May 17, 2007 Researchers from the Institut Pasteur associated with the CNRS, collaborating with scientists from the Karolinksa Institute (Stockholm) and the University of Bordeaux 1, have analysed the subtle balance between various types of nicotinic receptors in the brain during chronic exposure to nicotine. Their research, just published in PNAS, could make it possible to guide the development of more specific therapeutic molecules for smoking cessation, as well as for some neurological pathologies, such as Alzheimer's Disease and autism, or psychiatric conditions like schizophrenia.
Nicotine is the principal substance in tobacco involved in addiction, in particular through the changes it causes in the reward system that naturally manages our desires, our pleasures, and our emotions. It acts by binding to nicotinic acetylcholine receptors. These receptors result from the assembly of five subunits; as there are nine different subunits, the receptors, as a consequence, possess a wide variety of pharmacological properties. However, all are activated by the endogenous neurotransmitter acetylcholine, as well as by nicotine. These different types of receptors could therefore have distinct physiological functions, and represent specific pharmacological targets. Hence the importance of studying their respective roles.
This kind of analysis has just been achieved in a study led by Philippe Faure and Sylvie Granon, in the Integrative Neurobiology of Cholinergic Systems Unit of the Institut Pasteur, associated with the CNRS. Last year, these researchers deciphered the molecular basis for activation of our reward system during an acute injection of nicotine. They demonstrated the major role of one subunit of the nicotinic receptor, called ß2, in this activation, and suggested the intervention of a second type of subunit, a7.
In the present study, the researchers analysed the role of these receptors during chronic exposure to nicotine. Over several weeks, they administered doses of nicotine to mice allowing them to obtain concentrations of nicotine in the plasma similar to those found in a smoker, and sufficient to trigger a withdrawal syndrome.
By comparing "control" mice and mice genetically lacking the ß2 receptor, they were able to demonstrate that chronic exposure to nicotine modified the equilibrium between two contrasting processes, orchestrated by the ß2 and a7 receptors. The ß2 receptors, after a sufficiently long period of exposure, undergo a long-term inactivation and desensitisation. This effect is counterbalanced by an adaptation of the neural circuits that depend on a7. This is especially obvious in mice deficient in ß2 subunits, for which the behavioural defects linked to the reward system are offset by the chronic exposure to nicotine. This compensation does not appear if the a7 receptors are blocked.
Therefore, in the light of this study, it seems necessary to take into account these two types of receptors in order to develop molecules that would aid in ending tobacco addiction.
In addition, the authors emphasise that there are pathologies that involve the nicotinic receptors, among other biochemical changes. "In particular, this is the case with schizophrenia", explains Faure. "The individuals treated for this disease smoke significantly more than the standard population, and some authors think that this would be a form of self-medication. This phenomenon could be due to the action of a compensatory mechanism linked to the a7 receptors". Other disorders, such as Alzheimer's, the hyperactivity syndrome Attention Deficit Hyperactivity Disorder (ADHD), or autism, also appear to affect various types of nicotinic receptors.
"These results offer new avenues for developing and fine-tuning 'nicotine-like' agents for the treatment of certain neurological and psychiatric pathologies", the authors conclude.
Reference: "Long-term effects of chronic nicotine exposure on brain nicotinic receptors": Proceedings of the Natural Academy of Sciences, May 2007.
Morgane Bresson, Sylvie Granon, Monica Mameli-Engvall, Isabelle Cloëz-Tayarani, Nicolas Maubourguet, Anne Cormier, Pierre Cazala, Vincent David, Jean-Pierre Changeux and Philippe Faure
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