Neurobiological model of stimulated dopamine neurotransmission to interpret fast-scan cyclic voltammetry data

• We electrochemically assessed pre-synaptic striatal dopamine (DA) neurotransmission.
• We propose a quantitative neurobiological method to interpret stimulated DA responses.
• We assumed DA release & reuptake efficiency decrease during stimulated DA responses.
• This method can uniquely characterize variable evoked striatal DA response patterns.
• Stimulation frequency & DAT inhibitor effects on evoked DA were successfully modeled.

Fast-scan cyclic voltammetry (FSCV) is an electrochemical method that can assess real-time in vivo dopamine (DA) concentration changes to study the kinetics of DA neurotransmission. Electrical stimulation of dopaminergic (DAergic) pathways can elicit FSCV DA responses that largely reflect a balance of DA release and reuptake. Interpretation of these evoked DA responses requires a framework to discern the contribution of DA release and reuptake. The current, widely implemented interpretive framework for doing so is the Michaelis–Menten (M–M) model, which is grounded on two assumptions- (1) DA release rate is constant during stimulation, and (2) DA reuptake occurs through dopamine transporters (DAT) in a manner consistent with M–M enzyme kinetics. Though the M–M model can simulate evoked DA responses that rise convexly, response types that predominate in the ventral striatum, the M-M model cannot simulate dorsal striatal responses that rise concavely. Based on current neurotransmission principles and experimental FSCV data, we developed a novel, quantitative, neurobiological framework to interpret DA responses that assumes DA release decreases exponentially during stimulation and continues post-stimulation at a diminishing rate. Our model also incorporates dynamic M–M kinetics to describe DA reuptake as a process of decreasing reuptake efficiency. We demonstrate that this quantitative, neurobiological model is an extension of the traditional M–M model that can simulate heterogeneous regional DA responses following manipulation of stimulation duration, frequency, and DA pharmacology. The proposed model can advance our interpretive framework for future in vivo FSCV studies examining regional DA kinetics and their alteration by disease and DA pharmacology.