Insensitivity of the microdialysis zero-net-flux method to nonlinear uptake and release processes

In the microdialysis zero-net-flux (ZNF) method the extraction efficiency is conventionally obtained by linear regression. The linear analysis may become invalid for certain analytes that have nonlinear uptake/release processes in the tissue. To examine this hypothesis, a nonlinear model was used to numerically investigate the nonlinearity of the ZNF plot caused by nonlinear uptake and release processes. Three findings from this analysis are: (i) the ZNF method is markedly insensitive to the nonlinear active processes; (ii) a slow infusion rate or a long probe membrane can suppress the nonlinearity; (iii) the release under autoreceptor control does not affect the slope and linearity of the concentration difference plot. It is concluded that in the nM infusion range, the ZNF method is unable to distinguish whether or not the tissue clearance process is nonlinear. During electrical stimulation, neurotransmitter overflow may cause the microdialysis ZNF method to exhibit nonlinearity.