Tricyclic antidepressants block cholinergic nicotinic receptors and ATP secretion in bovine chromaffin cells

Izaguirre, Víctor; Fernández-Fernández, José M.; Ceña, Valentı́n; González-García, Cristina

doi:10.1016/s0014-5793(97)01343-4

Cited by 26 publications

(19 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Few papers have studied effects of imipramine on muscle 24,25 and neuronal 26,27 AChRs. Here we complemented previous studies and performed a comparative electrophysiological characterization of effects of imipramine on muscle and neuronal AChRs.…”

Section: Discussionmentioning

confidence: 99%

“…11,13,21,22 Similarly, imipramine, a non-selective inhibitor of serotonin uptake, 23 blocks nicotinic receptors of frog motor endplate and electric organ in a noncompetitive and voltage-dependent way, 24,25 inhibits the current evoked by dimethylphenylpiperazinium in human neuroblastoma cells and blocks the secretion of ATP mediated by AChRs in chromaffin cells. 26,27 In this paper, we studied effects of various inhibitors of monoamine transporters on neuronal ␣2␤4 and muscle AChRs, with emphasis on the mechanisms of action of imipramine.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Antagonism of nicotinic acetylcholine receptors by inhibitors of monoamine uptake

López-Valdés

Garcı́a-Colunga

2001

Mol Psychiatry

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Antagonism of nicotinic acetylcholine receptors by inhibitors of monoamine uptake

López-Valdés

Garcı́a-Colunga

2001

Mol Psychiatry

View full text Add to dashboard Cite

show abstract

“…Over the past 20 years, several independent groups have reported on the nAChR inhibitory actions of classic tricyclic antidepressants including imipramine, [11][12][13] nortriptyline, amitriptyline, 14,15 and desipramine. 13,16 More recent studies have characterized newer, more selective monoamine reuptake inhibitors including fluoxetine, [17][18][19] sertraline, paroxetine, nefazodone, 20 nisoxetine, citalopram, nomifensine, 21 and GBR-12909 22 as nAChR antagonists.…”

Section: Antidepressants As Nicotinic Acetylcholine Receptor Antagonistsmentioning

confidence: 99%

“…13,16 More recent studies have characterized newer, more selective monoamine reuptake inhibitors including fluoxetine, [17][18][19] sertraline, paroxetine, nefazodone, 20 nisoxetine, citalopram, nomifensine, 21 and GBR-12909 22 as nAChR antagonists. Perhaps one of the most interesting antidepressants demonstrated to have nAChR inhibitory activity is the atypical antidepressant, bupropion.…”

Section: Antidepressants As Nicotinic Acetylcholine Receptor Antagonistsmentioning

confidence: 99%

Nicotinic acetylcholine receptors as targets for antidepressants

et al. 2002

View full text Add to dashboard Cite

While the monoamine deficiency hypothesis of depression is still most commonly used to explain the actions of antidepressant drugs, a growing body of evidence has accumulated that is not adequately explained by the hypothesis. This article draws attention to contributions from another apparently common pharmacological property of antidepressant medications-the inhibition of nicotinic acetylcholine receptors (nAChR). Evidence is presented suggesting the hypercholinergic neurotransmission, which is associated with depressed mood states, may be mediated through excessive neuronal nicotinic receptor activation and that the therapeutic actions of many antidepressants may be, in part, mediated through inhibition of these receptors. In support of this hypothesis, preliminary evidence is presented suggesting that the potent, centrally acting nAChR antagonist, mecamylamine, which is devoid of monoamine reuptake inhibition, may reduce symptoms of depression and mood instability in patients with comorbid depression and bipolar disorder. If this hypothesis is supported by further preclinical and clinical research, nicotinic acetylcholine receptor antagonists may represent a novel class of therapeutic agents for treating mood disorders.

show abstract

“…Nevertheless, SNRIs also behave as noncompetitive antagonists (NCAs) of several nicotinic acetylcholine receptors (nAChRs) (Hennings et al, 1999;Izaguirre et al, 1997;Miller et al, 2002;Rana et al, 1993;reviewed in Arias et al, 2006). nAChRs are members of the Cys-loop ligand-gated ion channel superfamily, which also includes types A and C g-aminobutyric acid, type 3 serotonin, and glycine receptors (reviewed in Arias et al, 2006;Arias, 2010;Albuquerque et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Functional and Structural Interaction of (−)-Reboxetine with the Human α4β2 Nicotinic Acetylcholine Receptor

Arias

Fedorov²,

Benson³

et al. 2012

J Pharmacol Exp Ther

View full text Add to dashboard Cite

The interaction of the selective norepinephrine reuptake inhibitor (2)-reboxetine with the human a4b2 nicotinic acetylcholine receptor (nAChR) in different conformational states was studied by several functional and structural approaches. Patch-clamp and Ca 21-influx results indicate that (2)-reboxetine does not activate ha4b2 nAChRs via interaction with the orthosteric sites, but inhibits agonist-induced ha4b2 activation by a noncompetitive mechanism. Consistently, the results from the electrophysiologybased functional approach suggest that (2)-reboxetine may act via open channel block; therefore, it is capable of producing a usedependent type of inhibition of the ha4b2 nAChR function. We tested whether (2)-reboxetine binds to the luminal [ 3 H]imipramine site. The results indicate that, although (2)-reboxetine binds with low affinity to this site, it discriminates between the resting and desensitized ha4b2 nAChR ion channels. Patch-clamp results also indicate that (2)-reboxetine progressively inhibits the ha4b2 nAChR with two-fold higher potency at the end of one-second application of agonist, compared with the peak current. The molecular docking studies show that (2)-reboxetine blocks the ion channel at the level of the imipramine locus, between M2 rings 69 and 149. In addition, we found a (2)-reboxetine conformer that docks in the helix bundle of the a4 subunit, near the middle region. According to molecular dynamics simulations, (2)-reboxetine binding is stable for both sites, albeit less stable than imipramine. The interaction of these drugs with the helix bundle might alter allostericaly the functionality of the channel. In conclusion, the clinical action of (2)-reboxetine may be produced (at least partially) by its inhibitory action on ha4b2 nAChRs.

show abstract

Tricyclic antidepressants block cholinergic nicotinic receptors and ATP secretion in bovine chromaffin cells

Cited by 26 publications

References 21 publications

Antagonism of nicotinic acetylcholine receptors by inhibitors of monoamine uptake

Antagonism of nicotinic acetylcholine receptors by inhibitors of monoamine uptake

Nicotinic acetylcholine receptors as targets for antidepressants

Functional and Structural Interaction of (−)-Reboxetine with the Human α4β2 Nicotinic Acetylcholine Receptor

Contact Info

Product

Resources

About