Small differences in a particular region of the genome may alter the addictive substance nicotine's consumption, a new study in mice has found.
Genetic factors are known to play a role in smoking behaviours. Nicotine binds to and activates specific receptors on nerve cells in the brain that can also bind the neurotransmitter acetylcholine.
These receptors are made up of five subunits, and human genetic studies show that changes in a single subunit can alter nicotine behaviour.
Researchers at Pennsylvania State University and the University of Colorado in US focused on the gene that encodes the beta-3 subunit, which is found in areas of the brain important in drug behaviour.
They used a mouse model to study how reducing how much of the beta-3 subunit was made, or preventing its production completely, affected nicotine consumption. They used genetic engineering techniques to remove one or both copies of the beta-3 gene.
Then, to measure how much the mice wanted the drug, the researchers provided each mouse with two water bottles, one with nicotine and one without nicotine, and recorded how much water the mice drank from each bottle.
Mice lacking one or both copies of the gene encoding the beta-3 subunit consumed less nicotine than normal mice.
The researchers performed these tests using two different strains of mice, but the lower consumption of nicotine was only seen in one of the strains, indicating that other genetic factors also play a role in nicotine cravings.
Finally, by individually reversing each of the three genetic differences in the minor allele in mouse cells in culture, the researchers found that only one of the three differences reduced the amount of beta-3 protein the cells produced.
"All three of these single nucleotide changes are inherited together, so in a human population, you get a sequence where all three nucleotides are either major or minor," said Helen Kamens from Penn State.
"Using a cell culture system, we were able to disentangle which of the nucleotide changes actually has an effect on protein amounts, which is something we could never see in a human population," she added.
According to researchers, in humans, two naturally occurring variants in the area of the genome that initiates expression of genes linked to nicotine use have been identified.
People carrying the more common version of the beta-3 subunit of nicotinic acetylcholine receptors - the major allele - are more likely to have problems with nicotine use. People with the less common version - the minor allele - are protected against nicotine dependence.
The minor allele differs from the major allele in having three differences in the DNA sequence in the area involved in turning on nicotine-related genes.
The findings were published in the journal Neuropharmacology.
