Abstract
Prescription stimulants, such as d-amphetamine or methylphenidate are used to treat suffering from attention-deficit hyperactivity disorder (ADHD). They potently release dopamine (DA) and norepinephrine (NE) and cause phosphorylation of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit GluA1 in the striatum. Whether other brain regions are also affected remains elusive. Here, we demonstrate that d-amphetamine and methylphenidate increase phosphorylation at Ser845 (pS845-GluA1) in the membrane fraction of mouse cerebellum homogenate. We identify Bergmann glial cells as the source of pS845-GluA1 and demonstrate a requirement for intact NE release. Consequently, d-amphetamine-induced pS845-GluA1 was prevented by β1-adenoreceptor antagonist, whereas the blockade of DA D1 receptor had no effect. Together, these results indicate that NE regulates GluA1 phosphorylation in Bergmann glial cells in response to prescription stimulants.
Highlights
Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by a myriad of symptoms including distractibility, hyperactivity and impulsivity (Wilens and Spencer, 2010)
The present findings show that systemic administration of d-amphetamine and methylphenidate enhanced cAMP/protein kinase (PKA)-regulated phosphorylation of AMPA subunit A1 dopamine transporter (DAT) (GluA1) subunit of the AMPA receptors in Bergmann Glia Cells Purkinje cells (PC) (BGCs)
Our study identified transcriptional alterations of several components of the cAMP/PKA pathway which may account for the maintenance of the stimulant medications ability to increase GluA1 phosphorylation following drug administration
Summary
Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by a myriad of symptoms including distractibility, hyperactivity and impulsivity (Wilens and Spencer, 2010). A better understanding of the molecular actions of stimulant exposure on brain function is needed. The therapeutic efficacy of these drugs as well as their ability to precipitate the development of substance use disorders mainly rely on their actions on dopaminergic and noradrenergic systems (Engert and Pruessner, 2008; Gatley et al, 1996; Pierce and Kalivas, 1997; Sulzer et al, 1995; White and Kalivas, 1998). By rising up extracellular concentrations of dopamine (DA) and norepinephrine (NE) in the striatum and the prefrontal cortex, these drugs increase alertness and attention improving ADHD symptoms (Kuczenski and Segal, 1997) but can hijack reward processing, motivation, motor and executive functions in case of misuse (Weyandt et al, 2016). Given the widespread DA and NE projections throughout the central nervous system, stimulant-induced molecular adaptations may exist in other brain regions
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