Unit 1130 Neuroscience Paris Seine
Neurophysiology and behavior team
Tel.: +33 (0)1 44 27 39 40
Researchers from Inserm, CNRS and Sorbonne Université at the Paris-Seine Neuroscience laboratory1 in collaboration with Institut Pasteur2, New York University (NYU) and University of California Berkeley (UC Berkeley) have succeeded in controlling the activity of nicotine receptors in the brains of mice. To do this, they developed an optogenetic pharmacology strategy in which light is used to block the nicotine receptors, with the result being the possibility to control the addictive effects of nicotine. This study was published in eLIFE on September 4, 2018.
Every year, more than 7 million people die from smoking worldwide. Nicotine, the main addictive substance in tobacco, acts on the brain by binding to the nicotine receptors. At present, standard pharmacology techniques do not enable precise and reversible action on these receptors. That is why researchers had the idea of producing molecular tools able to interrupt the functioning of these receptors in the brain through the use of light.
In this study, the researchers modified the nicotine receptor in mice in order to attach a chemical nanoswitch which reacts to light. Under the effect of violet light, the switch folds away, preventing the nicotine from binding: the receptor is “off”. Under the effect of green light, or in darkness, the switch unfolds and allows the nicotine to act: the receptor is “on”.
For this study, the researchers focused on a specific nicotine receptor –type β2– and on a key area of the reward circuit, which delivers dopamine. When nicotine is injected intravenously, the dopamine neurons respond with an increase in their electrical activity, with the resulting dopamine release being key to acquiring the addiction. In this research, this effect of nicotine was found to be greatly reduced when the nanoswitch was triggered by the violet light but was rapidly restored under green light.
Crédits : A.Mourot/S.Mondoloni/R.Durand de Cuttoli
This study proves that it is possible to manipulate the attraction for nicotine in mice, both rapidly and reversibly. Alexandre Mourot, Inserm researcher in charge of the study, states: “This innovative technology provides us with a better understanding of the role of the various nicotine receptors and neuron pathways in acquiring and maintaining nicotine addiction, and also in the processes of withdrawal and relapse. This step is particularly important when it comes to identifying suitable new therapeutic targets for fighting nicotine addiction“.
1 Laboratory located on the Pierre et Marie Curie campus of Sorbonne Université, shared with CNRS and Inserm
2 At the Genes, synapses and cognition laboratory (Institut Pasteur/CNRS).
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Manipulating midbrain dopamine neurons and reward-related behaviors with lightcontrollable nicotinic acetylcholine receptors
Romain Durand-de Cuttoli1†, Sarah Mondoloni1†, Fabio Marti1, Damien Lemoine1, Claire Nguyen1, Jérémie Naudé1, Thibaut d’Izarny-Gargas1, Stéphanie Pons2, Uwe Maskos2, Dirk Trauner3, Richard H. Kramer4, Philippe Faure1* and Alexandre Mourot1
1Sorbonne Université, INSERM, CNRS, Neuroscience Paris Seine – Institut de Biologie Paris Seine (NPS – IBPS), 75005 Paris, France.
2 Unité de Neurobiologie Intégrative des Systèmes Cholinergiques, Department of Neuroscience, CNRS UMR 3571, Institut Pasteur, Paris, France.
3 Department of Chemistry, New York University, New York City, New York.
4 Department of Molecular and Cell Biology, University of California Berkeley, Berkeley, CA 94720, USA
† 17 equal contribution