Dopamine-mediated volume transmission in midbrain is regulated by distinctextracellular geometry and uptake

Somatodendritic release of dopamine (DA) in midbrain is, at least in part, nonsynaptic; moreover, midbrain DA receptors are predominantly extrasynapti c. Thus somatodendritic DA mediates volume transmission, with an efficacy r egulated by the diffusion and uptake characteristics of the local extracell ular microenvironment. Here, we quantitatively evaluated diffusion and upta ke in substantia nigra pars compacta (SNc) and reticulata (SNr), ventral te gmental area (VTA), and cerebral cortex in guinea pig brain slices. The geo metric parameters that govern diffusion, extracellular volume fraction (alp ha) and tortuosity (lambda), together with linear uptake (k'), were determi ned for tetramethylammonium (TMA(+)), and for DA, using point-source diffus ion combined with ion-selective and carbon-fiber microelectrodes. TMA(+)-di ffusion measurements revealed a large alpha of 30% in SNc, SNr, and VTA, wh ich 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 gr eater decrease in k' in SNc than in VTA. In addition, DA uptake was slightl y decreased by the norepinephrine transport inhibitor, desipramine in both regions, although this was statistically significant only in VTA. We used t hese data to model the radius of influence of DA in midbrain. Simulated rel ease from a 20-vesicle point source produced DA concentrations sufficient f or receptor activation up to 20 mum away with a DA half-life at this distan ce of several hundred milliseconds. Most importantly, this model showed tha t diffusion rather than uptake was the most important determinant of DA tim e course in midbrain, which contrasts strikingly with the striatum where up take dominates. The issues considered here, while specific for DA in midbra in, illustrate fundamental biophysical properties relevant for all extracel lular communication.