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- PMID: 22089318
- UKPMCID: 22089318
- DOI: 10.1038/npp.2011.287
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Csnk1e is a genetic regulator of sensitivity to psychostimulants and opioids.
Bryant, Camron D; Parker, Clarissa C; Zhou, Lili; Olker, Christopher; Chandrasekaran, Ramalakshmi Y; Wager, Travis T; Bolivar, Valerie J; Loudon, Andrew S; Vitaterna, Martha H; Turek, Fred W; Palmer, Abraham A
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2012;37(4):1026-35.
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Full-text held externally
- PMID: 22089318
- UKPMCID: 22089318
- DOI: 10.1038/npp.2011.287
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.
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- F32DA026697, NIDA NIH HHS, United States
- K99DA029635, NIDA NIH HHS, United States
- R01 DA021336-01, NIDA NIH HHS, United States
- R01 DA021336-02, NIDA NIH HHS, United States
- R01 DA021336-03, NIDA NIH HHS, United States
- R01 DA021336-03S1, NIDA NIH HHS, United States
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- R01 DA021336-04S1, NIDA NIH HHS, United States
- R01 DA021336-04S2, NIDA NIH HHS, United States
- R01 DA021336-05, NIDA NIH HHS, United States
- R01 DA021336-06, NIDA NIH HHS, United States
- R01 DA021336-07, NIDA NIH HHS, United States
- R01 GM097737-01A1, NIGMS NIH HHS, United States
- R01 GM097737-02, NIGMS NIH HHS, United States
- R01 MH079103-01, NIMH NIH HHS, United States
- R01 MH079103-02, NIMH NIH HHS, United States
- R01 MH079103-03, NIMH NIH HHS, United States
- R01 MH079103-03S1, NIMH NIH HHS, United States
- R01 MH079103-04, NIMH NIH HHS, United States
- R01 MH079103-05, NIMH NIH HHS, United States
- R01DA021336, NIDA NIH HHS, United States
- R01MH068013, NIMH NIH HHS, United States
- R01MH079103, NIMH NIH HHS, United States
- R03 DA027545-01, NIDA NIH HHS, United States
- R03 DA027545-02, NIDA NIH HHS, United States
- R21 DA024845-01, NIDA NIH HHS, United States
- R21 DA024845-02, NIDA NIH HHS, United States
- T32DA007255, NIDA NIH HHS, United States