Dopamine-Mediated Volume Transmission in Midbrain Is Regulated by Distinct Extracellular Geometry and Uptake

Abstract

Somatodendritic release of dopamine (DA) in midbrain is, at least in part, nonsynaptic; moreover, midbrain DA receptors are predominantly extrasynaptic. Thus somatodendritic DA mediates volume transmission, with an efficacy regulated by the diffusion and uptake characteristics of the local extracellular microenvironment. Here, we quantitatively evaluated diffusion and uptake in substantia nigra pars compacta (SNc) and reticulata (SNr), ventral tegmental area (VTA), and cerebral cortex in guinea pig brain slices. The geometric parameters that govern diffusion, extracellular volume fraction (alpha) and tortuosity (lambda), together with linear uptake (k'), were determined for tetramethylammonium (TMA(+)), and for DA, using point-source diffusion combined with ion-selective and carbon-fiber microelectrodes. TMA(+)-diffusion measurements revealed a large alpha of 30% in SNc, SNr, and VTA, which was significantly higher than the 22% in cortex. Values for lambda and k' for TMA(+) were similar among regions. Point-source DA-diffusion curves fitted theory well with linear uptake, with significantly higher values of k' for DA in SNc and VTA (0.08--0.09 s(-1)) than in SNr (0.006 s(-1)), where DA processes are sparser. Inhibition of DA uptake by GBR-12909 caused a greater decrease in k' in SNc than in VTA. In addition, DA uptake was slightly decreased by the norepinephrine transport inhibitor, desipramine in both regions, although this was statistically significant only in VTA. We used these data to model the radius of influence of DA in midbrain. Simulated release from a 20-vesicle point source produced DA concentrations sufficient for receptor activation up to 20 microm away with a DA half-life at this distance of several hundred milliseconds. Most importantly, this model showed that diffusion rather than uptake was the most important determinant of DA time course in midbrain, which contrasts strikingly with the striatum where uptake dominates. The issues considered here, while specific for DA in midbrain, illustrate fundamental biophysical properties relevant for all extracellular communication.

Somatodendritic dopamine release: recent mechanistic insights

“…Expression of the DAT also differs, with higher protein and mRNA levels in ventral tier SNc neurons than in dorsal tier cells in SNc or VTA [97,100,101]. This difference is reflected in the greater DAT-dependent regulation of [DA] o in SNc versus VTA [19,102]. Similarly, SNc DA neurons have greater D2 autoreceptor expression versus VTA [100], which is reflected in greater autoreceptor regulation of somatodendritic DA release in SNc than in VTA [38].…”

“…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].…”

A model for simulation and patient-specific visualization of the tissue volume of influence during brain microdialysis

“…The loss rate constant, k: The values of k are assumed to be evenly distributed on the interval 0.003 -0.010 s -1 , based on literature data for small molecules, such as neurotransmitters, when specific, high-affinity uptake is absent [17][18][19].…”

“…A mean  of about 1.6 is in agreement with other studies [9,33], so the assumption is considered appropriate. The k values used for this study are based on data proposed for small molecules, including neurotransmitters, when high-affinity uptake is absent [10,[17][18][19], and result in an interval causing large variations of the r TVImax ( Figure 3). This is in accordance with previous studies,…”

“…The loss rate term takes only nonspecific, linear uptake into account, in order to keep the model as general as possible. Biologically active molecules such as neurotransmitters may experience a more complex, increased loss pattern due to specific uptake and metabolism [9,34,35], which is an important factor in determining the analyte time course in certain regions of the brain [19,36,37]. Consequently, neglecting the specific uptake may result in a large overestimation of the r TVImax .…”