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J. Biol. Chem., Vol. 283, Issue 15, 9659-9665, April 11, 2008

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High Affinity Binding of Epibatidine to Serotonin Type 3 Receptors^*

Renaldo C. Drisdel, Douglas Sharp, Tricia Henderson, Tim G. Hales^¶, and William N. Green¹

From the Department of Neurobiology, University of Chicago, Chicago, Illinois 60637 and the Departments of Anesthesiology and Critical Care Medicine and ^¶Pharmacology and Physiology, The George Washington University Medical Center, Washington, D.C. 20037

Epibatidine and mecamylamine are ligands used widely in the study of nicotinic acetylcholine receptors (nAChRs) in the central and peripheral nervous systems. In the present study, we find that nicotine blocks only 75% of ¹²⁵I-epibatidine binding to rat brain membranes, whereas ligands specific for serotonin type 3 receptors (5-HT₃Rs) block the remaining 25%. ¹²⁵I-Epibatidine binds with a high affinity to native 5-HT₃Rs of N1E-115 cells and to receptors composed of only 5-HT_3A subunits expressed in HEK cells. In these cells, serotonin, the 5-HT₃R-specific antagonist MDL72222, and the 5-HT₃R agonist chlorophenylbiguanide readily competed with ¹²⁵I-epibatidine binding to 5-HT₃Rs. Nicotine was a poor competitor for ¹²⁵I-epibatidine binding to 5-HT₃Rs. However, the noncompetitive nAChR antagonist mecamylamine acted as a potent competitive inhibitor of ¹²⁵I-epibatidine binding to 5-HT₃Rs. Epibatidine inhibited serotonin-induced currents mediated by endogenous 5-HT₃Rs in neuroblastoma cell lines and 5-HT_3ARs expressed in HEK cells in a competitive manner. Our results demonstrate that 5-HT₃Rs are previously uncharacterized high affinity epibatidine binding sites in the brain and indicate that epibatidine and mecamylamine act as 5-HT₃R antagonists. Previous studies that depended on epibatidine and mecamylamine as nAChR-specific ligands, in particular studies of analgesic properties of epibatidine, may need to be reinterpreted with respect to the potential role of 5-HT₃Rs.

Received for publication, May 3, 2007 , and in revised form, August 15, 2007.

^* This work was supported by National Institute of Drug Abuse (NIDA) Grant R01 DA13602 (to W. N. G.), National Institutes of Health Grants RO1 NS 32693 and R01 NS43782 (to W. N. G.), and NIDA Grant DA05010 (to T. G. H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Neurobiology, University of Chicago, 947 E. 58th St., Chicago, IL 60637. E-mail: wgreen{at}midway.uchicago.edu.

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