Csnk1e is a genetic regulator of sensitivity to psychostimulants and opioids

Neuropsychopharmacology. 2012 Mar;37(4):1026-35. doi: 10.1038/npp.2011.287. Epub 2011 Nov 16.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Analgesics, Opioid / pharmacology*
  • Animals
  • Casein Kinase Iepsilon / deficiency
  • Casein Kinase Iepsilon / genetics*
  • Central Nervous System Stimulants / pharmacology*
  • Drug Resistance / genetics*
  • Female
  • Genome-Wide Association Study / methods
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred DBA
  • Mice, Inbred Strains
  • Mice, Knockout
  • Motor Activity / drug effects
  • Motor Activity / genetics
  • Quantitative Trait Loci / genetics*

Substances

  • Analgesics, Opioid
  • Central Nervous System Stimulants
  • Casein Kinase Iepsilon

Grant support