title: 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 alpha2beta4 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 > clomipramine > indatraline > fluoxetine > imipramine > zimelidine > 6-nitro-quipazine > trazodone for neuronal alpha2beta4 AChRs, and norfluoxetine > fluoxetine > imipramine > clomipramine > indatraline > zimelidine > trazodone > 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 alpha2beta4 and muscle AChRs. The half-inhibitory concentrations of imipramine were 3.65 +/- 0.30 microM for neuronal alpha2beta4 and 5.57 +/- 0.19 microM 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 approximately 0.10 and approximately 0.12 for neuronal alpha2beta4 and muscle AChRs respectively. Moreover, imipramine accelerated the rate of decay of ACh- currents of both muscle and neuronal AChRs. The ACh-current inhibition was stronger when oocytes, expressing neuronal alpha2beta4 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 non- competitively neuronal alpha2beta4 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.
authors.affiliation: Centro de Neurobiología, Universidad Nacional Autónoma de México, Campus Juriquilla, Apartado Postal 1-1141, Juriquilla, Querétaro 76001, México.
authors.forename: H E
authors.initials: HE
authors.lastname: López-Valdés
authors.forename: J
authors.initials: J
authors.lastname: García-Colunga
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D015306:Biogenic Monoamines / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D005473:Fluoxetine / Q000494:pharmacology; D007099:Imipramine / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D018482:Muscle, Skeletal / Q000502:physiology; D009474:Neurons / Q000502:physiology; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology*; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D021122:Protein Subunits; D051381:Rats; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D011994:Recombinant Proteins / Q000187:drug effects / Q000378:metabolism; D014982:Xenopus laevis; D015031:Zimeldine / Q000494:pharmacology
chemical_list: D000928:Antidepressive Agents; D015306:Biogenic Monoamines; D014179:Neurotransmitter Uptake Inhibitors; D021122:Protein Subunits; D011978:Receptors, Nicotinic; D011994:Recombinant Proteins; D005473:Fluoxetine; D015031:Zimeldine; D000109:Acetylcholine; D007099:Imipramine