Recent optical observations of dopamine at axon terminals and kinetic modeling of evoked dopamine responses measured by fast scan cyclic voltammetry (FSCV) support local restriction of dopamine diffusion at synaptic release sites. Yet, how this diffusion barrier affects synaptic and volume transmission is unknown. Here, a deficiency in a previous kinetic model's fitting of stimulus trains is remedied by replacing an earlier assumption that dopamine transporters (DATs) are present only on the outer side of the diffusion barrier with the assumption that they are present on both sides. This is consistent with the known distribution of DATs, which does not show obvious DAT-free zones proximal to dopamine release sites. A simultaneous multifitting strategy is then shown to enable unique model fits to sets of evoked dopamine FSCV responses acquired in vivo or in brain slices. This data analysis technique permits, for the first time, the calculation of the fraction of dopamine which spills over from what appears to be the perisynaptic space, as well as other parameters such as dopamine release, release plasticity, and uptake. This analysis shows that dopamine's diffusion away from its release sites is remarkably hindered (τ = 5 s), but dopamine responses are rapid because of DAT activity. Furthermore, the new analysis reveals that uptake inhibitors can inhibit dopamine release during a stimulus train, apparently by depleting the releasable pool. It is suggested that ongoing uptake is critical for maintaining ongoing synaptic dopamine release and that the previously reported and also herein claimed increase of the initial dopamine release of some uptake inhibitors might be an important mechanism in addiction. Finally, brain mapping data reveal that the diffusion barrier is conserved, but there are variations in perisynaptic uptake, volume transmission, and release plasticity within the rat striatum. Therefore, an analysis paradigm is developed to quantify previously unmeasured features of brain dopaminergic transmission and to reveal regional functional differences among dopamine synapses.
Keywords: Spillover; dopamine; kinetic model; perisynaptic; plasticity; synaptic.