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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 ?-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.

SUBMITTER: Bryant CD

PROVIDER: S-EPMC3280656 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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Csnk1e is a genetic regulator of sensitivity to psychostimulants and opioids.

Bryant Camron D CD Parker Clarissa C CC Zhou Lili L Olker Christopher C Chandrasekaran Ramalakshmi Y RY Wager Travis T TT Bolivar Valerie J VJ Loudon Andrew S AS Vitaterna Martha H MH Turek Fred W FW Palmer Abraham A AA

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20111116 4

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 ...[more]

PMID: 22089318

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Project description:BackgroundDrug-related emergency department (ED) visits are escalating, especially for stimulant use (i.e., cocaine and psychostimulants such as methamphetamine). We sought to characterize rates, presentation, and management of ED visits related to cocaine and psychostimulant use, compared to opioid use, in the United States (US).MethodsWe used 2008-2018 National Hospital Ambulatory Medical Care Survey data to identify a nationally representative sample of ED visits related to cocaine and psychostimulant use, with opioids as the comparator. To make visits mutually exclusive for analysis, we excluded visits related to 2 or more of the three possible drug categories. We estimated annual rate trends using unadjusted Poisson regression; described demographics, presenting concerns, and management; and determined associations between drug-type and presenting concerns (categorized as psychiatric, neurologic, cardiopulmonary, and drug toxicity/withdrawal) using logistic regression, adjusting for age, sex, race/ethnicity, and homelessness.ResultsCocaine-related ED visits did not significantly increase, while psychostimulant-related ED visits increased from 2008 to 2018 (2.2 visits per 10,000 population to 12.9 visits per 10,000 population; p < 0.001). Cocaine-related ED visits had higher usage of cardiac testing, while psychostimulant-related ED visits had higher usage of chemical restraints than opioid-related ED visits. Cocaine- and psychostimulant-related ED visits had greater odds of presenting with cardiopulmonary concerns (cocaine adjusted odds ratio [aOR] 2.95, 95% CI 1.70-5.13; psychostimulant aOR 2.46, 95% CI 1.42-4.26), while psychostimulant-related visits had greater odds of presenting with psychiatric concerns (aOR 2.69, 95% CI 1.83-3.95) and lower odds of presenting with drug toxicity/withdrawal concerns (aOR 0.47, 95%CI 0.30-0.73) compared to opioid-related ED visits.ConclusionPresentations for stimulant-related ED visits differ from opioid-related ED visits: compared to opioids, ED presentations related to cocaine and psychostimulants are less often identified as related to drug toxicity/withdrawal and more often require interventions to address acute cardiopulmonary and psychiatric complications.

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Csnk1e is a genetic regulator of sensitivity to psychostimulants and opioids.

Publications

Csnk1e is a genetic regulator of sensitivity to psychostimulants and opioids.

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