Genetic dissociation of two behaviors associated with nicotine addiction: Beta-2 containing nicotinic receptors are involved in nicotine reinforcement but not in withdrawal syndrome

Rationale: Nicotine addiction is characterized by two distinct behaviors, chronic compulsive self-administration and the induction of a withdrawal syndrome upon cessation of nicotine consumption. Objective: To examine if these two processes rely on beta 2-containing nicotinic receptors-beta 2*nAChRs-we analyzed the behavior of mice lacking these receptors in the two situations. Results: First, we showed that, in contrast to wild-type (WT) mice, beta 2-knockout (beta 2-/-) mice exhibit no intra-ventral tegmental area (VTA) nicotine self-administration, whereas their ability to self-administer morphine is intact. However, beta 2-/- mice showed some sensitivity to locomotor effects of nicotine, implying an effect of the drug on other nicotinic subtypes. Then, we observed that beta 2-/- mice exhibited a normal nicotine withdrawal syndrome, i.e., increased levels of rearing and jumping upon precipitated withdrawal. Thus, the beta 2*nAChRs are not involved in the behaviors induced by cessation of nicotine consumption. Conclusion: Taken together, the present data demonstrated a genetic dissociation of two distinct behavioral patterns associated with nicotine addiction. They further suggested that independent molecular mechanisms underlie these two aspects, offering the possibility of controlling them separately.