Csnk1e is a genetic regulator of sensitivity to psychostimulants and opioids

Camron D. Bryant, Clarissa C. Parker, Lili Zhou, Christopher Olker, Ramalakshmi Y. Chandrasekaran, Travis T. Wager, Valerie J. Bolivar, Andrew S. Loudon, Martha H. Vitaterna, Fred W. Turek, Abraham A. Palmer

    Research output: Contribution to journalArticlepeer-review

    Abstract

    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. © 2012 American College of Neuropsychopharmacology. All rights reserved.
    Original languageEnglish
    Pages (from-to)1026-1035
    Number of pages9
    JournalNeuropsychopharmacology
    Volume37
    Issue number4
    DOIs
    Publication statusPublished - Mar 2012

    Keywords

    • CK-1
    • DARPP-32
    • dopamine
    • opiate
    • psychomotor
    • QTL

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