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Classic kappa opioid receptor (KOPr) agonists have shown anti-addictive properties in rat models of addiction (Heidbreder et al. 1998; Schenk et al. 1999; Sun et al. 2010), and this has been shown to be partially through modulation of dopamine and serotonin in the synapse (Thompson et al. 2000; Zhang et al. 2004; Zakharova et al. 2008a). However, they have side effects such as depression and dysphoria and therefore have not been moved into the clinic. The novel KOPr agonist salvinorin A has a completely different structure compared to the classic agonists, and along with its novel analogues has opened up a new family of KOPr agonists which may possess anti-addictive properties and have the potential to have decreased side effects. Salvinorin A has also demonstrated anti-addictive properties (Morani et al. 2009). In this study the novel KOPr agonist salvinorin A and its analogues DS-1-240 and DS-3-216 were investigated, along with the classic agonists U50,488H and U69,593. Their effects on the dopamine transporter (DAT) were measured using isolated rat brain tissue and cell models. The effects of U50,488H and salvinorin A on the serotonin transporter (SERT) was also measured in rat striatum using rotating disk electrode voltammetry, which was established to measure serotonin uptake in our lab during this study. We found that all of the kappa opioid receptor agonists studied in isolated rat brain tissue caused dose dependent increases in uptake of dopamine by the dopamine transporter and a decrease in uptake of serotonin by the serotonin transporter. The effect on the serotonin transporter was observed after a 15 min incubation with the agonists. Salvinorin A had a faster effect on the dopamine transporter than the other compounds investigated, with increases measured at 1 min rather than 4 min. DAT kinetics showed increases in Vmax for all agonists investigated, and both U69,593 and DS-1-240 also showed increased Km values. This demonstrates an overall increase in function, with the possibility of increased cell surface expression. Further investigation using cell models also found an increase in uptake of the fluorescent monoamine transporter substrate ASP+ by YFP tagged human DAT (YFP-hDAT). This effect was seen with all the agonists studied after incubations of less than 5 min and was YFP-hDAT trafficking-independent. The increase in uptake seen may be due to increased active YFP-hDAT found on the cell membrane as ASP+ binding studies demonstrated an increase in binding. The acute increase in YFP-hDAT function was found to be ERK1/2 dependent for all compounds studied, and was also dependent on intact lipid rafts in the cell membrane. After a 30 min incubation, salvinorin A and U50,488H still caused increased uptake of ASP+ by YFP-hDAT, whereas DS-1-240 and DS-3-216 did not. Increases in cell surface expression of YFP-hDATwas seen at this time point with salvinorin A, U69,593, and DS-3-216. Further investigation into this found that the increase in cell surface expression of YFP-hDAT after salvinorin A treatment was ERK1/2 dependent, whereas the increase seen with U69,593 appeared to be ERK1/2 independent. Overall, this data demonstrates that KOPr rapidly regulates DAT function by a trafficking-independent, ERK1/2-, and lipid raft-dependent mechanism. The classic KOPr agonist U50,488H and salvinorin A also caused a decrease in serotonin uptake by SERT, confirming that the KOPr also regulates SERT. The data from this study provides more information on how these classic and novel KOPr agonists function to regulate DAT and SERT, which may help explain some of the anti-addictive properties displayed by these compounds.

Investigating the Effects of Novel Kappa Opioid Receptor Agonists on the Dopamine Transporter