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Studies Underscore Genetic Involvement In Nicotine Addiction & Aggressive Hostility

March 17, 2005
American Psychological Association
Two new studies in the current issue of Behavioral Neuroscience present new evidence of how genes may foster two potentially harmful proclivities: one, to nicotine addiction; the other, to aggressively hostile behavior. Behavioral Neuroscience is published by the American Psychological Association (APA).

WASHINGTON -- Two new studies in the current issue of Behavioral Neuroscience present new evidence of how genes may foster two potentially harmful proclivities: one, to nicotine addiction; the other, to aggressively hostile behavior. Behavioral Neuroscience is published by the American Psychological Association (APA).

First, behavioral geneticists at the University of Colorado compared the average daily nicotine consumption in mice. Co-author Jerry Stitzel, PhD, and his team found that mice with the "threonine" polymorphism (an alteration to a gene's DNA sequence) in a gene called Chrna4 consumed significantly more nicotine than mice with an alanine polymorphism in the same gene. The authors think that this threonine variation may allow these mice to tolerate higher nicotine levels before experiencing negative nervous-system side effects.

Chrna4 (Cholinergic Receptor Nicotinic Alpha4) contains the instructions to build a protein that is part of a receptor that recognizes acetylcholine, a major neurotransmitter that plays a role in the brain's pleasure system and also aids learning and memory, sleep, control of muscle movement, heart rate, blood pressure and more. Because nicotine is chemically very similar to acetylcholine, it binds to the same receptors, including those with the protein made from Chrna4. Thus the nervous system responds to nicotine as if it were acetylcholine.

The authors conclude that natural variations in Chrna4 could, by varying how the nicotine receptors works, result in animal-by-animal variation in nicotine tolerance. That may explain why in humans (the gene is found in essentially all animals), CHRNA4 polymorphisms are associated with nicotine dependence. People with certain gene variations may be able to tolerate more nicotine before they get sick and as a result smoke more in the first place, promoting addiction. Nicotine is a natural insecticide found only in tobacco. Like other insecticides, it is extremely toxic to humans.

Understanding how genes change nicotine receptors may foster better treatments. Stitzel says, "No single gene is going to be the sole determinant of whether someone will become addicted to nicotine or any other substance, because addiction likely is due to the effects of many genes as well as social and other environmental factors."

However, he adds, "By identifying genes that contribute to whether an individual will become addicted, we will gain important knowledge about the biology of addiction. With that, we will be in a much better position to design more effective treatments for addiction. This approach may also lead to treatments tailored to the 'genetic profile' of the smoker."

The authors similarly determined that Chrna4 does not directly regulate alcohol intake because removal of Chrnb2, a gene whose protein partners with the Chrna4 protein, does not affect the relationship between Chrna4 and alcohol consumption. Therefore, Chrna4 may be associated with alcohol consumption through linkage to an as-yet undetermined gene that regulates alcohol intake. Stitzel concludes that, "Common genes likely play a part in why there is such a [strong] link between nicotine and ethanol intake, which in humans means smoking and drinking."

In addition, the finding could help to account for the tendency of smokers to "hand down" versions of genes that increase the likelihood of becoming a smoker. Stitzel says that about half of why a human becomes a smoker is genetically determined; the other half comes from environmental factors.

The second study, led by Juergen Hennig, PhD, at Germany's University of Giessen, added to a growing body of evidence that the type of aggressive behavior we think of as psychopathic or sociopathic has some genetic basis that may involve abnormally low levels of the neurotransmitter serotonin. Once again, gene polymorphisms appear to influence individual variance.

Specific components of aggression in 58 participants appeared to relate to the U allele (variation) of a gene called TPH (tryptophan hydroxylase), a marker that might be linked to another yet unknown gene with specific and functional aspects. Says Hennig, "Linkage means that both genes are transmitted together due to their being close neighbors on the same chromosome."

The researchers measured genotypes dubbed AA, AC and CC. The "AA" genotype was associated with the highest levels of aggression, whereas the "CC" genotype was associated with lowest levels.

Using another sample of 48 men, the authors also validated the distinction between irritable, verbally abusive "neurotic hostility" and more violent, guilt-free "aggressive hostility" found in the Buss-Durkee Hostility Inventory, a research tool used worldwide. The authors say that their finding underscores the value of distinguishing among different aspects of aggression.

Finally, only the "aggressively hostile" men released high levels of cortisol, a key stress-hormone, after taking an anti-depressant drug that makes serotonin more available in the brain. The authors speculate that, after being deprived of serotonin, these men's neural receptors were exquisitely sensitive and primed to over-react, in part by producing extra cortisol.

Tying together the three findings, Hennig concludes that, "We found that gene polymorphisms contribute to the variance that can be found in neuro-endocrine challenge tests and personality questionnaires in healthy individuals. This demonstrates that certain aspects of behavior relate to biological systems, such as neurotransmitter systems."


Articles:(1) "Modulation of Nicotine but Not Ethanol Preference by the Mouse Chrna4 A529T Polymorphism;" Christopher M. Butt, PhD, Nathan M. King, BA, Scott R. Hutton, BA, Allan C. Collins, PhD, and Jerry A. Stitzel, PhD; Institute for Behavioral Genetics, University of Colorado; Behavioral Neuroscience, Vol. 119, No. 1.

(2) "Two Types of Aggression Are Differentially Related to Serotonergic Activity and the A779C TPH Polymorphism;" J. Hennig, PhD, M. Reuter, PhD, P. Netter, PhD, and C. Burk, PhD, Center for Psychobiology and Behavioral Medicine, University of Giessen, Germany, and O. Landt, PhD, TIB MOLBIOL, Berlin; Behavioral Neuroscience, Vol. 119, No. 1.

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