2011;Popik et al, 2003).…”

Combined actions of zinc and fluoxetine on nicotinic acetylcholine receptors

“…All the I-V relations showed that the equilibrium potential remained unaltered (ca. 12 mV), and all displayed the inward rectification characteristic of ACh current mediated by neuronal nAChRs, 10,18 such that at voltages more positive than zero the membrane current was near zero.…”

“…For instance, they are modulated by cations, [5][6][7][8] 5-HT, 9-13 various agonists and antagonists of different types of 5-HT receptors, [9][10][11][12]14 as well as inhibitors of monoamine transporters that are used as antidepressants. 9,12,[15][16][17][18][19][20] The most common action of clinically used antidepressants on nAChRs appears to be a noncompetitive inhibitory process, 9,12,[15][16][17][18][19][20] and it is probable that this action contributes to improving depressed mood states. 21 On the other hand, zinc is contained in neurons that are widely distributed throughout the nervous system; 22 and it is released from GABAergic and glutamatergic nerve endings, 23,24 reaching an extracellular concentration of B300 mM.…”

Nicotine (NC)-induced "depressive" behavioral symptoms and effects of antidepressants including cannabinoids (CBs)

“…Close functional interactions between nAChRs and monoamine neurons, the targets of clinically used antidepressants, have been demonstrated by experiments modifying nAChRs by inhibiting monoamine reuptake (Lopez-Valdes and Garcia-Colunga, 2001). Therefore, it is possible that clinically-used antidepressants such as brain monoamine reuptake inhibitors are effective against these NC-induced depressive behavioral alterations.…”