Dopamine spillover after quantal release: Rethinking dopamine transmission in the nigrostriatal pathway

Abstract

The predominance of dopamine (DA) receptors at extrasynaptic versus synaptic sites implies that dopamine signaling is by diffusion-based volume transmission. In this review, we compare characteristics that regulate extracellular DA behavior in substantia nigra pars compacta (SNc) and striatum, including regional differences in structure (a 40% greater extracellular volume fraction in SNc vs. striatum) and in dynamic DA uptake (a 200-fold greater DA uptake rate in striatum vs. SNc). Furthermore, we test the assumption of diffusion-based volume transmission for SNc and striatum by modeling dynamic DA behavior after quantal release using region-specific parameters for diffusion and uptake at 37 °C. Our model shows that DA uptake does not affect peak DA concentration within 1 μm of a release site in either SNc or striatum because of the slow kinetics of DATs versus diffusion. Rather, diffusion and dilution are the dominant factors governing DA concentration after quantal release. In SNc, limited DAT efficacy is reflected in a lack of influence of uptake on either amplitude or time course of DA transients after quantal release up to 10 μm from a release site. In striatum, the lack of effect of the DAT within 1 μm of a release site means that perisynaptic DATs do not "gate" synaptic spillover. This contrasts with the conventional view of DA synapses, in which DATs efficiently recycle DA by re-uptake into the releasing axon terminal. However, the model also shows that a primary effect of striatal uptake is to curtail DA lifetime after release. In both SNc and striatum, effective DA radius after quantal release is ~2 μm for activation of low-affinity DA receptors and 7-8 μm for high-affinity receptors; the corresponding spheres of influence would encompass tens to thousands of synapses. Thus, the primary mode of intercellular communication by DA, regardless of region, is volume transmission.

The role of transmitter diffusion and flow versus extracellular vesicles in volume transmission in the brain neural–glial networks

“…VT mediated by monoamines seems to depend on extrasynaptic release and transmitter spread to extrasynaptic receptors [11,14,15,18,33] since inter alia a large proportion of monoamine terminals lack postjunctional complexes [34,35]. Rice & Cragg [36] have modelled DA extrasynaptic transmission from terminals based on DA spillover after quantal release, considering a large number of experimental data from their own and other groups. In the updated DA synapse, if present since many DA terminals are asynaptic, the DA release is unconstrained by the extrasynapic DA transporter (DAT), the diffusion process being too fast for the DAT.…”

Somatodendritic dopamine release: recent mechanistic insights

“…Moreover, DA receptors and the DAT on DA cell bodies and dendrites are largely extrasynaptic [110,[114][115][116], as are D1 receptors on non-dopaminergic terminals in these regions [115,117]. Thus, somatodendritically released DA relies on volume transmission [53,118,119], with an efficacy regulated by the diffusion and uptake characteristics of the local extracellular microenvironment, and negligible contributions from enzymatic degradation [53,102]. Consistent with the higher density of DA somata and dendrites in the SNc and VTA than in the SNr (figure 1), experimentally determined uptake rates for DA in guinea pig midbrain slices are higher in SNc and VTA than in SNr [102].…”

“…Data from these experimental studies were then used to model the influence of a 20-vesicle point source, which produced sufficiently high [DA] o for DA receptor activation (assuming 10 nM sensitivity) up to 20 mm away, with a DA half-life at this distance of several hundred milliseconds [102]. This model also showed that diffusion rather than uptake was the most important determinant of DA time course in midbrain [53,102]. In contrast to these findings based on DA diffusion and uptake assessed using voltammetric detection, a different picture emerges from evaluation of D2-IPSCs, which appear to be largely diffusion independent [23,24,69].…”

“…Several previous reviews of somatodendritic DA release have summarized the history and fundamental issues [49][50][51][52][53][54][55]. To complement and extend those earlier articles, this review will emphasize recent findings that shed light on unresolved questions, including the role of volume transmission in somatodendritic DA transmission, mechanisms of somatodendritic DA release, the Ca 2þ dependence of release, and regulation by autoreceptor and heteroreceptor activation.…”

Are cyclooxygenase-2 and nitric oxide involved in the dyskinesia of Parkinson's disease induced byl-DOPA?

“…Various subtypes of extrasynaptic dopamine receptors [123][124][125] are located in projection neurons and interneurons as well as on the afferent nerve terminal networks.…”