Mathematical modeling of dopamine rhythms and timing of dopamine reuptake inhibitors

Dopamine (DA) plays a vital role in mood, alertness, and behavior, with dysregulation linked to disorders such as Parkinson’s disease, ADHD, depression, and addiction. In this study, we develop and analyze a reduced mathematical model of dopamine synthesis, release, and reuptake to investigate how daily rhythms influence dopamine dynamics and the efficacy of dopamine reuptake inhibitors (DRIs) used in the treatment of various neuropsychiatric conditions. We simplify a detailed mathematical model of dopamine synthesis, release, and reuptake and demonstrate that our reduced system maintains key dynamical features including homeostatic regulation via autoreceptors. Our model captures core autoregulatory mechanisms and reveals that DRIs can exert substantial time-of-day effects, allowing for dopamine levels to be sustained at elevated levels when administered at circadian troughs. These fluctuations depend sensitively on the timing of DRI administration relative to circadian variations in enzyme activity. We further extend the model to incorporate feedback from local dopaminergic tone, which generates ultradian oscillations in the model independent of circadian regulation. Administration of DRIs lengthens the ultradian periodicity. Our findings provide strong evidence that intrinsic fluctuations in DA should be considered in the clinical use of DRIs, offering a mechanistic framework for improving chronotherapeutic strategies targeting dopaminergic dysfunction.Author summary: Dopamine levels can fluctuate throughout the day, and these changes are in part regulated by the circadian clock. Many drugs prescribed for neurological or psychiatric conditions influence dopamine metabolism, but their time-of-day effects are not well understood. Using mathematical modeling, we present evidence of time-of-day effects of dopamine reuptake inhibitors like modafinil or bupropion. We find in the model that taking doses at the wrong time of day can cause large spikes and subsequent crashes in dopamine levels, while strategic timing can sustain dopamine levels for much longer. Our model can be used to explore the outcomes of different dose schedules and to inform treatment strategies. In addition, we find that incorporating population-level activity of dopaminergic neurons generates intrinsic, 4-hour ultradian rhythms that are separate from circadian input. Dopamine fluctuates periodically even without a circadian drive, but the underlying mechanisms have not been understood. Our model provides a plausible explanation of dopamine ultradian oscillations as a neuronal population-level phenomenon.