Association between the casein kinase I epsilon gene region and subjective response to D-amphetamine

Abstract

Animal models suggest that the casein kinase I epsilon gene (CsnkIe) contributes to variability in stimulant response. CsnkIe is a key component in the Darpp-32 (Dopamine-And-cAMP-Regulated-Phosphoprotein-32 kDa) second messenger pathway and has been implicated in previous pharmacological and pharmacogenetic studies in mice. Mice bred for methamphetamine sensitivity showed linkage to the region of chromosome 15 that contains CsnkIe and also showed a 10-fold increase in expression of CsnkIe. We used a double-blind, crossover design in healthy human volunteers to test association between polymorphisms in the CSNKIE region and subjective response to placebo, 10, or 20 mg of oral D-amphetamine. Repeated-measures ANOVA was used to analyze interactions between genotype and drug response. The primary outcome measure, subjects' ratings of whether they felt a drug effect (Drug Effects Questionnaire (DEQ)), revealed a significant effect (p = 0.010) at one single-nucleotide polymorphism (rs135745). Subjects with more copies of the rs135745 C allele were more sensitive to the low dose of D-amphetamine (p = 0.001), which corresponded to a leftward shift in the dose-response curve. These findings demonstrate the successful translation of pharmacogenetic results from mice to humans. © 2006 Nature Publishing Group All rights reserved.