Methcathinone decreases dopamine transporter function: Role of protein kinase C

Methcathinone (MCAT) is a psychostimulant of abuse that can cause both persistent striatal dopaminergic and serotonergic, as well as hippocampal serotonergic, deficits. Evidence suggests that the rapid effects of stimulants that are structurally and mechanistically similar to MCAT on monoamine transporter function may contribute to the abuse liability and/or persistent monoaminergic deficits caused by these agents. Thus, effects of MCAT on 1) striatal dopamine (DA) transporter (DAT); and 2) striatal and hippocampal serotonin transporter (SERT) function, as determined in tissues from adult male rats, were assessed. As reported previously, a single administration of MCAT rapidly (within 1 hr) decreases striatal [3H]DA uptake. Similarly, incubation of rat synaptosomes with MCAT at 37℃ (but not 4˚C) decreased striatal [3H]DA uptake. Incubation with MCAT likewise decreased [3H]5HT but not vesicular [3H]DA uptake. MCAT incubation in vitro was without effect on [3H]DA uptake in striatal synaptosomes prepared from MCAT‐treated rats. The decrease in [3H]DA uptake caused by MCAT incubation: (a) reflected a decrease in Vmax, with minimal change in Km, and (b) was attenuated by co‐incubation with the cell‐permeable calcium chelator, N,N'‐[1,2‐ethanediylbis(oxy‐2,1‐phenylene)]bis[N‐[2‐[(acetyloxy)methoxy]‐2‐oxoethyl]‐1,1'‐bis[(acetyloxy)methyl] ester‐glycine (BAPTA‐AM), as well as the non‐selective protein kinase‐C (PKC) inhibitors bisindolylmaleimide‐1 (BIM‐1) and 2‐[1‐3(Aminopropyl)indol‐3‐yl]‐3(1‐methyl‐1H‐indol‐3‐yl)maleimide (or Bisindolylmaleimide VIII; Ro‐31‐7549). Taken together, these results suggest that in vitro MCAT incubation may model important aspects of MCAT administration in vivo, and that calcium and PKC contribute to the in vitro effects of MCAT on DAT. Methcathinone is an abused psychostimulant that causes persistent monoaminergic deficits. Drug‐induced alterations in monoamine transporter function contribute to abuse liability and persistent monoaminergic deficits. Thus, the effects of methcathinone on the dopamine transporter were assessed. Similar to a single high‐dose methcathinone administration, in vitro methcathinone incubation in rat synaptosomes decreased striatal plasmalemmal, but not vesicular, [3H]DA uptake. The in vitro methcathinone‐induced decrease in plasmalemmal [3H]DA uptake: (a) reflected a decrease in Vmax, and (b) was attenuated by co‐incubation with a calcium chelator as well as the non‐selective protein kinase‐C inhibitors bis