Pharmacological characterization of 5-iodo-A-85380, a beta 2-selective nicotinic receptor agonist, in mice

Background: Because of their implications in several pathological conditions, alpha 4 beta 2* nicotinic acetylcholine receptors (nAChRs) are potential targets for the treatment of nicotine dependence, pain, and many psychiatric and neurodegenerative diseases. However, they exist in various subtypes, and finding selective tools to investigate them has proved challenging. The nicotinic receptor agonist, 5-iodo-A-85380 (5IA), has helped in delineating the function of beta 2-containing subtypes in vitro; however, much is still unknown about its behavioral effects. Furthermore, its effectiveness on alpha 6-containing subtypes is limited. Aims: To investigate the effects of 5IA on nociception (formalin, hot-plate, and tail-flick tests), locomotion, hypothermia, and conditioned reward after acute and repeated administration, and to examine the potential rote of beta 2 and alpha 6 nAChR subunits in these effects. Lastly, its selectivity for expressed tow sensitivity (LS) and high sensitivity (HS) alpha 4 beta 2 receptors is investigated. Results: 5IA dose-dependently induced hypothermia, locomotion suppression, conditioned place preference, and antinociception (only in the formalin test but not in the hot-plate or tail-flick tests). Furthermore, these effects were mediated by beta 2 but not alpha 6 nicotinic subunits. Finally, we show that 5-iodo-A-85380 potently activates both stoichiometries of alpha 4 beta 2 nAChRs with differential efficacies, being a full agonist on HS alpha 4(2)beta 2(3) nAChRs, and a partial agonist on LS alpha 4(3)beta 2(2) nAChRs and alpha 6-containing subtypes as well.