Craving for nicotine is in the genes

July 15, 2005

Brussels, 14 Jul 2005

Scientists from the Institut Pasteur in France, associated to the national centre for scientific research (CNRS), have revealed for the first time how and where nicotine dependence develops in mice, according to new research published in the scientific journal Nature.

Quitting smoking is perceived as a struggle of mind over matter, but nicotine dependence is partially determined by our genes. Dependence is linked to the expression of a receptor molecule for nicotine also involved in individuals' cognitive abilities.

From previous research, it was known that nicotine interacts with nicotinic acetylcholine receptors (nAChRs) in the brain, although how this interaction leads to a chemical dependence remained unclear. The new research at the Institut Pasteur has succeeded in identifying a specific area of one nAChR as a prime target in the development of nicotine dependence.

Also for the first time, scientists have established the existence of anatomical and molecular links between nicotine dependence and cognitive abilities. Understanding the subtle mechanisms by which nicotine acts should facilitate the development of tools that make it possible to fight smokers' addictions.

Tobacco is the single largest cause of avoidable mortality in the European Union, accounting for over half a million deaths each year and over a million deaths in Europe as a whole. It is estimated that 25 per cent of all cancer deaths and up to 15 per cent of all fatalities in the Union could be attributed to smoking. In order to curb this epidemic, the European Community is actively developing a comprehensive tobacco control policy. A new 4-year, 72 million euro anti-smoking campaign was launched on 1 March 2005 to help young people, non-smokers and those wanting to quit to get help to lead a life without tobacco. A major public health challenge, therefore, is finding ways to prevent dependency from taking hold in the first place.

Uwe Maskos's team in the Institut Pasteur/CNRS Receptors and Cognition Unit, in collaboration with three French neuroscience laboratories, showed that nicotine dependence in mice is linked to the expression of a specific molecule, the ß2 subunit of the nicotinic receptor, in a very specific region of the brain, the ventral tegmental area.

To achieve this, the researchers used a mouse model deficient in the expression of this ß2 subunit. These animals did not self-administer nicotine, and therefore did not become dependent on the nicotine administered to them. On the other hand, an impairment of their ability to explore open space indicated that their cognitive faculties were also reduced.

Using highly sophisticated viral vectors, researchers succeed in making the ß2 subunit of the nicotinic receptor express itself specifically in the ventral tegmental area of the midbrain, where the specialised dopamine neurons of reward mechanisms are found. They observed that the mice treated in this way recovered the nicotine self-administration reflexes characteristic of addiction. By using extensive behavioural tests, they also showed that these mice recovered normal exploration functions as well.

These results show the importance of the expression of the ß2 subunit of the receptor as well as the importance of the area of the brain where it is expressed for two essential aspects: nicotine dependence and certain cognitive capacities.

For many years, Jean-Pierre Changeux and his colleagues from the same unit at the Institut Pasteur have been studying the role of nicotinic receptors, the drug's target molecules, in tobacco addiction. The results of their recent investigations demonstrate the crucial role of the nicotinic receptor in establishing tobacco addiction. The researchers showed that nicotine is capable of penetrating into neurons in order to encourage the formation of receptors that have a high affinity for nicotine. Their over-expression on the surface of cells is the cause of increased sensitivity to nicotine.

Researchers are now working at characterising particular subcategories of nicotinic receptors expressed in this key zone, the ventral tegmental area, in order to determine the structures of receptors more specifically involved in nicotine dependence. The in-depth knowledge of these structures will allow them to start searching for new pharmacological agents that enable the specific inhibition of this addiction mechanism, without altering the dominant role of these ß2 units in individuals' cognitive learning abilities, and thereby fight tobacco addiction.

For further information, please consult the following web address:
http://www.pasteur.fr
Remarks: Peer reviewed publication and references: 'Nicotine reinforcement and cognition restored by targeted expression of nicotinic receptors', Nature, 7 July 2005.

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