Involvement of Norepinephrine in the Control of Activity and Attentive Processes in Animal Models of Attention Deficit Hyperactivity Disorder

摘要

Functional and morphological studies in children affected by Attention Deficit Hyperactivity Disorder (ADHD) suggest a prefrontal cortex (PFc) dysfunction. This cortical region is regulated by subcortical systems including noradrenergic (NEergic), dopaminergic (DAergic), cholinergic, serotonergic, and histaminergic pathways. A wealth of data in humans and in animal models demonstrates altered dopamine (DA) regulation. Drugs that modulate norepinephrine (NE) transmission are also effective in ADHD patients, thus leading to the hypothesis of a NEergic disorder. This review covers the regulation of PFc functions by NE and the interaction between the NE and DA systems, as suggested by pharmacological, electrophysiological, morphological, and gene knock out (KO)studies. A negative feedback between NE and DAneurons emerges from KO studies because KOmice showing increased (NE transporter (NET)KO) or decreased (DBH and VMAT2 KO) NElevels are respectively associated with lower andhigher DA levels. Locomotor activity can begenerally predicted by the DA level, whereassensitivity to amphetamines is by NE/DA balance.Some animal models of ADHD, such asspontaneously hypertensive rats (SHR), showalterations in the PFc and in the DA system.Evidence about a correlation between the NEsystem and hyper-locomotion activity in suchanimals has not yet been clarified. Therefore, thisreview also includes recent evidence on thebehavioral effects of two NET blockers,reboxetine and atomoxetine, in two animal modelsof ADHD: SHR and Naples High Excitability rats.As these drugs modulate the DA level in the PFc,certain effects are likely to be due to a rebalancedDA system. We discuss the significance of theresults for theories of ADHD and makesuggestions for future experimentation.