Csnk1e Is a Genetic Regulator of Sensitivity to Psychostimulants and Opioids

Csnk1e , the gene encoding casein kinase 1-epsilon, has been implicated in sensitivity to amphetamines. Additionally, a polymorphism in CSNK1E was associated with heroin addiction, suggesting that this gene may also affect opioid sensitivity. In this study, we first conducted genome-wide quantitative trait locus (QTL) mapping of methamphetamine (MA)-induced locomotor activity in C57BL/6J (B6) × DBA/2J (D2)-F 2 mice and a more highly recombinant F 8 advanced intercross line. We identified a QTL on chromosome 15 that contained Csnk1e (63–86 Mb; Csnk1e =79.25 Mb). We replicated this result and further narrowed the locus using B6.D2 Csnk1e and D2.B6 Csnk1e reciprocal congenic lines (78–86.8 and 78.7–81.6 Mb, respectively). This locus also affected sensitivity to the μ -opioid receptor agonist fentanyl. Next, we directly tested the hypothesis that Csnk1e is a genetic regulator of sensitivity to psychostimulants and opioids. Mice harboring a null allele of Csnk1e showed an increase in locomotor activity following MA administration. Consistent with this result, coadministration of a selective pharmacological inhibitor of Csnk1e (PF-4800567) increased the locomotor stimulant response to both MA and fentanyl. These results show that a narrow genetic locus that contains Csnk1e is associated with differences in sensitivity to MA and fentanyl. Furthermore, gene knockout and selective pharmacological inhibition of Csnk1e define its role as a negative regulator of sensitivity to psychostimulants and opioids.