Psychobiology
Spring 2001
GENETIC INFLUENCES INVOLVED IN     NICOTINE ADDICTION
				By Nicole Krupnick, 

	The nature-nurture dispute has been involved in attempting to 
determine the base of several different behaviors.  Cigarette smoking 
behavior has been researched with this debate in mind as well.  Is 
cigarette smoking behavior influenced by environmental factors or is 
there a genetic basis to these addictive behaviors?  As with many 
behaviors, one can probably find both aspects to be an influence, but 
there has been some research regarding genetic influences on nicotine 
addictions.
	Nicotine is a very powerful drug despite the fact that it appears 
to be rather tame in comparison to many other drugs.  Sigmund Freud, 
who was a medical doctor and knew the risks of nicotine, continued to 
smoke after parts of his jaw were removed as a result of nicotine 
related cancer. (Carlson, 2001).  As a psychotherapist, Freud 
specialized in changing behaviors, yet he himself could not stop his 
dangerous behavior, and passed away as a result of his cancer.  Out of 
the people that enroll in programs to quit smoking, only twenty percent 
manage to abstain for one year. (Carlson, 2001)  The numbers are even 
smaller for those whom attempt to quit on their own.  One-third manages 
to stop for one day, one-fourth for one week, and only four percent 
manage to abstain for six months.  (Carlson, 2001)  This seems to prove 
smoking to be a bit more powerful then the pleasurable habit that 
cigarette executives would claim it to be.
	When nicotine is injected into laboratory animals, it stimulates 
acetylcholine receptors.  It also increases the activity of 
dopaminergic neurons of the mesolimbic system, which contains those 
receptors. (Carlson, 2001)  This causes dopamine to be released in the 
nucleus accumbens.  According to the text, injection of a nicotinic 
agonist directly into the ventral tegmental area will reinforce a 
conditioned place preference. (Museo and Wise, 1994)  On the other 
side, an injection of a nicotinic antagonist into the ventral tegmental 
area will reduce the reinforcing effect of intravenous injections of 
nicotine. (Corrigal, Coen, and Adamson, 1994)  Through other studies, 
it has been discovered that the reinforcing effect of nicotine appears 
to occur in the ventral tegmental area, on nicotinic receptors on the 
dendrites of mesolimbic dopaminergic neurons. (Carlson, 2001)  There 
has been some research done to attempt to discover if some individuals 
have a predisposition to become addicted to this stimulation.
	 According to Carlson's text, most people who are exposed to 
highly addictive drugs do not become addicts. (Carlson, 2001)  This 
would lead one to believe that addictions, especially to substances 
such as nicotine, would be strongly effected by heredity.  Many 
researchers believe that studies of reinforcing and punishment would 
better help us to understand addictions.  Many studies involve animals' 
dopamine release.  
	One study that looks at the role of specific genetic factors in 
cigarette smoking was done by Caryn Lerman et al. in 1999.  This 
research attempted to target particular genotypes in nicotine addictive 
behavior.  Previous research prior to this study had suggested the 
dopamine transporter, SLC6A3-9, had a significant effect and a 
significant gene-gene interaction was found in a logistic regression 
model.  This indicated that individuals with SLC6A3-9 genotypes were 
significantly less likely to be smokers.  This was especially so if 
they had the dopamine receptor (DRD2-A2) genotypes.  (Lerman et al. 
1999) Smokers with SLC6A3-9 genotypes were also significantly less 
likely to have started smoking before sixteen years of age and had 
prior smoking histories that indicated a prior longer period smoking 
cessation.  This study shows preliminary evidence that the SLC6A3-9 
gene may influence smoking initiation and nicotine dependence. (Lerman 
et al. 1999)
	As earlier stated dopamine is thought to be the neurotransmitter 
responsible for these genetic effects. (Carr, Basham, York, & Rowell, 
1992).  The reinforcing properties of nicotine have been attributed to 
nicotine's effects on dopamine transmission, specifically the D2 
receptor.  This is also true of other psycho stimulants.  Nicotine 
stimulates dopamine release, yet also inhibits reuptake, which 
increases levels of synaptic dopamine and satisfies the reward 
mechanism. (Dani & Heinemann, 1996)  The DRD2-A1 allele has been 
associated with a reduced density of dopamine receptors.  Those 
individuals with DRD2-A1 genotypes, in comparison with those with DRD2-
A2 genotypes, were found to be more likely to show compulsive and 
addictive behaviors.  Cummings, Wu, et al. 1996.)  However several 
results have been inconsistent.  Other studies show that the SLC6A3 
gene regulates dopamine for coding for a reuptake protein called the 
dopamine transporter. (Bannon, Granneman & Kapatos, 1995).  This gene 
has been found in Parkinson's disease, attention deficit disorder, and 
Tourette's syndrome.  The 9-repeat allele (variant of the gene) has 
been associated with cocaine-induced paranoia, a state thought to 
diminish dopamine reuptake and greater availability of a synaptic 
dopamine. (Gelernter, Kranzler, Satel, & Rao, 1994)  This particular 
study used these research studies as a basis for this one.  The idea 
was to prove the prediction that the SLC6A3-9 and DRD-A2 genotypes 
would be associated with a reduced risk of cigarette smoking because of 
the greater availability of synaptic dopamine and functioning 
receptors.  (Lerman et. al. 1999)  This study involved looking at 289 
smokers and 233 non-smokers.
	The alleles found were consistent with prior studies.  The 
allelic and genotype frequencies were similar to those found in 
literature.  One interesting result was that the SLC6A3-9 was 
significantly less common in African Americans then in Caucasians.  
This particular study ended up showing that this was the first evidence 
for the dopamine transporter (SLC6A3-9) genotype associated with 
smoking risk, age at smoking initiation, and ability to stop smoking.  
There was a higher prevalence of SLC6A3-p in former smokers then among 
current smokers (Lerman, et al. 1999) There was some limitations found 
through this research design, yet this study provided a first step in 
research looking at the genetic basis of cigarette smoking.
	Another research study for genetic associations for cigarette 
smoking behavior was done by Sue Sabol et al. in 1999) This study had 
the same basis as the previous research project in stating that 
dopaminergic genes are like likely to be part of heritable influences 
on cigarette smoking.  Looking at the similar genotypes and alleles 
this study was meant to show that individuals carrying the SLC6A3-p 
polymorphism have altered dopamine transmission, which reduces their 
need for reward by external stimuli, including cigarettes. (Sabol et 
al. 1999)
	The reinforcing properties of nicotine are partly due to the 
activation of the mesolimbic dopamine reward system and the release of 
dopamine in the nucleus accumbens, the brain's pleasure and reward 
center. (Pontieri, Tanda, Orzi, & Di Chiari, 1996).  This mechanism is 
common in many addictive drugs.  Brain scans of rat's ingesting 
nicotine are pretty much the same as rat's ingesting cocaine.  
Cigarette smoke also contains substances that inhibit brain monoamine 
oxidase B, which degrades dopamine and other monoamine 
neurotransmitters. (Fowler et al. 1996)
	This particular study found the effect size of the SLC6A3 gene to 
be small, accounting for less then two percent of the total variance in 
both smoking behavior and personality traits.  This means that, 
according to this study, the dopamine transporter gene is only one of 
many factors, both genetic and environmental, that influence smoking 
behavior.  This particular gene cannot be a cigarette-smoking gene 
because it evolved long before tobacco was introduced to humans. (Sabol 
et al, 1999)  It also cannot be considered the gene needed to quit 
smoking because several of the former smokers didn't have it. (Sabol et 
al. 1999)  A much greater knowledge of the genetics of cigarette 
smoking behavior would be needed to truly understand the source of the 
behavior.
	These studies in genetics are tricky because certain levels of 
significance appear that seem important, but the researcher does not 
have enough info on them to validate them drawing conclusions from the 
findings.  These warrant more further research and more work to draw 
further conclusions from the findings.  When studying the effects of 
genetics in cigarette smoking behavior, several studies use twin 
studies and adoption studies.  These bring researchers closer to 
drawing a conclusion about the nature-nurture debate position in 
cigarette addiction behavior.  Many studies take place by injecting 
nicotine into lab animals to study their addiction behavior.  Other 
studies involve taking blood tests from smokers and non-smokers to test 
their DNA. This aids in finding genetic links to their behavior.
	

	REFERENCES

Gynther, L.M., Hewitt, J.K., Heath, A.C., &Eaves, L.J. (1999)  
Phenotypic and Genetic Factors in Motives for Smoking.  Behavior 
Genetics 29:5, 291-301

Lerman, C., Caporaso, E.N., Audrain, J., Main, D., Bowman, E.D., 
Lockshin, B., Boyd, N., Shields, P.G., (1999) Evidence Suggesting the 
Role of Specific Genetic in Cigarette Smoking Health Psychology Vol.18, 
No.1, 14-20

Sabol, S., Nelson, M.L., Fisher, C. Gunzerath, L., Brody, C., Hu, S., 
Sirota, L., Marcus, S., Greenberg, B., Lucas, F., Benjamin, J., Murphy, 
D., Hamer, D.   A Genetic Association for Cigarette Smoking Behavior, 
Health Psychology, Vol.18, No.1, 7-13

Carlson, Neil, Physiology of Behavior, (2001) Allan and Bacon, A Person 
Education Company, Needham Heights, Massachusetts

Copyright © 2001, Dr. John M. Morgan, All rights reserved - This page last edited 8 May, 2001
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