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N°33 I quarterly I April 2014 Live from the Labs | 9 w Biology Researchers have demonstrated that a mutation in the nicotine receptor is associated to heavy smoking. Genetics of Nicotine Addiction by Emma Walton Nicotine addiction could be genetically encoded, reports a new study1 led by CNRS researchers Philippe Faure2 and “We turned the X-ray fluorescence beam of the SOLEIL synchrotron (a particular type of particle accelerator) on a trio of fossils to detect and map deposits of ‘rare earth’ elements in the specimens,” explains IPANEMA director Loïc Bertrand. “Rare earths” are metals such as neodymium and yttrium that are dispersed in small amounts throughout the Earth’s crust and contained as trace elements (1 to 1000 micrograms/g) in fossils. “However, the quantity of trace elements incorporated during fossilization varies depending on the type of tissue,” explains Bertrand. By applying a sophisticated statistical analysis to the pattern of deposits within the fossils, the team was able to create an image of skin, muscles, and concealed bones previously hidden within the ancient sediments. Because the technique is non-invasive, and can penetrate a few millimeters under the surface, it is ideal for delicate and flattened artifacts. The fossils examined in this case consisted of two fish and a shrimp, dating from the Cretaceous period. One of those fish, which had a bony “blade” in its skull, was so compressed that its anatomy was impossible to reconstruct. “We knew it was a new species not previously identified,” says Bertrand, “but the way the bones were articulated just above this bony blade made it difficult to observe under light microscopy. The rare earth analysis helped us understand how this fish is taxonomically related to other fish.” 01. IPANEMA (CNRS / Ministère de la culture) is a European Ancient Materials synchrotron research platform. 02. P. Gueriau et al., “Trace elemental imaging of rare earth elements discriminates tissues at microscale in flat fossils,” PLoS ONE, 2014. DOI: 10.1371/journal. pone.0086946. Uwe Maskos.3 When a person smokes, nicotine, the main addictive substance in tobacco, travels through the bloodstream to the brain’s reward circuitry where it binds to a receptor called the nicotinic receptor. This triggers the release of dopamine, leading to feelings of pleasure that drive addiction. Thus, how much a person smokes depends on how efficiently the receptor turns the binding of nicotine into dopamine release. In approximately 90% of heavy smokers— who smoke at least 25 cigarettes a day—nicotinic receptors have a single point mutation. To investigate how this mutation affects the function of the receptor, Faure’s team produced mice bearing either the normal or the mutated receptor, and examined how they responded to increasing doses of nicotine. The rodents were hooked up to an intravenous line that delivered a defined dose of nicotine. By poking their nose through a hole in the cage, they could get a new dose of nicotine on demand. Like humans, mice appear to enjoy nicotine, and responded by increasing the number of nose pokes. Surprisingly, those bearing the mutated receptor required three times more nicotine than control mice to start poking their nose, suggesting that they had low sensitivity to nicotine. Going further, the team studied the effect of nicotine directly in the brain by measuring the electrical activity of dopamine producing neurons after nicotine exposure. Results show that it takes twice as much nicotine to turn on neuronal activity in mutant mice. “The brain of the mutant mice seems hardwired to release dopamine only at high concentrations of nicotine,” says Faure. Extended to humans, this result suggests that carriers of this mutation may need to smoke more than non-carriers to achieve the same level of satisfaction. “These findings identify a population at risk of addiction, i.e., whose nicotinic receptor may be less efficient than normal,” he concludes. This observation could lead to “personalized” smoking cessation treatments for carriers of this mutation. 01. C. Morel et al., “Nicotine consumption is regulated by a human polymorphism in dopamine neurons,” Mol. Psychiatry, 2013. doi: 10.1038/mp.2013.158 02. Neurosciences Paris Seine (CNRS / INSERM / Université de Pierre et Marie Curie). 03. Neurobiologie intégrative des systèmes cholinergiques (Institut Pasteur). Contact information: ENP, Paris. Philippe Faure > philippe.faure@snv.jussieu.fr Contact information: IPANEMA, Saint-Aubin. Loïc Bertrand > loic.bertrand@synchrotron-soleil.fr q M utated nicotine receptors (green) were expressed in a specific region of the mouse brain cortex. Cell nuclei are labeled in blue. Paris Saint-Aubin © U. Mas kos /Institut Pasteur


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