A role for casein kinase 1 epsilon in the locomotor stimulant response to methamphetamine.
BACKGROUND
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-epsilon) 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-epsilon 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-epsilon, to directly evaluate the role of Csnk1-epsilon 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-epsilon contributes to MA-induced locomotor activity. Furthermore, microinjection of PF (5 microg/side) into the NAc completely blocked the locomotor stimulant response to MA (2.5 microg/side) without affecting baseline activity.


CONCLUSIONS
These results provide direct evidence that Csnk1-epsilon is crucial for the locomotor stimulant response to a moderate dose of MA and suggest that genetic polymorphisms affecting Csnk1-epsilon expression or function could influence sensitivity to amphetamines in both mice and humans.
Bryant
Camron D
CD
Department of Human Genetics, University of Chicago, 920 E. 58th St. CLSC 507D, Chicago, IL 60637, USA.
Graham
Melissa E
ME
Distler
Margaret G
MG
Munoz
Michaelanne B
MB
Li
Dongdong
D
Vezina
Paul
P
Sokoloff
Greta
G
Palmer
Abraham A
AA
D000818:Animals; D048149:Casein Kinase 1 epsilon / Q000037:antagonists & inhibitors / Q000235:genetics*; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007274:Injections, Intraperitoneal; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D020641:Polymorphism, Single Nucleotide; D011743:Pyrimidines / Q000494:pharmacology; D040641:Quantitative Trait Loci
D000697:Central Nervous System Stimulants; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; C497929:Ppp1r1b protein, mouse; D011743:Pyrimidines; D008694:Methamphetamine; C522839:PF-670462; D048149:Casein Kinase 1 epsilon