Genetic variation of the dopamine transporter (DAT1) influences the acute subjective responses to cocaine in volunteers with cocaine use disorders

Abstract

Objective: The aim of this study was to identify gene variants of DAT1 (SLC6A3) that modulate subjective responses to acute cocaine exposure.

Methods: Non-treatment-seeking volunteers (n=66) with cocaine use disorders received a single bolus infusion of saline and cocaine (40 mg, intravenous) in a randomized order. Subjective effects were assessed with visual analog scales administered before (-15 min) and up to 20 min after infusion. Ratings of subjective effects were normalized to baseline, and saline infusion values were subtracted. Data were analyzed using repeated measures analysis of variance. DNA from the participants was genotyped for the DAT1 intron 8 (rs3836790) and 3'-untranslated region (rs28363170) variable number of tandem repeats.

Results: Participants were mostly male (∼80%) and African American (∼70%). No differences were found among drug use variables between groups for either polymorphism. Carriers of the 9-allele of the DAT1 3'-untranslated region (9,9 and 9,10) exhibited greater responses to cocaine for 'high', 'any drug effect', 'anxious', and 'stimulated' (all P-values<0.001) compared with individuals homozygous for the 10-allele. For the intron 8 polymorphism, individuals homozygous for the 6-allele exhibited greater responses for 'anxious' compared with carriers of the 5-allele (P<0.001). Individuals possessing the genotype pattern of 10,10 and at least one 5-allele reported lower responses to 'good effects', 'bad effects', 'depressed', and 'anxious' (all P-values<0.01).

Conclusion: The data presented here show for the first time support for the hypothesis that genetic differences in DAT1 contribute to the variation in subjective responses to cocaine among participants with cocaine use disorders.

Figure 1

Difference in scores between 10,10 and 9,9/9,10 individuals from the 3′ UTR sample, all plots. Data points indicate mean, and error bars indicate standard error of mean

Figure 2

“Anxious” scores between 6,6 and 5,5/5,6 individuals from the intron 8 sample. Data points indicate mean, and error bars indicate standard error of mean

Figure 3

Significant differences among subjective effects between groups after genotype pattern analysis. Individuals possessing DAT1 intron 8 5,5 or 5,6 and 3’ UTR 10,10 genotype are compared vs. all other genotypes. Data points indicate mean, and error bars indicate standard error of mean