Abstract

Several cytisine derivatives have been developed in the search for more selective drugs at nicotinic acetylcholine receptors (nAChR). Binding experiments in transfected cell lines showed that the iodination of cytisine in the position 3 of the pyridone ring increased potency at a7-nAChR and to a lesser extent at the a4ß2 subtypes, both of which are widely expressed in the brain. However, no in vivo studies have been published on this compound. Inhibition curves presented here using wild type, ß2, and ß4-null mutant mice confirm that 3-IC binds to a4ß2*, a7* and a3ß4* receptors with higher affinity than cytisine (asterisk indicates the receptor may contain additional subunits, Lukas et al., 1999). Intraperitoneal injection of 3-iodocytisine (3-IC) induced considerable dose-dependent hypothermia in DBA/2J and C57BL/6J mice. This response was blocked by mecamylamine and partially inhibited by hexamethonium. ß4-null mice displayed significantly less 3-IC-induced hypothermia than wild-type mice, ß2-null mice were somewhat less affected than wild types, while responses of a7*-null mice were similar to wild types. Mice treated chronically with 3-IC display a marked increase in a7* and a4ß2* binding sites determined by radioligand binding in membrane preparations from cerebral cortex and hippocampus. Quantitative autoradiographic analysis of 28 brain regions of mice treated with 3-IC was consistent with the membrane binding, detecting an increase of cytisine-sensitive [ 125I]epibatidine binding sites, while cytisine-resistant [ 125I]epibatidine sites were unchanged. [ 125I]a-Bungarotoxin binding sites also exhibited up-regulation. These results give a first evaluation of in vivo consequences of 3-IC as a potent agonist with marked effects on mice. © 2009 Elsevier Ltd. All rights reserved.