Regional Variation in Striatal Dopamine Spillover and Release Plasticity

Abstract

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.

Dopamine Receptor Subtypes, Physiology and Pharmacology: New Ligands and Concepts in Schizophrenia

“…The DA system is therefore also sensitive to a local presynaptic modulation from other neurotransmitters (like acetylcholine or endocannabinoids) ( Xu et al., 2018 ). DAT exerts a main presynaptic master control on DA release as recently demonstrated ( Condon et al., 2019 ; Walters et al., 2020 ). DA release is in fact directly modulated at the presynaptic terminals by a Rho-dependent internalization of DAT.…”

“…The DA system is therefore also sensitive to a local presynaptic modulation from other neurotransmitters (like acetylcholine or endocannabinoids) (Xu et al, 2018). DAT exerts a main presynaptic master control on DA release as recently demonstrated (Condon et al, 2019;Walters et al, 2020). DA release is in fact directly modulated at the presynaptic terminals by (Abi-Dargham, 2018;Mitelman et al, 2018;Tseng et al, 2018;Avram et al, 2019;D'Ambrosio et al, 2019;Kim et al, 2019;Rao et al, 2019;Sekiguchi et al, 2019;Weidenauer et al, 2020;Girgis et al, 2020;Brugger et al, 2020;Wulff et al, 2020;Frankle and Narendran, 2020) Post mortem DAT levels./Presynaptic dysregulation.…”

Simultaneous serotonin and dopamine monitoring across timescales by rapid pulse voltammetry with partial least squares regression

“…Here, we focus on voltammetry methods, including fast-scan cyclic voltammetry (FSCV), to detect electroactive neurotransmitters. The use of small carbon fiber microelectrodes (5-30 μm diameter) [40,41] and high sampling rates (10-100 Hz) [42,43] in FSCV can be used to differentiate release vs. reuptake processes [44]. While widely employed, FSCV suffers from poor analyte specificity.…”

Isoliquiritigenin Alleviates Semen Strychni-Induced Neurotoxicity by Restoring the Metabolic Pathway of Neurotransmitters in Rats

“…Trp and Tyr are involved in the two most important metabolic pathways of neurotransmitters--DA and Trp pathways. DA mainly exists in the striatum, providing learning signals by regulating synaptic plasticity ( Berke, 2018 ; Walters et al, 2020 ). The striatum is associated with motor function—damage to the striatum results in aberrant sequencing of spontaneous movements and sensory-guided movements ( Markowitz and Datta, 2020 ).…”