The Role of Genetics on the Dopaminergic System

        Several converging lines of research indicate that the reinforcing effects of nicotine are mediated by the neurotransmission of dopamine. In animal studies, dopamine has been established as the primary substrate for the rewarding effects of food, sex, and addictive drugs. More specifically, nicotine and other psychoactive substances have been shown to stimulate dopamine release and to inhibit re-uptake. Thus, genes involved in the brain's dopaminergic reward mechanisms are one possible source for genetic factors that influence smoking practices.      To date, the strongest evidence involves a polymorphism (variation) in the dopamine transporter (SLC6A3) gene. This gene codes for the dopamine transporter protein (DAT) which transports released dopamine, thereby limiting the level and duration of dopamine receptor activation. Recent studies suggest that variation in SLC6A3 is associated with the likelihood of being a smoker, age of smoking onset, and length of periods of smoking abstinence. Other studies have examined genes important in dopamine receptor function. For example, there is evidence for a slightly higher prevalence of the A1 and B1 alleles of the dopamine 2 receptor (DRD2) gene among smokers than among nonsmoking controls. Recent data also point to an association of the dopamine D4 receptor gene (DRD4) with smoking cessation in a small sample of African Americans . While preliminary, studies examining the association of dopaminergic genes with nicotine dependence can lay the foundation for developing pharmacologic interventions for smoking cessation which are tailored to the genotypes of individual smokers.

Journal Articles:

Lerman C. Caporaso NE. Audrain J. Main D. Bowman ED. Lockshin B. Boyd NR. Shields PG. Evidence suggesting the role of specific genetic factors in cigarette smoking [see comments]. Health Psychology. 18(1):14-20, 1999 Jan.

Noble EP. Addiction and its reward process through polymorphisms of the D2 dopamine receptor gene: a review. [Review] [74 refs] European Psychiatry: the Journal of the Association of European Psychiatrists. 15(2):79-89, 2000 Mar.

Noble EP. The DRD2 gene, smoking, and lung cancer [editorial; comment]. Journal of the National Cancer Institute. 90(5):343-5, 1998 Mar 4.

Noble EP. St. Jeor ST. Ritchie T. Syndulko K. St. Jeor SC. Fitch RJ. Brunner RL. Sparkes RS. D2 dopamine receptor gene and cigarette smoking: a reward gene?. Medical Hypotheses. 42(4):257-60, 1994 Apr.

Bierut LJ. Rice JP. Edenberg HJ. Goate A. Foroud T. Cloninger CR. Begleiter H. Conneally PM. Crowe RR. Hesselbrock V. Li TK. Nurnberger JI Jr. Porjesz B. Schuckit MA. Reich T. Family-based study of the association of the dopamine D2 receptor gene (DRD2) with habitual smoking. American Journal of Medical Genetics. 90(4):299-302, 2000 Feb 14.

Anokhin AP. Todorov AA. Madden PA. Grant JD. Heath AC. Brain event-related potentials, dopamine D2 receptor gene polymorphism, and smoking. Genetic Epidemiology. 17 Suppl 1:S37-42, 1999.

Comings DE. Ferry L. Bradshaw-Robinson S. Burchette R. Chiu C. Muhleman D. The dopamine D2 receptor (DRD2) gene: a genetic risk factor in smoking. Pharmacogenetics. 6(1):73-9, 1996 Feb.

Comings DE. Gade R. Wu S. Chiu C. Dietz G. Muhleman D. Saucier G. Ferry L. Rosenthal RJ. Lesieur HR. Rugle LJ. MacMurray P. Studies of the potential role of the dopamine D1 receptor gene in addictive behaviors. Molecular Psychiatry. 2(1):44-56, 1997 Jan.

Blum K. Sheridan PJ. Wood RC. Braverman ER. Chen TJ. Comings DE. Dopamine D2 receptor gene variants: association and linkage studies in impulsive-addictive-compulsive behaviour. [Review] [122 refs] Pharmacogenetics. 5(3):121-41, 1995 Jun.

Noble EP. St. Jeor ST. Ritchie T. Syndulko K. St. Jeor SC. Fitch RJ. Brunner RL. Sparkes RS. D2 dopamine receptor gene and cigarette smoking: a reward gene?. Medical Hypotheses. 42(4):257-60, 1994 Apr.

Internet Resources:

Study finds genetic link to addiction

NICOTINE GENE SMOKING BEHAVIOR

Gene might affect vulnerability to nicotine addiction

Research to look at role of genes in smoking