Individuals appear to vary in their vulnerability to drug abuse. The reward system in humans is composed of dopaminergic (DA) neurons and the administration of addicting drugs results in the stimulation of this system. A reasonable hypothesis for the neurochemical basis of drug abuse is that vulnerable individuals self medicate to compensate for defects in the dopaminergic reward system. To investigate the possibility that variations in the prevalence of different forms of the dopamine D2 receptor (DRD2) gene in drug addicts may be involved in the vulnerability to drug addiction, we determined the frequency of the DRD2 variants in several hundred substance abusers. This showed a high correlation between the frequency of the TaqI A1 variant and multisubstance abuse, based upon the number of drugs on which more than $25 per week were spent, (p= 0.006). Using the Defense Style Questionnaire, drug addicts carrying the l haplotype, which is in linkage disequilibrium with the D2A1 variant, showed much greater use of immature defenses than non-1 carriers. These preliminary studies support the concept that differences in the prevalence of DA receptor variants play an important role in fundamental personality traits that affect a person's vulnerability to drug abuse, and other impulsive, compulsive, addictive behaviors. To attempt to verify this association, we propose the following studies on 200 male substance abusers, from the Addictions Treatment Ward at the Jerry L. Pettis V.A. Hospital and 200 sex age, race, and ethnically matched controls: l) Genetic testing of the D2A1, B1, C1 and haplotype variants of the DRD2 gene, 2) Genetic testing for variants of the dopamine D1, D3, D4 and D5 receptor genes and the dopamine transporter gene 3) Testing of all genotyped subjects with the Diagnostic Interview Schedule, MMP1, Addiction Severity Index, Defense Style Questionnaire and Axis II Personality Index. 4) Statistical analysis to test for possible correlations between the independent genetic variables, personality variables and drug abuse.
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