Prefrontal cortex in the brain damaged by both alcoholism and chronic smoking

Apr 26 2006

Alcoholism is commonly associated with chronic smoking, and both alcohol and nicotine are believed to act on the same brain region. A study in the May issue of Alcoholism: Clinical & Experimental Research builds upon previous research that identified four potential alcohol-sensitive genes in the prefrontal cortex, finding that smoking also influences the expression of these genes.

"Nicotine and alcohol are both addictive drugs," said Traute Flatscher-Bader, a postdoctoral research officer at the Alcohol Research Unit of the University of Queensland, Brisbane and corresponding author for the study. "They act on the same brain region, the 'drug reward pathway' or mesocorticolimbic system (MDS). The MDS contains the 'feel-good' neurotransmitter dopamine. Acute nicotine and alcohol cause an imbalance within the MDS by artificially increasing dopamine levels through direct and/or indirect modulation of dopaminergic neurons. While the long-term effect of alcoholism on the human brain has been investigated, surprisingly little is known about the long-term effect of nicotine on specific regions of the drug reward pathway in the human brain."

"Studies into the molecular changes that alcohol and smoking have on the body and particularly the brain are crucial for understanding the disease state," said Nikki Zuvela, a doctoral student in molecular neuroscience at The University of Queensland. "There are actual molecular changes to parts of the brain involved in developing addiction; most importantly, within those centres known to mediate desire, craving, pleasure, self control, decision making, fear and emotion."

All of our cells have exactly the same deoxyribonucleic acid (DNA), which means they all have the same genes. Different cells can appear and work so differently with the same genes (giving us, for example, unique eyes, skin, hair, etc.) because only some genes are used or 'turned on' in each cell. This is called gene expression. The sequence of events is for DNA, or genes, to make ribonucleic acid (RNA), also called a 'message,' which is then used to make proteins. These proteins determine the appearance and function of each cell and, in turn, the proteins' existence depends on gene expression. Thus, gene expression is a normal function of all cells and is well regulated by the body to avoid mistakes.

Zuvela's expertise lays in the examination of changes to gene expression caused by consumption and abuse of alcohol and nicotine. "Some of these changes manifest in alterations to the most important and elemental system we have: the neurotransmitters of the brain which relay messages and information to every part of our brain and body," she said. "Changes to the release or reception of neurotransmitters effect downstream functioning of these centres and, as such, play an important role in the development of addiction and tolerance, craving and loss of impulse control witnessed in so many drug-affected states. It also helps to understand on a physiological and molecular level why the behaviour may be difficult to stop, despite knowledge of negative consequences."

For this study, researchers classified post-mortem brain samples (n=30) into four groups: nonsmoker, nonalcoholic; nonsmoker, alcoholic; smoker, alcoholic; and smoker, nonalcoholic. All of the brain-tissue samples were measured for mRNA expression of four genes or proteins previously identified as potentially alcohol sensitive: apolipoprotein D (ApoD), involved in the transport of small lipids; metalloproteinase inhibitor, member 3 (TIMP3), a secreted protein that associates closely with the extracellular matrix; glial high affinity glutamate transporter (GLAST1), a membrane protein that is vital for the removal of glutamate from the synaptic cleft terminating excitatory neurotransmission; and midkine (MDK), generally neuroprotective.

"Alcoholism and nicotine appear to have a higher number of genetic targets in common than previously expected," said Flatscher-Bader. "While we know that alcoholism has a drastic effect on the prefrontal cortex, this study indicates that - while not as dramatic - the effect of chronic smoking on the prefrontal cortex may be stronger than previously expected. The study also indicates that the combination of smoking and drinking may aggravate the negative long-term effects of either drug on the human brain."

"Future research of these dual effects in other brain regions may eventually lead to therapeutic solutions, gene therapy, or pharmaceuticals which may help decrease or reverse these effects," said Zuvela, "ultimately helping people to stop drinking or stop smoking before it eventually impacts on their health. Hopefully this research will also help people realize that these addictions are physical diseases and that quitting is not as simple as being strong, because physical changes to basic systems underlay these states."