Antidepressants Noncompetitively Inhibit Nicotinic Acetylcholine Receptor Function John D. Fryer and Ronald J. Lukas Division of Neurobiology, Barrow Neurological Institute, Phoenix, Arizona, U.S.A. Abstract: Nicotinic acetylcholine receptors (nAChRs) 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 for the first time the acute functional effects of sertraline (Zoloft), paroxetine (Paxil), nefaz- odone (Serzone), and venlafaxine (Effexor) on two hu- man and one chick nAChR subtype. This study also confirms previous findings of nAChR functional block by fluoxetine (Prozac). Function of human muscle-type nAChR (1) in TE671/RD cells, human autonomic nAChR (345  2) in SH-SY5Y neuroblastoma cells, or chick V274T mutant 7-nAChR heterologously expressed in native nAChR-null SH-EP1 epithelial cells was measured using 86 Rb + efflux assays. Functional blockade of human muscle-type and autonomic nAChRs is produced by each of the drugs in the low to intermediate micromolar range, and functional block- ade of chick V274T-7-nAChR is produced in the in- termediate to high micromolar range. Functional block- ade is insurmountable by increasing agonist concen- trations 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 therapeutic antidepressants and could play roles in clinical depression. Key Words: Nicotinic receptor— Acetylcholine—Fluoxetine—Sertraline—Paroxetine— Nefazodone—Venlafaxine—Depression. J. Neurochem. 72, 1117–1124 (1999). Nicotinic acetylcholine receptors (nAChRs) are di- verse members of the neurotransmitter-gated ion channel superfamily (for review, see Lukas and Bencherif, 1992; Galzi and Changeux, 1994; Lindstrom, 1996; Lukas, 1998). nAChRs are found throughout the nervous system where they play critical and diverse physiological roles. Each nAChR subtype has a distinctive subunit composi- tion, and each nAChR subunit is encoded by one of at least 16 different genes (1–9, 1–4, , , and ). Muscle-type nAChRs are composed as pentamers of two 1 and one each of 1, , and either  (fetal) or  (adult) subunits. One form of autonomic nAChR contains 3, 4, and 5 with or without 2 subunits (Lukas, 1993; Conroy and Berg, 1995). A numerically abundant form of high-affinity nicotine-binding nAChR in the brain is composed of 4 and 2 subunits, and the high-affinity -bungarotoxin-binding nAChR in the mammalian cen- tral and autonomic nervous systems seems to be a ho- momer containing 7 subunits (for review, see Lind- strom, 1996; Lukas, 1998). Many studies have correlated smoking and nicotine consumption with depression and mood disorders (Anda et al., 1990; Glassman et al., 1990). There have also been previous reports of actions at nAChRs of classic tricyclic antidepressants such as imipramine (Eldefrawi et al., 1981; Arita et al., 1987), amitriptyline and nortriptyline (Schofield et al., 1981), desipramine (Rana et al., 1993), and maprotiline (Arita et al., 1987). Tricyclic antidepres- sants have been suggested to act as noncompetitive an- tagonists of muscle-type nAChRs from Torpedo ocellata electric organ (Eldefrawi et al., 1982). Further studies have shown interactions of fluoxetine (Prozac) at nAChRs (Garcia-Colunga et al., 1997; Hennings et al., 1997; Maggi et al., 1998). Our previous studies have shown that bupropion noncompetitively blocks nAChR function at clinically relevant doses (Fryer and Lukas, 1998, 1999). Collectively, these studies prompted our hypothesis of possible roles of nAChRs in depression and perhaps other mood disorders and as possible targets for clinically useful antidepressants (Fryer and Lukas, 1998, 1999). The past decade has shown a marked increase in the use of the selective serotonin reuptake inhibitors fluox- etine, sertraline (Zoloft), and paroxetine (Paxil), the se- rotonin-norepinephrine reuptake inhibitor venlafaxine (Effexor), and the serotonin 5-HT 2A antagonist and mod- erate serotonin–noradrenaline reuptake inhibitor nefaz- odone (Serzone) to treat depression (for review, see Andrews and Nemeroff, 1994; Stoudemire, 1995). In the Resubmitted manuscript received September 18, 1998; accepted October 22, 1998. Address correspondence and reprint requests to Mr. J. D. Fryer at Division of Neurobiology, Barrow Neurological Institute, 350 W. Thomas Rd., Phoenix, AZ 85013, U.S.A. Abbreviations used: carb, carbamylcholine; EBDN, epibatidine; I- Bgt, 125 I-labeled -bungarotoxin; MLA, methyllycaconitine; nAChR, nicotinic acetylcholine receptor; nicotine, (-)-nicotine. 1117 Journal of Neurochemistry Lippincott Williams & Wilkins, Inc., Philadelphia © 1999 International Society for Neurochemistry