Decreased withdrawal symptoms but normal tolerance to nicotine in mice null for the alpha7 nicotinic acetylcholine receptor subunit.

Withdrawal symptoms are a major deterrent when people try to quit smoking. The alpha7 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 alpha7-containing nAChRs on nicotine withdrawal and tolerance, in wild type mice and mice null for the alpha7 nAChR subunit (alpha7 -/-). 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 alpha7 -/- mice, the somatic effects of MEC-precipitated nicotine withdrawal were significantly reduced. Interestingly, the presumed alpha7-specific antagonist MLA also precipitated withdrawal. Tolerance, which was measured as a decrease in nicotine-induced hypolocomotion after subchronic nicotine treatment, was normal in alpha7 -/- mice. Finally, because anxiety and withdrawal symptoms are highly correlated in humans, we studied anxiety-like behaviors in alpha7 -/- mice using a battery of anxiety-related tests. The behavior of alpha7 -/- mice was indistinguishable from that of control mice. Our results point to the alpha7 subunit as one of the players in nicotine withdrawal, but not in nicotine tolerance or basal anxiety-like behavior.