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Marked Global Reduction in mGluR5 Binding in Smokers and Ex-smokers Determined by [11C]ABP688 Positron Emission Tomography

Akkus, Funda and Ametamey, Simon and Treyer, Valerie and Burger, Cyrill and Johayem, Annas and Umbricht, Daniel and Gomez-Mancilla, Baltazar and Sovago, Judit and Buck, Alfred and Hasler, Gregor (2012) Marked Global Reduction in mGluR5 Binding in Smokers and Ex-smokers Determined by [11C]ABP688 Positron Emission Tomography. Proceedings of the National Academy of Sciences, 110 (2). pp. 737-742. ISSN 0027-8424

Abstract

Nicotine addiction is a major public health problem, resulting in primary glutamatergic dysfunction. We measured the glutamate receptor binding in the human brain and provided direct evidence for the abnormal glutamate system in smokers. Since antagonism of the metabotropic glutamate receptor 5 (mGluR5) reduced nicotine self-administration in rats and mice, mGluR5 is suggested to be involved in nicotine addiction. mGluR5 binding specifically to an allosteric site was observed using positron emission tomography with [11C]ABP688. We found a marked global reduction (20.6%; p < 0.0001) in the mGluR5 distribution volume ratio (DVR) in the gray matter of 14 smokers. The most prominent reductions were found in the bilateral medial orbitofrontal cortex. Compared to non-smokers, ex-smokers had global reductions in the average gray matter mGluR5 DVR (12.4%; p < 0.005). In contrast, the differences in mGluR5 DVR in any brain region between smokers and ex-smokers did not reach statistical significance after Bonferroni correction. In smokers, age was positively correlated with mGluR5 DVR in most regions of interest, and the strongest correlations were found in the putamen. Clinical variables reflecting current nicotine consumption, dependence, and abstinence were not correlated with mGluR5 DVR. These findings suggest that the reduced mGluR5 may not reflect a simple consequence of nicotine consumption but may represent a precondition of nicotine dependence and/or a trait-like pathogenetic or compensatory change associated with nicotine addiction. This study encourages the development and testing of drugs against addiction that directly target the glutamatergic system.

Item Type: Article
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Keywords: nicotine, addiction, glutamate, mGluR5, positron emission tomography
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Date Deposited: 13 Oct 2015 13:14
Last Modified: 13 Oct 2015 13:14
URI: https://oak.novartis.com/id/eprint/8073

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