Noncompetitive functional inhibition at diverse, human nicotinic acetylcholine receptor subtypes by bupropion, phencyclidine, and ibogaine

Nicotinic acetylcholine receptors (nAChR) are diverse members of the neurot ransmitter-gated ion channel superfamily and play critical roles in chemica l signaling throughout the nervous system. The present study establishes th e acute functional effects of bupropion, phencyclidine, and ibogaine on two human nAChR subtypes. Function of muscle-type nAChR (alpha 1 beta gamma de lta) in TE671/RD cells or of ganglionic nAChR (alpha 3 beta 4 alpha 5+/-bet a 2) in SH-SY5Y neuroblastoma cells was measured with Rb-86(+) efflux assay s. Functional blockade of human muscle-type and ganglionic nAChR is produce d by each of the drugs in the low to intermediate micromolar range. Functio nal blockade is insurmountable by increasing agonist concentrations in TE67 1/RD and SH-SY5Y cells for each of these drugs, suggesting noncompetitive i nhibition of nAChR function. Based on these findings, we hypothesize that n AChR are targets of diverse substances of abuse and agents used in antiaddi ction/smoking cessation strategies. We also hypothesize that nAChR play her etofore underappreciated roles in depression and as targets for clinically useful antidepressants.