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Human Molecular Genetics Advance Access originally published online on October 10, 2007
Human Molecular Genetics 2008 17(1):38-51; doi:10.1093/hmg/ddm283
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Smoking and alcoholism target genes associated with plasticity and glutamate transmission in the human ventral tegmental area

T. Flatscher-Bader*, N. Zuvela, N. Landis and P.A. Wilce

Department of Biochemistry, School of Molecular and Microbial Sciences, Alcohol Research Unit, The University of Queensland, St Lucia, Queensland 4073, Australia

* To whom correspondence should be addressed. Tel: +61 732142228; Fax: +61 732142480; Email: t.flatscher-bader{at}uq.edu.au

Received August 13, 2007; Revised August 13, 2007; Accepted September 14, 2007

Drugs of abuse including nicotine and alcohol elicit their effect by stimulating the mesocorticolimbic dopaminergic system. There is a high incidence of nicotine dependence in alcoholics. To date only limited data is available on the molecular mechanism underlying the action of alcohol and nicotine in the human brain. This study utilized gene expression screening to identify genes sensitive to chronic alcohol abuse within the ventral tegmental area (VTA) of the human brain. Alcohol-responsive genes encoded proteins primarily involved in structural plasticity and neurotransmitter transport and release. In particular, genes involved with brain-derived neurotrophic factor signalling and glutamatergic transmission were found to be affected. The possibility that glutamate transport was a target of chronic alcohol and/or tobacco abuse was further investigated in an extended case set by measurement of mRNA and protein expression. Expression levels of vesicular glutamate transporters SLC17A6 and SLC17A7 were robustly induced by smoking, an effect that was reduced by alcohol co-exposure. Glutamatergic transmission is vital for the control of the VTA and may also be critical to the weighting of novelty and importance of a stimulus, an essential output of this brain region. We conclude that enduring plasticity within the VTA may be a major molecular mechanism for the maintenance of smoking addiction and that alcohol, nicotine and co-abuse have distinct impacts on glutamatergic transmission with important implications for the control of this core mesolimbic structure.


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