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NICOTINE GENE & SMOKING BEHAVIOR


SAN DIEGO - Many of the forbidden pleasures of the modern day-nicotine, alcohol and over-eating- appear to be linked by common genetic factors, according to recent studies.

Genetic variables appear to play a key role in every aspect of nicotine addiction, from the tendency to begin smoking, to the chances of quitting, reported researchers at the first conference of the Society for Research on Nicotine and Tobacco.

Evidence is now converging from behavioral studies, twin studies and molecular genetic research that provides a clearer understanding of the biobehavioral basis for nicotine dependence. Ultimately this should lead to the development of improved methods for assessment and treatment of dependence, said Gary Swann, Ph.D., of the Stanford Research Institute.

"Behavioral scientists have made great progress in defining the phenotype and carefully pointing out the variables that have to be taken into account in describing individual differences in smoking behaviors. Molecular biologists have made great progress in identifying an array of nicotinic receptors, the genes involved and their locations, and other neurochemicals (particularly dopamine) that may be involved in regulation and activation of nicotine related behavior," he noted.

Dr. Swan and colleagues analyzed more than 20 studies of smoking behaviors in monozygotic and dizygotic twins. They found consistent evidence of genetic influences governing the developmental stages of smoking (initiation, maintenance, cessation), smoking intensity (light to heavy), as well as for level alcohol consumption.

Five years ago, Dr. Ernest Noble and colleagues reported the discovery of a gene that appeared to be associated with alcoholism, the D2 dopamine receptor gene (DRD2). Since that time Dr. Noble has conducted further studies implicating this gene in behaviors associated with tobacco, cocaine and obesity.

There are two main dopaminergic pathways in brain. The first begins in the area called the substantia nigra and is involved with movement. Defects in this part of the brain are associated with movement disorders such as Parkinson's disease. The second pathway, the mesolimbic dopamine system, is associated with emotion activation.

"When alcohol, nicotine, cocaine, or food are ingested, dopamine levels increase in this area. Therefore, we think these areas are associated with reward and pleasure," noted Dr. Noble, a professor of psychiatry at UCLA.

The DRD2 gene is found on chromosome 11, in the q22-23 region. There are two alleles of interest, A1 found in 25% of the population and A2 found in 75%. Studies comparing alcoholics to controls showed a significantly higher incidence of A1 allele. The A1 allele is associated with significantly reduced levels of D2 dopamine receptors in the brain.

"This led us to hypothesize that individuals with the A1 allele may have an inherent deficit of the dopaminergic system. To compensate for that deficiency, they are high risk for using alcohol, and other substances which by releasing dopamine activate these areas," he explained.

Dr. Noble recently completed a study of the association between this gene with smoking and obesity. This study showed that male, but not female, smokers with the A1 allele began to smoke at an earlier age than those with the A2 allele. Also, the female smokers with the A1 allele were less likely to be obese, while male smokers with the A1 allele were more likely to be obese. The study also showed that non-obese female smokers with the A1 allele had higher levels of anxiety and depression, while obese female smokers had lower anxiety scores.

"These studies add further support for the role of this gene in weight and mood in smokers and non-smokers. However, the differences seen in males and females suggest that besides DRD2 gene, other epigenetic and environmental factors play a role in contributing to these gender differences," he said.

These findings could point the way to useful therapies for those attempting to quit smoking or drinking. A recent study with bromocriptine, a drug that increases levels of DRD2, showed significant improvements in craving and anxiety among alcoholics trying to quit.

For more information see: Nature Medicine, 4/4/95, Noble et al.; Science, 4/26/95, Wehner et al.; or contact the Society for Research on Nicotine and Tobacco at tel: (301) 251-2792.

Transmitted: 95-05-10 15:15:27 EDT


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