BioWorld International Correspondent

LONDON - Details of how nicotine interacts with the neurons in the brain that are involved in drug addiction have been elucidated by a team of researchers based in France. The finding gives hope that, one day, it may be possible to develop drugs to treat or prevent nicotine addiction.

The neurons concerned are those forming a key part of the "reward circuitry" - neurons with interactions that produce pleasurable sensations and are likely to be required for addiction to any psychoactive drug, including alcohol, nicotine and opiates.

In a fascinating twist, the team's work with mice also linked the neurophysiological mechanisms that they describe as being important for addiction, to murine behaviors that are classified as curiosity and novelty-seeking behavior.

The study, by Jean-Pierre Changeux and Philippe Faure of the Institut Pasteur in Paris, is published in the June 15, 2006, issue of Neuron. The title of the paper is "Hierarchical control of dopamine neuron-firing patterns by nicotinic receptors." Monica Mameli-Engvall is first author.

Writing in their conclusion, Changeux, Faure and their colleagues stated that further investigation of the neural circuits involved in the expression of exploratory and novelty-seeking behaviors may well be "crucial [if we are] to understand the mechanisms responsible for the vulnerability to drugs of abuse."

Changeux told BioWorld International: "We have identified the specific receptor subtype for nicotine in the brain. We can anticipate that, now that we know this, it may be possible to design drugs directed to this molecular target. Such novel drugs might potentially be useful to treat or prevent nicotine addiction."

Changeux and his colleagues set out to study the ways in which dopamine-producing nerve cells can be stimulated. Those cells have what is called nicotinic acetylcholine receptors (nAChRs) on their surface. The neurotransmitter that normally stimulates those receptors - causing the cell to produce a nerve impulse - is acetylcholine.

Nicotine mimics the action of acetylcholine on the receptor. Research has shown that when nicotine stimulates nAChRs, the dopamine neurons become more responsive to acetylcholine. The cells fire more often, and the frequency at which the neurons fire "bursts" of action potentials also increases.

Little was known, however, about how nicotine could stimulate nAChRs, and there was an equal dearth of information about how acetylcholine itself regulates nerve cell activity via these receptors. Recently, however, it has been found that nAChRs can be divided into different categories, depending on the firing pattern that results when they are stimulated. Subunits called b2 and a7 are thought to influence how those receptors respond to nicotine.

The strategy taken by Changeux and his colleagues was to knock out in mice the gene encoding the b2 subunit of the nAChR receptor. In a separate experiment, mice were bred that lacked a functional copy of the a7 subunit of the nAChR receptor.

The research team found the dopamine neurons of mice that lacked the b2 subunit of the nAChR receptor did not respond to nicotine, unlike the dopamine neurons of normal mice, which responded by increased firing. In mice lacking the a7 subunit of the nAChR receptor, the dopamine neurons did respond, but not in a normal way.

The researchers confirmed the importance of the b2 subunit by using a lentivirus to ferry the gene encoding it back into a specific region of the brain, called the ventral tegmental area. That, they found, restored the neurons' normal response to nicotine.

Other experiments examined the action of acetylcholine alone on the b2 subunit of the nAChR receptor. Those showed that acetylcholine also increased the spontaneous appearance of the firing pattern that normally followed stimulation with nicotine. "This suggests that these receptors are involved in the daily management of our emotions and pleasures," Changeux said in a statement.

In addition, a previous study had shown that mice lacking the b2 subunit showed reduced exploratory behavior, which was restored when the researchers added the subunit back.

The researchers also suggested the nAChR receptors containing the b2 subunit might provide a pharmacological target not only for nicotine dependence, but also for other pathological conditions that might be linked to a defect in the activity of the dopamine-producing neurons, such as attention deficit hyperactivity disorder.