Noncompetitive Functional Inhibition at Diverse, Human Nicotinic Acetylcholine Receptor Subtypes by Bupropion, Phencyclidine, and Ibogaine

Bupropion, phencyclidine, and ibogaine each block two types of human nicotinic acetylcholine receptors (nAChR): the muscle-type (alpha1 beta gamma delta) and the ganglionic type (alpha3 beta4 alpha5+/-beta2). The blockade occurs at low to intermediate micromolar concentrations and cannot be overcome by increasing the amount of agonist, indicating noncompetitive inhibition. These findings suggest that nAChR are targets for diverse substances of abuse and for agents used in antiaddiction and smoking cessation strategies, and that nAChR may play underappreciated roles in depression and as targets for clinically useful antidepressants.

Study at a glance

Abstract

Nicotinic acetylcholine receptors (nAChR) are diverse members of the neurotransmitter-gated ion channel superfamily and play critical roles in chemical signaling throughout the nervous system. The present study establishes the acute functional effects of bupropion, phencyclidine, and ibogaine on two human nAChR subtypes. Function of muscle-type nAChR (alpha1 beta gamma delta) in TE671/RD cells or of ganglionic nAChR (alpha3 beta4 alpha5+/-beta2) in SH-SY5Y neuroblastoma cells was measured with 86Rb+ efflux assays. Functional blockade of human muscle-type and ganglionic nAChR is produced by each of the drugs in the low to intermediate micromolar range. Functional blockade is insurmountable by increasing agonist concentrations in TE671/RD and SH-SY5Y cells for each of these drugs, suggesting noncompetitive inhibition of nAChR function. Based on these findings, we hypothesize that nAChR are targets of diverse substances of abuse and agents used in antiaddiction/smoking cessation strategies. We also hypothesize that nAChR play heretofore underappreciated roles in depression and as targets for clinically useful antidepressants.