Kynurenine pathway dysregulation in attention-deficit hyperactivity disorder: Impact on N-methyl-D-aspartate receptors and phasic dopamine maturation
Abstract
Recent evidence highlights a significant shift in the kynurenine pathway (KP) toward a neurotoxic profile in medication-naïve children with attention-deficit/hyperactivity disorder (ADHD). This article contextualizes these metabolic alterations - specifically the reduction in kynurenic acid (KYNA) and the elevation of the quinolinic acid (QUIN)/KYNA ratio - as active drivers of neurodevelopmental pathology rather than mere biomarkers. We hypothesize that chronic KP dysregulation disrupts the "N-methyl-D-aspartate-dopamine link", where KYNA deficiency leads to N-methyl-D-aspartate receptor disinhibition, subsequently interfering with the phasic dopaminergic signaling essential for executive function. Furthermore, the convergence of these metabolic signatures with those found in affective disorders provides a biological rationale for the high rates of depressive comorbidity in ADHD. We discuss the potential for targeting the KP, particularly through kynurenine 3-monooxygenase inhibition, to restore glutamatergic homeostasis. Crucially, we address the role of blood-brain barrier permeability in ADHD as a factor that may exacerbate the impact of peripheral kynurenine metabolites on central nervous system function.
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