title: Interaction of bupropion and zinc with neuronal nicotinic acetylcholine receptors.
abstract: Zinc is known to exert antidepressant-like actions and to make the effects of some antidepressants more efficient in animal models of depression. Both zinc and bupropion interact with nicotinic acetylcholine receptors (nAChRs) which are related with depression. Here we examined the effects of bupropion, in the absence and presence of zinc, on the ion current elicited by acetylcholine (ACh-current) in Xenopus oocytes expressing neuronal α4β4 nAChRs. We found that bupropion-inhibited ACh-currents depending on ACh and bupropion concentrations. Thus, the IC(50) of bupropion was lower with a higher ACh concentration: 3.51 and 2.27 μM for the current elicited with 0.5 and 2 μM ACh, respectively. The inhibitory effect of bupropion was more potent in the presence of zinc, e.g. the IC(50) was 0.81 μM in the presence of 100 μM zinc and 2 μM ACh. Furthermore, the zinc-potentiated ACh-current decreased with increasing bupropion concentration. Thus, zinc potentiation was 5.05 and 1.25 fold of the ACh-current inhibited by 10 nM and 5 μM bupropion, respectively. The ACh-current inhibited by 3 μM bupropion was voltage-independent, decreasing to 0.48 of the ACh-current at all voltages. Zinc potentiation of the bupropion-inhibited ACh-current was slight and voltage-independent. In addition, the zinc-potentiated ACh-current was slightly voltage-dependent: 1.8 fold of the ACh-current at -120 mV and 2.3 at -40 mV. Bupropion inhibition of the zinc-potentiated ACh-current was strong and voltage-independent, decreasing to 0.15 of the zinc-potentiated ACh-current at all voltages. Accordingly, zinc may interact within the ion channel, whereas bupropion, and bupropion in the presence of zinc (which causes greater inhibition) interact in an external region of the receptor-channel complex. These results suggest that bupropion interacts with α4β4 nAChRs in a non-competitive manner, that zinc increases the sensitivity of nAChRs to bupropion, and that bupropion decreases the sensitivity of nAChRs to zinc.
authors.affiliation: Departamento de Neurobiología Celular y Molecular, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Campus Juriquilla, Boulevard Juriquilla 3001, Querétaro 76230, Mexico. garciacolunga@unam.mx
authors.forename: Jesús
authors.initials: J
authors.lastname: García-Colunga
authors.forename: Ulises
authors.initials: U
authors.lastname: Godoy-García
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Vázquez-Gómez
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D016642:Bupropion / Q000494:pharmacology*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004558:Electric Stimulation; D020128:Inhibitory Concentration 50; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D008845:Microinjections / Q000379:methods; D009865:Oocytes; D018408:Patch-Clamp Techniques; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism*; D014981:Xenopus; D015032:Zinc / Q000494:pharmacology*
chemical_list: D018765:Dopamine Uptake Inhibitors; D011978:Receptors, Nicotinic; C427403:alpha(4)beta(4) nicotinic receptor; D016642:Bupropion; D015032:Zinc; D000109:Acetylcholine