Decreased withdrawal symptoms but normal tolerance to nicotine in mice null for the α7 nicotinic acetylcholine receptor subunit

Withdrawal symptoms are a major deterrent when people try to quit smoking. The alpha 7 subunit of the neuronal nicotinic acetylcholine receptor (nAChR) is highly expressed in the brain, and has been suspected to play a major role in nicotine addiction. We studied the influence of alpha 7-containing nAChRs on nicotine withdrawal and tolerance, in wild type mice and mice null for the alpha 7 nAChR subunit (alpha 7 -/-). For withdrawal experiments, animals were implanted with osmotic minipumps delivering nicotine for 13 days. A single intraperitoneal injection of the nAChR antagonists mecamylamine (MEC) or methyllycaconitine (MLA) was used to precipitate withdrawal. In wild type mice, both MEC- and MLA-precipitated somatic signs of withdrawal such as increased grooming, scratching and shaking. In alpha 7 -/- mice, the somatic effects of MEC-precipitated nicotine withdrawal were significantly reduced. Interestingly, the presumed alpha 7-specific antagonist MLA also precipitated withdrawal. Tolerance, which was measured as a decrease in nicotine-induced hypolocomotion after subchronic nicotine treatment, was normal in alpha 7 -/- mice. Finally, because anxiety and withdrawal symptoms are highly correlated in humans, we studied anxiety-like behaviors in alpha 7 -/- mice using a battery of anxiety-related tests. The behavior of alpha 7 -/- mice was indistinguishable from that of control mice. Our results point to the alpha 7 subunit as one of the players in nicotine withdrawal, but not in nicotine tolerance or basal anxiety-like behavior. (c) 2007 Elsevier Ltd. All rights reserved.