Methcathinone Rapidly Decreases Dopamine Transporter Function: Role of Calcium and Protein Kinase C

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Methcathinone (MCAT) is a synthetic cathinone that causes both persistent striatal dopaminergic as well as striatal and hippocampal serotonergic deficits. It has been demonstrated that the rapid effects of similar stimulants on dopamine (DA) transporter (DAT) function contribute to persistent monoaminergic deficits. Thus, the effect of MCAT on DAT was assessed. Results revealed that MCAT self‐administration (SA) decreased striatal [3H]DA uptake, as assessed ex vivo in synaptosomes prepared from male rats 1 h after the final MCAT SA session. In vitro co‐incubation of synaptosomes with MCAT (1, 10, 100 μM) at 37°C likewise decreased striatal [3H]DA uptake. There was no effect of in vitro co‐incubation with MCAT at 4°C, suggesting that decreases in [3H]DA uptake are not due to residual drug. These effects were not limited to DAT as MCAT SA decreased hippocampal [3H]serotonin uptake. Further, in vitro co‐incubation of synaptosomes with MCAT decreased both striatal and hippocampal [3H]serotonin uptake. The in vitro effect on DAT function was attenuated by co‐incubation with the cell‐permeable calcium chelator, 1,2‐bis (2‐aminophenoxy) ethane‐N, N, N, N‐tetraacetic acid acetoxymethyl ester (BAPTA‐AM), as well as with the structurally related non‐specific protein kinase C (PKC) inhibitors bisindolylmaleimide I and Ro‐31‐7549. In contrast, this in vitro decrease in DAT function was not attenuated by co‐incubation with other non‐specific PKC inhibitors (NPC‐15437 and Go6976), nor with the PKC‐β inhibitor ruboxistaurin. Neither co‐incubation with the Ca2+/calmodulin‐dependent protein kinase II inhibitor, KN‐93, nor the glycogen synthase kinase 3β inhibitor, SB‐216763, attenuated the MCAT‐induced decrease in [3H]DA uptake. Taken together, these results suggest that MCAT self‐administration and in vitro MCAT exposure have comparable effects to investigator administered MCAT on DAT and SERT function in the striatum and hippocampus; further, in vitro data suggest that the MCAT‐induced effect on DAT is dependent upon calcium and some, but not all, PKC isoforms.Support or Funding InformationR01‐DA039145