Lateralised alterations in forebrain monoaminergic systems and behavioural correlations in ADHD-like hyperactive and impulsive male rats.

Abstract

First-line stimulant therapies for attention deficit hyperactivity disorder (ADHD) implicate the forebrain monoaminergic neurotransmitter systems of dopamine, noradrenaline and serotonin. However, there is no curative treatment. Investigation of neurochemical monoaminergic changes, followed by curative treatments, requires sub-type specific animal models. In a novel rat model of the hyperactive-impulsive and attentive subtype of ADHD, specific changes in forebrain monoamines, and correlations with ADHD-like hyperactivity/impulsivity after delayed reward, are unknown. To address this, we investigated the monoaminergic systems using high performance liquid chromatography at ~2 and 7 months-of-age. We correlated the latter findings with ADHD-like hyperactivity and impulsivity that was measured after delayed reward. We observed long-term effects on the serotonergic, dopaminergic and noradrenergic systems in the forebrain of ADHD-like, hyperactive-impulsive male rats exposed to repeated hypoxia during postnatal day 1-3, the equivalent of extreme prematurity. These long-term effects were strikingly correlated with ADHD-like impulsive, and mostly with ADHD-like hyperactive, behaviour after delayed reward. The correlation was stronger for the dopaminergic and noradrenergic systems and weaker for the serotonergic system. The findings strongly implicate the dopaminergic system in the right prefrontal cortex, the noradrenergic system in the left prefrontal cortex and the serotonergic system in the right posterior caudate-putamen in ADHD-like hyperactivity and ADHD-like impulsivity. Earlier reports of forebrain lateralisation and lifespan changes of monoamines and their metabolites, and of marked differences between the anterior versus posterior caudate-putamen bilaterally, were confirmed and extended. New treatments to collectively cure the neurochemical changes can now be investigated in this unique, ADHD-like subtype-specific animal model.