Dopamine transporter gene associated with diminished subjective response to amphetamine

Individual variability in responses to stimulant drugs may influence risk of stimulant abuse and treatment response. However, the genetic determinants of this variability have yet to be elucidated. The dopamine transporter is an important site of amphetamine action. Therefore, the dopamine transporter gene (DAT1) is a logical candidate gene to study. Using a drug challenge approach, we tested for association between DAT1 genotype and subjective responses to amphetamine in healthy adults. Volunteers participated in a double-blind, crossover design, randomly receiving placebo, 10 mg, and 20 mg oral D-amphetamine, and completed self-report measures on subjective effects including anxiety and euphoria. Subjects were genotyped for the DAT1 3'-untranslated region VNTR polymorphism and divided into groups based on genotype: homozygous for nine repeats (9/9, N=8), heterozygous (9/10, N=36) and homozygous for 10 repeats (10/10, N=52). The effects of amphetamine on ratings of Feel Drug, Anxiety, and Euphoria were examined with ANCOVA. In 9/10 and 10/10 subjects, amphetamine produced its expected effects of increased Euphoria, Anxiety, and Feel Drug (p<0.01). However, in 9/9 subjects, the effects of amphetamine were indistinguishable from placebo, suggesting that the 9/9 genotype has diminished subjective response to acute amphetamine. Interestingly, recent findings also implicate the 9/9 genotype in decreased therapeutic response to the stimulant methylphenidate in ADHD children. The current findings have important implications for understanding the genetic determinants of variability in stimulant response and risk of abuse.