1. ¹Institute of Juvenile Research, Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, USA
2. ²Department of Psychiatry, University of Chicago, Chicago, IL, USA
3. ³Department of Human Genetics, University of Chicago, Chicago, IL, USA

Correspondence: Dr H de Wit, Department of Psychiatry, University of Chicago, 5841 S. Maryland Avenue, MC 3077, Chicago, IL 60637, USA. Tel: +1 773 702 1537; Fax: +1 773 702 7698; E-mail: hdew@uchicago.edu

Received 19 May 2005; Revised 29 August 2005; Accepted 6 September 2005; Published online 12 October 2005.

Abstract

Animal models suggest that the casein kinase 1 epsilon gene (Csnk1e) contributes to variability in stimulant response. Csnk1e 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 Csnk1e and also showed a 10-fold increase in expression of Csnk1e. We used a double-blind, crossover design in healthy human volunteers to test association between polymorphisms in the CSNK1E 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.