Even tobacco companies have admitted that nicotine is addictive, but exactly why the brain craves another cigarette is murky. Now researchers report that they have sorted out how the drug toys with nicotine receptors in the brain. The finding, reported in this month's Journal of Pharmacology and Experimental Therapeutics, may lead to more effective ways to help people quit smoking and also may aid in the development of nicotine-based drugs to treat brain diseases such as Parkinson's disease, Tourette's syndrome, and schizophrenia.
Previous research had shown that nicotine seems to have conflicting effects on different types of nicotinic acetylcholine receptors, proteins on the surface of brain cells that respond to nicotine and the naturally occurring neurotransmitter acetylcholine. In cell cultures, the presence of nicotine seemed to increase the number of such receptors present, but also numbed some of them. Neuroscientist Jon Lindstrom of the University of Pennsylvania Medical Center in Philadelphia and his colleagues set out to determine more precisely how extended exposure to nicotine affected three different types of receptors.
Lindstrom and his colleagues inserted genes for human nicotinic receptors into frog eggs and incubated them with levels of nicotine similar to those found in the blood of a human smoker. To check how desensitized the cells had become, they measured the cells' response to acetylcholine. After 2 days of continuous exposure to nicotine, two types of receptors, a-4 and a-7, would no longer respond to acetylcholine. But a third type, a-3, still fired away happily. Lindstrom says the deadening of the a-4 and a-7 receptors might explain why longtime smokers can handle amounts of nicotine that would make a first-time smoker very ill. But the a-3 receptors or their cousins, he says, may provide the signal that keeps addicted smokers coming back for more.
The work "nails to the wall" the theory that different receptors respond very differently to nicotine, says pharmacologist Allan Collins of the University of Colorado, Boulder. His own work with mice "provides converging evidence" that "this variant of the nicotinic receptor doesn't follow the same rules as the others do." A better understanding of such receptors, he says, may help researchers more efficiently target nicotinelike drugs in patients with diseases that may involve nicotinic receptors, including Parkinson's disease, Tourette's syndrome, and schizophrenia.