title: Csnk1e is a genetic regulator of sensitivity to psychostimulants and opioids.
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.
authors.affiliation: Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Camron D
authors.initials: CD
authors.lastname: Bryant
authors.forename: Clarissa C
authors.initials: CC
authors.lastname: Parker
authors.forename: Lili
authors.initials: L
authors.lastname: Zhou
authors.forename: Christopher
authors.initials: C
authors.lastname: Olker
authors.forename: Ramalakshmi Y
authors.initials: RY
authors.lastname: Chandrasekaran
authors.forename: Travis T
authors.initials: TT
authors.lastname: Wager
authors.forename: Valerie J
authors.initials: VJ
authors.lastname: Bolivar
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Loudon
authors.forename: Martha H
authors.initials: MH
authors.lastname: Vitaterna
authors.forename: Fred W
authors.initials: FW
authors.lastname: Turek
authors.forename: Abraham A
authors.initials: AA
authors.lastname: Palmer
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D048149:Casein Kinase 1 epsilon / Q000172:deficiency / Q000235:genetics*; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D004351:Drug Resistance / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics*
chemical_list: D000701:Analgesics, Opioid; D000697:Central Nervous System Stimulants; D048149:Casein Kinase 1 epsilon
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