Simple transporter trafficking model for amphetamine-induced dopamine efflux.
Amphetamine and its derivatives are important drugs of abuse causing both short-term excitatory and long-term addictive effects. The short-term excitatory effects are linked to amphetamine's ability to maintain high levels of dopamine (DA) outside the cell both by inhibiting DA reuptake after synaptic transmission and by enhancing the efflux of DA from the dopaminergic cells. The molecular mechanisms by which amphetamine elicits the efflux of DA and similar monoamines are still unclear. Recent literature data suggest that trafficking of the monoamine transporters is a phenomenon that underlies observed changes in amphetamine-induced monoamine reuptake and efflux. We develop an ordinary differential equation model incorporating the diverse mechanistic details behind amphetamine-induced DA efflux and demonstrate its utility in describing our experimental data. We also demonstrate an experimental method to track the time-varying concentration of membrane-bound transporter molecules from the DA efflux data. The good fit between our model and the experimental data supports the hypothesis that amphetamine-induced transporter trafficking is necessary to produce extended efflux of DA. This model can explain the relative significance of different processes associated with DA efflux at different times and at different concentration ranges of amphetamine and DA.
Thwar
Prasanna K
PK
Department of Chemical Engineering, University of Michigan, Ann Arbor, Michigan 48109, USA.
Guptaroy
Bipasha
B
Zhang
Minjia
M
Gnegy
Margaret E
ME
Burns
Mark A
MA
Linderman
Jennifer J
JJ
D000661:Amphetamine / Q000494:pharmacology*; D002461:Cell Line, Transformed; D004298:Dopamine / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008954:Models, Biological; D021381:Protein Transport / Q000187:drug effects; D050493:Vesicular Monoamine Transport Proteins / Q000378:metabolism*
D018765:Dopamine Uptake Inhibitors; D050493:Vesicular Monoamine Transport Proteins; D000661:Amphetamine; D004298:Dopamine