Intranasal dopamine: Anatomical pathways, biological mechanisms and neuromodulatory potential

Dopamine (DA) regulates motor control, motivation, learning and memory, cognition, and social behavior, and its dysregulation underlies a wide range of neurological and psychiatric disorders. In Parkinson's disease (PD), degeneration of dopaminergic neurons in the substantia nigra depletes striatal DA, making dopaminergic restoration a central therapeutic target. Because DA does not cross the blood-brain barrier (BBB), treatment relies on its precursor L-DOPA. Intranasal (IN) administration offers a non-invasive alternative: it enables rapid absorption, avoids hepatic first-pass metabolism, and provides partial brain access via nose-to-brain pathways, positioning IN-DA as a potential tool to directly influence central dopaminergic function. This review integrates current knowledge on IN-DA. We first examine nasal anatomy, the biological and physicochemical variables governing IN delivery, and the mechanisms of nose-to-brain transport, followed by a focused synthesis of IN-DA findings. Preclinical evidence shows that IN-DA and IN-L-DOPA increase extracellular DA levels and turnover in the striatum, with IN-DA appearing to enhance dopaminergic tone through presynaptic uptake and storage. Behaviorally, IN-DA produces state-dependent improvements across cognitive, emotional, and social domains, particularly in neuropsychiatric rodent models. Although nanoparticle-based DA formulations are being developed primarily to improve delivery efficiency for PD therapy, emerging evidence suggests that IN-DA may serve more broadly as a neuromodulatory approach for disorders involving catecholamine dysregulation.