Melatonin–Dopamine Crosstalk: A Central Axis in Circadian Regulation and Clinical Chronopharmacology

Circadian rhythms regulate essential physiological and behavioral functions by aligning them with the environmental light–dark cycle. Melatonin and dopamine are two key neuromodulators that exhibit reciprocal activity patterns and exert opposing effects across the circadian cycle. This review aimed to explore the molecular mechanisms, neurophysiological roles, and clinical relevance of the melatonin–dopamine axis in circadian regulation. A comprehensive analysis of current literature was conducted, focusing on studies describing receptor-mediated signaling and reciprocal regulation of melatonin and dopamine. Emphasis was placed on their functional interactions, as well as their role in the modulation of sleep–wake cycles and circadian entrainment. Clinical studies addressing neurodegenerative and psychiatric disorders were also reviewed to evaluate translational significance. Evidence indicates that melatonin, synthesized during the dark phase, promotes nocturnal physiology and sleep initiation. Conversely, dopamine predominates during the light phase, enhancing arousal, reward processing, and motor activity. Dysregulation of this axis was implicated in Parkinson’s disease, depression, schizophrenia, and addiction. The melatonin–dopamine axis plays a pivotal role in maintaining circadian homeostasis by integrating hormonal and neurotransmitter signals. Targeting this interplay through chronopharmacological interventions holds promise for restoring circadian alignment and improving outcomes in neurological and psychiatric disorders.