Therapeutic doses of antidepressants are projected not to inhibit human α4β2 nicotinic acetylcholine receptors.

Abstract Inhibition of central α4β2 nAChRs by antidepressants, proposed to contribute to their clinical efficacy, was assessed for monoamine reuptake inhibitors (amitriptyline, nortriptyline, fluoxetine, sertraline, paroxetine, citalopram) by comparing projected human unbound brain drug concentrations ( C u,b ) at therapeutic doses with concentrations that inhibit human α4β2 nAChRs in vitro. Inhibitory concentrations (IC 50 ) were determined by patch clamp and ranged from 0.8–3.2 μM, except for nortriptyline (IC 50  = 100 nM). C u,b values were calculated from human unbound plasma drug concentrations ( C u,p ) and rat-derived brain-to-plasma and extracellular fluid-to-plasma ratios for the unbound drug, which are near unity, due to much higher brain tissue binding than plasma protein binding of these drugs. Accordingly in humans, antidepressant C u,b are projected to essentially equal C u,p , with average values from 3–87 nM, which are 30-to-250-fold below their IC 50 concentrations. Based on our model, monoaminergic antidepressants minimally inhibit central nAChRs and it is unlikely that α4β2 nAChR antagonism contributes to their antidepressant activity. Nortriptyline is an exception with a C u,b that is 2-fold below its IC 50 , which is comparable to the nAChR antagonist (±)-mecamylamine, for which C u,b is 4-fold below its IC 50 ; both drugs will inhibit a substantial fraction of α4β2 nAChRs. The C u,b of the α4β2 nAChR partial agonist varenicline, which has antidepressant-like activity in a murine model, is higher than its IC 50 and varenicline is projected to cause ∼70% inhibition of α4β2 nAChRs. Taken together these data may help explain the negative outcome of recent antidepressant augmentation trials with mecamylamine and the partial agonist CP-601927.