August 25, 2020
Written by: Greer Prettyman
Chances are good that you’ve seen a picture comparing the lungs of a cigarette smoker and a non-smoker. We know that smoking cigarettes increases risk for lung cancer and has many negative effects on the body. But smoking also changes the brain in a variety of ways. Recent research found markers in the brains of smokers that point to some ways that smoking affects more than just the lungs.
One reason cigarette smoking is so dangerous is that nicotine is a highly addictive chemical. Addictive drugs alter the brain in ways that make it hard to stop seeking and using the drug. When someone smokes a cigarette, the nicotine-containing smoke passes through the lining of the lungs into the blood, and then into the brain. In the bran, nicotine acts by binding to a type of neurotransmitter receptor called nicotinic acetylcholine receptors (nAChRs)1. These nAChRs are ion channel receptors that allow ions to cross cell membranes, causing the neuron to fire electrical signals to communicate with other neurons. The channels can be opened by a neurotransmitter called acetylcholine and also by nicotine.
Nicotine has a strong effect in midbrain regions where activation of nAChRs leads to the release of dopamine, a neurotransmitter involved in feelings of reward2. The activity of dopamine in a region called the nucleus accumbens is the primary cause of nicotine’s addictiveness and leads to cravings for the drug. However, repeated exposure to nicotine desensitizes these receptors so that more nicotine is necessary in order to achieve the same effect, impairing normal cell signaling and promoting craving and addiction3.
In addition to changing cell signaling through nAChRs in the brain, new research suggests that smoking cigarettes can change the expression of genes in brain tissue. Epigenetics refers to the way the genes on your DNA are expressed, or used by cells. While the actual DNA sequence we inherit from our parents doesn’t change across our lifetime, the way these genes are expressed can. Our experiences can cause epigenetic changes that increase or decrease the expression of certain genes through a process called DNA methylation, which is the addition of a compound called a methyl group to the DNA.
One way researchers investigate the role of genetic makeup on outcomes in life is by doing genome wide association studies, or GWAS. Each person’s DNA is made up of nucleotide base pairs; adenine, thymine, cytosine, and guanine. At each position on the 22 chromosomes, a person has one of the 4 nucleotides. The specific sequence of nucleotides across a person’s DNA makes up their genetic fingerprint. GWAS is a statistical technique that involves inputting a person’s entire genome, the nucleotide at each position on their DNA, into an analysis looking for an effect of interest, such as a disease diagnosis.
From a GWAS, scientists can locate specific regions in the DNA, called loci, that are different in people who do and do not have a specific disease, for example. By looking at the location of these loci on the DNA and using what is known about the function of certain genes, scientists can get unique insight into the biochemical underpinnings of a disease that can increase understanding of its causes and potentially be used to develop new treatments.
There is evidence from GWAS studies that nicotine dependence is partially explained by genetic variance. For example, the genes neurexin and BDNF have been associated with smoking status3. This suggests that there are some genetic predispositions to developing nicotine addiction that are inherited in the DNA. However, it’s not as if there is one genetic variant that determines who will and will not smoke cigarettes.
Now, in addition to looking at the unique sets of base pairs that make up a person’s genome, scientists can use a similar technique to look at the expression of genes based on experience. This technique is called EWAS, which stands for epigenome-wide association study4. While GWAS studies help scientists to learn about associations with our DNA fingerprints, EWAS can increase understanding about the malleable changes in gene expression over the course of our lives.
Recently, an EWAS was used to examine how smoking cigarettes changed the expression of genes in the brain5. To do this, researchers took advantage of a collection of postmortem human brains from individuals that included both cigarette smokers and non-smokers. While markers of DNA methylation related to smoking have been identified in the blood, prior to this study they had not been studied in brain tissue. This study focused on DNA methylation changes in the nucleus accumbens, a key brain region involved in addiction.
Researchers found 7 areas on DNA in the nucleus accumbens tissue where methylation differed between smokers and non-smokers. The epigenetic changes found in the brain were different than those found in the blood, indicating that there are brain-specific effects of smoking. By analyzing results of this study compared to a GWAS of nicotine smoking, researchers concluded that these epigenetic changes were likely due to exposure to cigarette smoke and nicotine rather than to a genetic predisposition to smoking. These changes may produce broader effects in the brain that lead to craving and addiction.
While EWAS studies are a cool new way to look at epigenetic changes, they do have some limitations. The actual effects of DNA methylation differences are not always interpretable. The size of the sample can also limit conclusions; for example this study relied on a relatively small sample of 221 brains, making it possible that these changes would not be consistent in a larger group of smokers. However, by starting to identify areas of epigenetic change in the brain, researchers can move closer to a full understanding of the many biological consequences of smoking.
Of course, there are many reasons not to smoke cigarettes, including increased risk of complications from COVID-19. Although smoking affects the brain and creates strong addiction to nicotine, if you are a smoker and trying to quit, strategies to help with quitting can be effective ways to change the brain through behavior.
- Alkam, T., & Nabeshima, T. (2019). Molecular mechanisms for nicotine intoxication. Neurochemistry International. Elsevier Ltd. 125, 117-126.
- Dani, J. A. (2015). Neuronal Nicotinic Acetylcholine Receptor Structure and Function and Response to Nicotine. In International Review of Neurobiology (Vol. 124, pp. 3–19). Academic Press Inc.
- Pérez-Rubio, G., Sansores, R., Ramírez-Venegas, A., Camarena, Á., Pérez-Rodríguez, M. E., & Falfán-Valencia, R. (2015). Nicotine Addiction Development: From Epidemiology to Genetic Factors. Rev Inves Clin (Vol. 67).
- Flanagan, J. M. (2015). Epigenome-wide association studies (EWAS): past, present, and future. Methods in Molecular Biology (Clifton, N.J.). Humana Press, New York, NY.
- Markunas, C. A., Semick, S. A., Quach, B. C., Tao, R., Deep-Soboslay, A., Carnes, M. U., … Hancock, D. B. (2020). Genome-wide DNA methylation differences in nucleus accumbens of smokers vs. nonsmokers. Neuropsychopharmacology, 1–7.