title: Bupropion-induced inhibition of α7 nicotinic acetylcholine receptors expressed in heterologous cells and neurons from dorsal raphe nucleus and hippocampus.
abstract: The pharmacological activity of bupropion was compared between α7 nicotinic acetylcholine receptors expressed in heterologous cells and hippocampal and dorsal raphe nucleus neurons. The inhibitory activity of bupropion was studied on GH3-α7 cells by Ca2+ influx, as well as on neurons from the dorsal raphe nucleus and interneurons from the stratum radiatum of the hippocampal CA1 region by using a whole-cell voltage-clamp technique. In addition, the interaction of bupropion with the α7 nicotinic acetylcholine receptor was determined by [3H]imipramine competition binding assays and molecular docking. The fast component of acetylcholine- and choline-induced currents from both brain regions was inhibited by methyllycaconitine, indicating the participation of α7-containing nicotinic acetylcholine receptors. Choline-induced currents in hippocampal interneurons were partially inhibited by 10 µM bupropion, a concentration that could be reached in the brain during clinical administration. Additionally, both agonist-induced currents were reversibly inhibited by bupropion at concentrations that coincide with its inhibitory potency (IC50=54 µM) and binding affinity (Ki=63 µM) for α7 nicotinic acetylcholine receptors from heterologous cells. The [3H]imipramine competition binding and molecular docking results support a luminal location for the bupropion binding site(s). This study may help to understand the mechanisms of actions of bupropion at neuronal and molecular levels related with its therapeutic actions on depression and for smoking cessation.
authors.affiliation: Departamento de Fisiología, Facultad de Medicina, Universidad Nacional Autónoma de México, México.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Vázquez-Gómez
authors.affiliation: Department of Medical Education, California Northstate University College of Medicine, 9700W. Taron Dr., Elk Grove, CA 95757, USA. Electronic address: hugo.arias@cnsu.edu.
authors.forename: Hugo R
authors.initials: HR
authors.lastname: Arias
authors.affiliation: Neuroscience Research, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Dominik
authors.initials: D
authors.lastname: Feuerbach
authors.affiliation: Departamento de Neurobiología Celular y Molecular, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Campus Juriquilla 3001, Querétaro 76230, México.
authors.forename: Marcela
authors.initials: M
authors.lastname: Miranda-Morales
authors.affiliation: Departamento de Fisiología, Facultad de Medicina, Universidad Nacional Autónoma de México, México.
authors.forename: Stefan
authors.initials: S
authors.lastname: Mihailescu
authors.affiliation: Department of Chemistry, Laboratory of Medicinal Chemistry and Neuroengineering, Medical University of Lublin, Lublin, Poland.
authors.forename: Katarzyna M
authors.initials: KM
authors.lastname: Targowska-Duda
authors.affiliation: Department of Chemistry, Laboratory of Medicinal Chemistry and Neuroengineering, Medical University of Lublin, Lublin, Poland.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Jozwiak
authors.affiliation: Departamento de Neurobiología Celular y Molecular, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Campus Juriquilla 3001, Querétaro 76230, México. Electronic address: garciacolunga@unam.mx.
authors.forename: Jesús
authors.initials: J
authors.lastname: García-Colunga
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D016642:Bupropion / Q000494:pharmacology*; D002794:Choline / Q000494:pharmacology; D065847:Dorsal Raphe Nucleus / Q000166:cytology; D006624:Hippocampus / Q000166:cytology; D007099:Imipramine / Q000494:pharmacology; D062105:Molecular Docking Simulation; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D017208:Rats, Wistar; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D064569:alpha7 Nicotinic Acetylcholine Receptor; D016642:Bupropion; D002794:Choline; D000109:Acetylcholine; D007099:Imipramine
keywords: Antidepressants; Bupropion; Bupropion (PubChem CID: 62884); Dorsal raphe nucleus; Hippocampus; Molecular docking; α7 nicotinic acetylcholine receptor