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

Marjelo A. Mines, Eleonore Beurel, Richard S Jope

Research output: Contribution to journalArticle

9 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)252-258
Number of pages7
JournalEuropean Journal of Pharmacology
Volume698
Issue number1-3
DOIs
StatePublished - Jan 5 2013

Fingerprint

Glycogen Synthase Kinase 3
Methylphenidate
Amphetamine
Lithium
Locomotion
Sensory Gating
Attention Deficit Disorder with Hyperactivity
Psychiatry
Inhibition (Psychology)
Protein Isoforms

Keywords

  • Amphetamine
  • Attention deficit hyperactivity disorder
  • Glycogen synthase kinase-3
  • Methylphenidate
  • Pre-pulse inhibition

ASJC Scopus subject areas

  • Pharmacology

Cite this

Examination of methylphenidate-mediated behavior regulation by glycogen synthase kinase-3 in mice. / Mines, Marjelo A.; Beurel, Eleonore; Jope, Richard S.

In: European Journal of Pharmacology, Vol. 698, No. 1-3, 05.01.2013, p. 252-258.

Research output: Contribution to journalArticle

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