July 07, 2005
The Molecular Basis of Nicotine Dependence Unveiled
Researchers from the Institut Pasteur associated with the CNRS have revealed for the first time in work published in Nature how and where nicotine dependence develops in mice. Dependence is linked to the expression of a receptor molecule for nicotine that is also involved in individuals' cognitive abilities. Therefore for the first time, they have established the existence of anatomical and molecular links between nicotine dependence and cognitive abilities. Understanding the subtle mechanisms of the way nicotine acts should facilitate the development of tools that make it possible to fight smokers' addictions.
Tobacco use could be responsible for the death of more than 100 million people worldwide over the course of this century. A major public health challenge thus consists of finding ways to prevent dependency from taking hold in order to avoid excessive cigarette consumption. For many years, Jean-Pierre Changeux and his colleagues have been studying the role of nicotinic acetylcholine receptors, the target molecules of this drug’s action, in tobacco addiction.
Uwe Maskos’s team in the Institut Pasteur/CNRS Receptors and Cognition Unit directed by Changeux, in collaboration with three french neuroscience laboratories, has shown that nicotine dependence in mice is linked to the expression of a specific molecule, the β2 subunit of the nicotinic receptor, in a very specific region of the brain, the ventral tegmental area. For this, researchers have used a mouse model deficient in the expression of this β2 subunit. These animals do not self-administer nicotine, an indication that they do not become dependent on the nicotine administered to them. On the other hand, an impairment of their ability to explore open space indicates that their cognitive faculties are also reduced.
Researchers used highly sophisticated viral vectors with which they were able to make the β2 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 recover nicotine self-administration reflexes characteristic of addiction. By using extensive behavioural tests, they also showed that these mice recover the exploration functions of normal mice, again linked to the fixation of the endogenous neurotransmitter, acetylcholine, on this receptor. These results show the importance of the expression of the β2 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.
The crucial role of the nicotinic receptor in establishing tobacco addiction is supported by other research published recently in the journal Neuron by Pierre-Jean Corringer’s team, from the same unit at the Institut Pasteur. 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 this very same 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.
It will be possible from the in-depth knowledge of these structures to start searching for new pharmacological agents that enable the specific inhibition of this addiction phenomenon, without altering the dominant role of these β2 units in individuals’ learning abilities, and thereby to fight tobacco addiction.
U. Maskos (1), B.E. Molles (1), S. Pons (1), M. Bessons(1,2), B.P. Guiard (2), J.-P. Guilloux (2), A. Evrard (1), P. Cazala (3), A. Cormier (1), M. Mameli-Engvall (1), N. Dufour (4,5), I. Cloëz-Tayarani (1), A.-P. Bemelmans (4), J. Mallet (4), A.M. Gardier (2), V. David (3), P. Faure (1), S. Granon (1) et J.-P. Changeux (1)
1. Unité Récepteurs et Cognition, CNRS URA 2182, Institut Pasteur
2. Laboratoire de Neuropharmacologie EA3544, Faculté de Pharmacie, Université, Paris-Sud, 92296 Chatenay-Malabry
3. Laboratoire de Neurosciences Cognitives, CNRS UMR 5106, Université de Bordeaux-I33405 Talence
4. Laboratoire de Génétique Moléculaire de la Neurotransmission et des Processus Neurodégénératifs (LGN), CNRS-UMR 7091, Hôpital de la Pitié-Salpétrière,Paris
"Nicotine up-regulates its own receptors through enhanced intracellular maturation" Neuron, 19 mai 2005.
Jérôme Sallette, Stéphanie Pons, Anne Devillers-Thiery, Martine Soudant, Lia Prado De Carvalho, Jean-Pierre Changeux et Pierre Jean Corringe
Unité Récepteurs et Cognition, CNRS URA 2182, Institut Pasteur
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