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. 2013 Jan 5;698(1-3):252-8.
doi: 10.1016/j.ejphar.2012.10.018. Epub 2012 Oct 23.

Examination of methylphenidate-mediated behavior regulation by glycogen synthase kinase-3 in mice

Marjelo A Mines  1 , Eleonore Beurel, Richard S Jope
Affiliations

Examination of methylphenidate-mediated behavior regulation by glycogen synthase kinase-3 in mice

Marjelo A Mines et al. Eur J Pharmacol. .

Abstract

Abnormalities in dopaminergic activity have been implicated in psychiatric diseases, such as attention deficit hyperactivity disorder (ADHD), and are treated with therapeutic stimulants, commonly methylphenidate or amphetamine. Amphetamine administration increases glycogen synthase kinase-3 (GSK3) activation, which is necessary for certain acute behavioral responses to amphetamine, including increased locomotor activity and impaired sensorimotor gating. Here, we tested if modulating GSK3 by administration of the GSK3 inhibitor lithium or expression of constitutively active GSK3 altered behavioral responses to methylphenidate administered to mice acutely or daily for 8 days. Methylphenidate or amphetamine was administered to mice intraperitoneally for 1 or 8 days. Open-field activity and pre-pulse inhibition (PPI) were measured. In contrast to lithium's blockade of acute amphetamine-induced locomotor hyperactivity, lithium treatment did not significantly reduce methylphenidate-induced locomotor hyperactivity in wild-type mice after acute or 8 days of repeated methylphenidate administration. Lithium treatment significantly increased the impairment in PPI caused by methylphenidate, but significantly reduced the amphetamine-induced PPI deficit. In GSK3 knockin mice, expression of constitutively active GSK3β, but not GSK3α, significantly increased locomotor hyperactivity after acute methylphenidate treatment, and significantly impaired PPI, preventing further methylphenidate-induced impairment of PPI that was evident in wild-type mice and GSK3α knockin mice. Lithium does not counteract locomotor activity and PPI responses to methylphenidate as it does these responses to amphetamine, indicating that different mechanisms mediate these behavioral responses to methylphenidate and amphetamine. Only active GSK3β, not GSK3α, modulates behavioral responses to MPH, indicating selectivity in the actions of GSK3 isoforms.

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Figures

Fig. 1
Fig. 1
Psychostimulant responses in wild-type mice. (A) Open-field activity responses to 0 (saline control), 5, 10, or 20 mg/kg methylphenidate in wild-type mice after 15 min acclimation to the test chamber. *P≤0.05, post-test, as compared to vehicle-treated control mice. (B) Effects of 8 days of repeated administration of 10 mg/kg methylphenidate on open-field activity. (C) Effects of 8 days of repeated administration of 20 mg/kg methylphenidate on open-field activity. *P≤0.05, post-test, as compared to Day 1. (D) Effects of 1 or 8 days of repeated administration of 20 mg/kg methylphenidate on stereotypic behavior. *P≤0.05, post-test, as compared to vehicle-treated control mice. (E) Effects of 2 mg/kg amphetamine on open-field activity. (F) Effects of 1 or 8 days of repeated administration of 2 mg/kg amphetamine on stereotypic behavior *P≤0.05, post-test, as compared to vehicle-treated control mice. Values are expressed as means±S.E.M.
Fig. 2
Fig. 2
Effects of lithium treatment on psychostimulant-induced responses in wild-type mice. (A) Effect of lithium treatment on open-field activity after acute administration of 20 mg/kg methylphenidate in wild-type mice. (B) Effect of lithium treatment on open-field activity after 8 days of administration of 20 mg/kg methylphenidate. (C) Effect of lithium treatment on open-field activity after acute administration of 2 mg/kg amphetamine. *P≤0.05, post-test, as compared to the response to amphetamine in the absence of lithium. (D) Effect of lithium treatment on open-field activity after 8 days of administration of 2 mg/kg amphetamine. Values are expressed as means±S.E.M.
Fig. 3
Fig. 3
Effects of lithium on sensorimotor gating in wild-type mice. (A) Effect of acute administration of 20 mg/kg methylphenidate on PPI with or without lithium pre-treatment in wild-type mice. *P≤0.05, as compared to previous tone intensity; &P≤0.05, as compared to vehicle-treated control mice, t test; #P≤0.05, as compared to methylphenidate treatment alone, t test. (B) Effect of acute administration of 2 mg/kg amphetamine on PPI with or without lithium pretreatment in wild-type mice. *P≤0.05, as compared to previous tone intensity; &P≤0.05, as compared to vehicle-treated control mice, t test. Values are expressed as means±S.E.M.
Fig. 4
Fig. 4
GSK3 is involved in methylphenidate-induced open-field behavior. (A) Effect of acute administration of 20 mg/kg methylphenidate on open-field activity in GSK3α knockin mice. (B) Effect of 8 days of repeated administration of 20 mg/kg methylphenidate on open-field activity in GSK3α knockin mice. *P≤0.05, post-test, as compared d to Day 1. (C) Effect of acute administration of 20 mg/kg methylphenidate on open-field activity in GSK3β knockin mice. *P≤0.05, post-test, as compared to wild-type mice. (D) Effect of 8 days of repeated administration of 20 mg/kg methylphenidate on open-field activity in GSK3β knockin mice. *P≤0.05, post-test, as compared to Day 1. Values are expressed as means±S.E.M.
Fig. 5
Fig. 5
GSK3 affects methylphenidate-induced sensorimotor behaviors. (A) Effect of 20 mg/kg methylphenidate on PPI in GSK3α knockin mice. *P≤0.05, as compared to previous tone intensity; &P≤0.05, as compared to control, t test. (B) Effect of 20 mg/kg methylphenidate on PPI in GSK3β knockin mice. Values are expressed as means±S.E.M.
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