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

Abstract

The predominance of dopamine (DA) receptors at extrasynaptic vs. synaptic sites implies that DA 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 vs. 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.

Introduction

The nigrostriatal dopamine (DA) pathway extends from the substantia nigra pars compacta (SNc) to the dorsal striatum via the median forebrain bundle. Somatodendritic release of DA in the SNc and as axonal DA release in the striatum are both necessary for basal ganglia-mediated motor behaviors (Robertson and Robertson, 1989, Timmerman and Abercrombie, 1996, Bergquist et al., 2003). Transporters for DA (DATs) are expressed exclusively by DA neurons and are found extrasynaptically on DA axons in striatum and on DA somata and dendrites in midbrain (Ciliax et al., 1995, Nirenberg et al., 1996, Hersch et al., 1997). Moreover, DA receptors are also predominantly extrasynaptic (Sesack et al., 1994, Yung et al., 1995, Hersch et al., 1995, Khan et al., 1998). This implies that intercellular communication by DA requires diffusion-based volume transmission (Fuxe and Agnati, 1991), which is most simply defined as “a functionally significant association of release and receptor sites via extrasynaptic diffusion” (Rice, 2000).

One would expect, therefore, that extracellular DA concentration ([DA]_o) and lifetime after release would be regulated by diffusion, as well as uptake. This is indeed the case, although the relative contribution of each process differs between striatum and SNc. In striatum, [DA]_o is often considered to be “uptake limited”, with strong local regulation by the DAT (Stamford et al., 1988, Giros et al., 1996, Floresco et al., 2003), whereas in SNc, the influence of uptake is much less (Cragg et al., 1997), so that diffusion-based volume transmission is expected to dominate (Rice, 2000, Cragg et al., 2001). Recently, however, both of these basic expectations have been challenged. Evidence from physiological recording in midbrain DA neurons suggests limited diffusional contributions to DA transmission in the SNc (Beckstead et al., 2004, Beckstead et al., 2007), whereas modeling of quantal DA release from DA axons in striatum indicates minimal regulation of synaptic spillover by the DAT (Cragg and Rice, 2004).

In this review, we extend our previously published model of quantal DA release in striatum (Cragg and Rice, 2004) to include somatodendritic release in SNc. Other models that have been used to estimate the sphere of influence of released DA have been limited by the single distance examined (Gonon, 1997, Cragg et al., 2001) or by the evaluation of a population response in which DA diffusion, and thus diffusion distance, is irrelevant (Garris et al., 1994, Sulzer and Pothos, 2000). The model used here is based on experimentally determined parameters for diffusion and uptake in SNc and striatum and permits comparison of the duration and sphere of influence of [DA]_o after single-vesicle release in both regions. Our findings confirm the comparatively limited role of uptake in regulating DA behavior in SNc vs. striatum and call for a revision of the current concept of synaptic DA release regulation, in which the DAT “gates” DA overflow by re-uptake into the releasing presynaptic terminal.