The conservative view: is it necessary to implant a stent into the dopamine transporter?

Abstract

This article is a reply to De Felice LJ and Cameron KN (2015). Comments on ‘A quantitative model of amphetamine action on the serotonin transporter’, by Sandtner et al., Br J Pharmacol 171: 1007–1018. Br J Pharmacol 172: this issue, doi: 10.1111/bph.12767, commenting on Sandtner W, Schmid D, Schicker K, Gerstbrein K, Koenig X, Mayer FP, Boehm S, Freissmuth M and Sitte HH (2014). A quantitative model of amphetamine action on the 5-HT transporter. Br J Pharmacol 171: 1007–1018. doi: 10.1111/bph.12520

Figure 1

Panel A shows a simulated HEK-293 cell attached to a patch electrode. The images are snapshots of the simulation that were taken at t = 0, 0.15, 0.30, 0.45 and 0.6 s. The concentration of (S+)amphetamine is colour coded as indicated in the scaling bar. Panel B shows the (S+)amphetamine concentration within the cell over time. The time course of the efflux of (S+)amphetamine from the cell in the presence and in the absence of the patch electrode are shown in red (τ = 0.62 s) and blue (τ = 1.81 s) respectively. The run time for the simulation was 3 s.

Figure 2

Panel A shows a kinetic model of the DAT transport cycle embedded into our model for substrate fluxes. The rates for dopamine (DA) binding and unbinding were adapted to account for the EC₅₀ for the induction of dopamine currents in Xenopus laevis oocytes. For modelling the currents by (S+)amphetamine, (S+)methamphetamine, and (S-)methcathinone we used the same rates as for dopamine. However, for modelling currents by (R-)amphetamine and (S+)methylenedioxymethamphetamine, we utilized a different set of rates (shown in blue ) to account for the lower affinity of these compounds. Panel B shows a table of substrate-specific parameters that are critical in the prediction of the currents. Panel C shows examples of simulated current traces. The red trace shows the response to 10 μM dopamine for an application period of 60 s. The blue trace is the response to 10 μM (S+)amphetamine respectively. Panel D is a comparison of the persistent current observed by DeFelice et al. 60 s after removal and the values predicted by the model. Open circles always indicate observed values whereas predicted values are indicated by open triangles. (S+)Methamphetamine, (S+)METH; (S+)amphetamine, (S+)AMPH); (R–)amphetamine, (R-)AMPH); (S-)methcathinone, (S–)MCAT; (S+)Methylenedioxymethamphetamine, (S+)MDMA ; dopamine, (DA).