Research on nicotine's molecular targets in the brain has provided new insight into the mechanism of nicotine addiction. The researchers hope that their work, published in the 5 November issue of Science, may one day lead to more effective ways to wean people off tobacco.
Nicotine's addictive power comes from its ability to elicit pleasure by mimicking chemicals that stimulate the brain's "reward" circuits. One of these chemicals is acetylcholine. Once in the brain, nicotine hijacks neurons' receptors for acetylcholine, causing them to fire even in the absence of the real thing. Acetylcholine receptors are made up of several subunits. Scientists have identified 12 such subunits that can be mixed and matched to form receptors with different physiological properties. But they haven't been able to nail down which subunits are the most important for addiction.
To narrow down the list, a team of researchers led by Henry Lester, a neuroscientist at the California Institute of Technology in Pasadena, designed a mouse with a mutant version of the a4* acetylcholine receptor subunit. Acetylcholine receptors containing the mutant subunit were about 50 times more sensitive than usual. That meant that the scientists could activate the a4*-containing receptors with doses of nicotine too small to affect other types of acetylcholine receptors. Even on these low doses of nicotine, the genetically engineered mice still exhibited the classic symptoms of addiction. The results provide strong evidence that the a4* receptors are sufficient to create nicotine addiction.
Lester hopes that the finding will point the way to treatments for people with nicotine addiction. However, because the a4* receptor subunit is important for learning, memory, appetite, and biological clock timing, treatments that narrowly target a4* receptors could cause significant side effects, says Daniel McGehee, a neurobiologist at the University of Chicago. But such concerns "don't diminish the importance of the study," he says. "The diversity of receptor subtypes is a daunting problem in the field, and this study does an outstanding job of highlighting the effects of a4*. It's a major step forward."