Regulation of GluA1 Phosphorylation by D-amphetamine and Methylphenidate in the Cerebellum

Abstract

Prescription stimulants, such as d-amphetamine or methylphenidate, are potent dopamine (DA) and norepinephrine (NE) releasers used to treat children and adults diagnosed for attention-deficit/hyperactivity disorder (ADHD). Although increased phosphorylation of the AMPA receptor subunit GluA1 at Ser845 (pS845-GluA1) in the striatum has been identified as an important cellular effector for the actions of these drugs, regulation of this posttranslational modification in the cerebellum has never been recognized. Here, we demonstrate that d-amphetamine and methylphenidate increase pS845-GluA1 in the membrane fraction in both vermis and lateral hemispheres of the mouse cerebellum. This regulation occurs selectively in Bergmann Glia Cells and requires intact norepinephrine release since the effects were abolished in mice lacking the vesicular monoamine transporter-2 selectively in NE neurons. Moreover, d-amphetamine-induced pS845-GluA1 was prevented by β1-adenoreceptor antagonist, whereas the blockade of dopamine D1 receptor had no effect. Additionally, we identified transcriptional alterations of several regulators of the cAMP/PKA pathway, which might account for the absence of pS845-GluA1 desensitization in mice repeatedly exposed to d-amphetamine or methylphenidate. Together, these results point to norepinephrine transmission as a key regulator of GluA1 phosphorylation in Bergmann Glial Cells, which may represent a new target for the treatment of ADHD.Competing Interest StatementThe authors have declared no competing interest.AbbreviationsBGCsBergmann Glia CellsPCPurkinje cellsCCCerebellar CortexDADopamineNENoradrenalineD1RDopamine D1 receptorβ-ARBeta-adrenergic receptorsβ1-ARBeta-1-adrenergic receptorsACAdenylyl cylasePKAProtein Kinase APKCProtein Kinase CAMPAα-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acidGluA1AMPA subunit A1DATDopamine transporterTHTyrosine hydroxylaseVMAT2Vesicular monoamine transporter 2VTAVentral Tegmental AreaSNSubstantia nigraLCLocus CoeruleusD-amphD-amphetamineMphMethylphenidateADHDattention-deficit/hyperactivity disorderHAhemagglutininView Full Text