An MCPEM approach to understanding inter-animal and inter-treatment changes with in vivo striatal dopamine clearance in rats.
Robert R. Bies1, Serge Guzy2, Joshua Sokoloski3, Laura Drewencki3, and Amy K. Wagner3.
1.Department of Pharmaceutical Sciences and Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA
Objective: To capture the between animal, between occasion and between treatment differences in striatal dopamine clearance kinetics using a nonlinear mixed effects approach.
Methods: Striatal dopamine (DA) concentration versus time profiles were measured using fast scan cyclic voltammetry and a stimulated release paradigm in naïve rats and rats subjected to experimental traumatic brain injury (TBI). Three stimulus responses (occasions), reported as DA concentration versus time, were collected both before and after treatment with either saline (vehicle) or 5mg/kg methylphenidate (MPH). Pdx-MCPEM was used to evaluate the DA clearance profiles for each stimulus response using a Vmax and Km (saturable) model parameterization with 200 EM evaluations and between 3,000 and 30,000 vectors in the likelihood space for each assessment.
Results: The system was best described using both between animal and inter-occasion variability to obtain the Vmax and the Km values reflective of DA clearance after evoked release (>300 objective function value point reduction).
Conclusions: A between animal and within animal (between occasion) structure best described differences across this experimental design using two induced conditions and three different treatments. Specific deviations from this structure will guide the implementation of the structure of covariate relationships with treatment and injury status.
