The α3β4*nicotinic acetylcholine receptor subtype mediates nicotine reward and physical nicotine withdrawal signs independently of the α5 subunit in the mouse

The 15q25 gene cluster contains genes that code for the alpha 5, alpha 3, and beta 4 nicotinic acetylcholine receptor (nAChRs) subunits, and in human genetic studies, has shown the most robust association with smoking behavior and nicotine dependence to date. The limited available animal studies implicate a role for the alpha 5 and beta 4 nAChR subunits in nicotine dependence and withdrawal; however studies focusing on the behavioral role of the alpha 3 beta 4* nAChR receptor subtype in nicotine dependence are lacking. Because of the apparent role of the alpha 3 beta 4* nAChR subtype in nicotine dependence, the goal of the current study was to better evaluate the involvement of this subtype in nicotine mediated behavioral responses. Using the selective alpha 3 beta 4* nAChR antagonist, alpha-conotoxin AuIB, we assessed the role of alpha 3 beta 4* nAChRs in acute nicotine, nicotine reward, and physical and affective nicotine withdrawal. Because alpha 5 has also been implicated in nicotine dependence behaviors in mice and can form functional receptors with alpha 3 beta 4*, we also evaluated the role of the alpha 3 beta 4 alpha 5* nAChR subtype in nicotine reward and somatic nicotine withdrawal signs by blocking the alpha 3 beta 4* nAChR subtype in alpha 5 nAChR knockout mice with AuIB. AuIB had no significant effect on acute nicotine behaviors, but dose-dependently attenuated nicotine reward and physical withdrawal signs, with no significant effect in affective withdrawal measures. Interestingly, AuIB also attenuated nicotine reward and somatic signs in alpha 5 nAChR knockout mice. This study shows that alpha 3 beta 4* nAChRs mediate nicotine reward and physical nicotine withdrawal, but not acute nicotine behaviors or affective nicotine withdrawal signs in mice. The alpha 5 subunit is not required in the receptor assembly to mediate these effects. Our findings suggest an important role for the alpha 3 beta 4* nAChR subtype in nicotine reward and physical aspects of the nicotine withdrawal syndrome. (C) 2013 Elsevier Ltd. All rights reserved.