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NICOTINE ADDICTION GENE IDENTIFIED
The receptors normally are activated by acetylcholine, a molecule that carries signals between nerve cells and has multiple functions in the body. A large number of acetylcholine receptors have been identified, each with subunits adapted for a specific function. Twelve of those receptors also are activated by nicotine. Experiments with genetically engineered mice show that a mutation in a subunit of a nicotinic acetylcholine receptor, designated alpha4, makes the animals unusually sensitive to the effects of nicotine, said a report in the Science by researchers at the California Institute of Technology. "It hasn't been known which nicotinic acetylcholine receptor has been primarily responsible for nicotine addiction," said research leader Henry A. Lester, a professor of biology at Cal Tech. "This finding goes a long way toward saying that a particular kind of receptor is sufficient for many of the events of nicotine addiction." The finding was made by breeding mice that lacked specific receptor subunits and testing their response to nicotine. Mice lacking the subunit designated beta2 had reduced sensitivity to nicotine, while mice bred to have a mutated form of the alpha4 subunit were unusually sensitive to it, the researchers reported. "These data indicate that activation of alpha4 is sufficient for nicotine-induced reward, tolerance and sensitization," they wrote. The path ahead for a treatment to stop nicotine addiction would seem to be clear: simply find a molecule that blocks the alpha4 subunit. But the complex nature of the nicotinic acetylcholine system makes that pathway anything but smooth, Lester said. He and his colleagues now are doing "molecular detective work to look at the downstream events that occur after receptor activation." They are trying to identify the molecules that result from the nicotine-receptor interaction and that cause addiction. "We are also filling in the blanks for an animal model of nicotine addiction," Lester said. Developing a mouse that lives only for nicotine will accelerate the development of a cure for human addiction, he said. He warned against expecting quick results. If nicotine addiction is made a major issue for expanded funding, his estimate is that a treatment could be developed in "between five and 20 years." Daniel McGehee, an assistant professor in the University of Chicago department of anesthesiology and critical care who has been working on nicotine addiction for years, had an enthusiastic but qualified response to the report. "This is an exciting paper that provides compelling support for a specific type of receptor," McGehee said. But, he added, "there is more to it than just identifying a subunit." "The only caveat is that these receptors are doing other things as well," McGehee said. "If you target this receptor specifically, you may have other side effects." Still, even if there are undesirable side effects, a blocker may be useful for "a chronically addicted smoker who has tried everything else," he said.
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