Antidepressants noncompetitively inhibit nicotinic acetylcholine receptor function

Nicotinic acetylcholine receptors (nAChRs) are diverse members of the neuro transmitter-gated ion channel superfamily and play critical roles in chemic al signaling throughout the nervous system. The present study establishes f or the first time the acute functional effects of sertraline (Zoloft), paro xetine (Paxil), nefazodone (Serzone), and venlafaxine (Effexor) on two huma n and one chick nAChR subtype. This study also confirms previous findings o f nAChR functional block by fluoxetine (Prozac). Function of human muscle-t ype nAChR (alpha 1 beta gamma delta) in TE671/RD cells, human autonomic nAC hR (alpha 3 beta 4 alpha 5 +/- beta 2) in SH-SY5Y neuroblastoma cells, or c hick V274T mutant alpha 7-nAChR heterologously expressed in native nAChR-nu ll SH-EPI epithelial cells was measured using Rb-86(+) efflux assays. Funct ional blockade of human muscle-type and autonomic nAChRs is produced by eac h of the drugs in the low to intermediate micromolar range, and functional blockade of chick V274T-alpha 7-nAChR is produced in the intermediate to hi gh micromolar range. Functional blockade is insurmountable by increasing ag onist concentrations at each nAChR subtype tested for each of these drugs, suggesting noncompetitive inhibition of nAChR function. These studies open the possibilities that nAChR subtypes in the brain could be targets for the rapeutic antidepressants and could play roles in clinical depression.