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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1026-1035
Number of pages10
JournalNeuropsychopharmacology
Volume37
Issue number4
DOIs
StatePublished - Mar 2012

Keywords

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

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health

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