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A role for casein kinase 1 epsilon in the locomotor stimulant response to methamphetamine

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Abstract

Rationale

We previously colocalized a quantitative trait locus (QTL) for sensitivity to the locomotor stimulant effects of methamphetamine (MA) with a QTL for expression of casein kinase 1 epsilon (Csnk1-ɛ) in the nucleus accumbens (NAc). Subsequently, we identified a single nucleotide polymorphism in CSNK1E (rs135745) that was associated with increased sensitivity to the subjective effects of d-amphetamine in healthy human subjects. Based on these results, we hypothesized that differential expression of Csnk1-ɛ causes differential sensitivity to MA-induced locomotor activity in mice.

Objective

In the present study, we used PF-670462 (PF), which is a selective inhibitor of Csnk1-ɛ, to directly evaluate the role of Csnk1-ɛ in the locomotor stimulant response to MA in male C57BL/6J mice.

Methods

We administered vehicle, PF, MA, or MA + PF, either via intraperitoneal injections or bilateral intra-NAc microinjections. We also examined Darpp-32 phosphorylation in mice receiving intraperitoneal injections.

Results

Intraperitoneal PF (20–40 mg/kg) attenuated the locomotor stimulant response to MA (2 mg/kg) without affecting baseline activity. The high dose of PF also significantly inhibited MA-induced phosphorylation of Darpp-32, providing a potential mechanism by which Csnk1-ɛ contributes to MA-induced locomotor activity. Furthermore, microinjection of PF (5 μg/side) into the NAc completely blocked the locomotor stimulant response to MA (2.5 μg/side) without affecting baseline activity.

Conclusions

These results provide direct evidence that Csnk1-ɛ is crucial for the locomotor stimulant response to a moderate dose of MA and suggest that genetic polymorphisms affecting Csnk1-ɛ expression or function could influence sensitivity to amphetamines in both mice and humans.

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Abbreviations

MA:

Methamphetamine

Csnk1-ɛ:

Casein kinase 1-epsilon

Darpp-32:

Dopamine and cyclic AMP-regulated phosphoprotein-32

PF:

PF-670462

QTL:

Quantitative trait loci

NAc:

Nucleus accumbens

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Acknowledgments

The experiments comply with the current laws in the USA. The authors declare they have no conflict of interest. The authors would like to thank Carolyn Cain, Ryan Walters, and Pei-Chun Chen for technical assistance on the present study and in previous pilot studies. This work was supported by DA021336-02 (A.A.P.), DA09397 (P.V.), T32DA007255 (C.D.B.), the Biological Sciences Collegiate Division Research endowments at the University of Chicago (M.E.G.), and the National Institute of General Medical Sciences Medical Scientist National Research Service Award T32GM07281 (M.G.D.).

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Authors and Affiliations

  1. Department of Human Genetics, University of Chicago, 920 E. 58th St. CLSC 507D, Chicago, IL, 60637, USA

    Camron D. Bryant, Melissa E. Graham, Margaret G. Distler, Michaelanne B. Munoz, Greta Sokoloff & Abraham A. Palmer

  2. Department of Psychiatry and Behavioral Neuroscience, University of Chicago, 5841 S. Maryland Av MC 3077, Chicago, IL, 60637, USA

    Dongdong Li, Paul Vezina & Abraham A. Palmer

Authors
  1. Camron D. Bryant
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  2. Melissa E. Graham
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  3. Margaret G. Distler
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  4. Michaelanne B. Munoz
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  5. Dongdong Li
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  6. Paul Vezina
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  7. Greta Sokoloff
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  8. Abraham A. Palmer
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Corresponding author

Correspondence to Abraham A. Palmer.

Additional information

Funding: DA021336-02 (A.A.P.), DA09397 (P.V.), 2T32DA007255 (C.D.B.), 5T32GM07281 (M.G.D.).

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Bryant, C.D., Graham, M.E., Distler, M.G. et al. A role for casein kinase 1 epsilon in the locomotor stimulant response to methamphetamine. Psychopharmacology 203, 703–711 (2009). https://doi.org/10.1007/s00213-008-1417-z

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  • DOI: https://doi.org/10.1007/s00213-008-1417-z

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