Dopamine Evokes a Trace Amine Receptor-dependent Inward Current that is Regulated by AMP Kinase in Substantia Nigra Dopamine Neurons

[Display omitted] •Dopamine evokes a slowly developing inward current in SNC neurons.•This inward current is blocked by DAT inhibitors.•AMPK inhibitors permit the emergence of inward current despite DAT inhibition.•Dopamine-induced inward current is blocked by a TAAR1 antagonist.•We conclude that dopamine evokes a TAAR1 current modulated by AMPK. We reported recently that activators of AMP-activated protein kinase (AMPK) slow the rundown of current evoked by the D2 autoreceptor agonist quinpirole in rat substantia nigra compacta (SNC) dopamine neurons. The present study examined the effect of AMPK on current generated by dopamine, which unlike quinpirole, is a substrate for the dopamine transporter (DAT). Using whole-cell patch-clamp, we constructed current–voltage (I–V) plots while superfusing brain slices with dopamine (100 μM) for 25 min. Two minutes after starting superfusion, dopamine evoked a peak current with an average slope conductance of 0.97 nS and an estimated reversal potential (Erev) of −113 mV, which is near that expected for K+. But after 10 min of superfusion, dopamine-evoked currents had shifted to more depolarized values with a slope conductance of 0.64 nS and an Erev of −83 mV. This inward shift in current was completely blocked by the DAT inhibitor GBR12935. However, an AMPK blocking agent (dorsomorphin) permitted the emergence of inward current despite the continued presence of the DAT inhibitor. When D2 autoreceptors were blocked by sulpiride, I–V plots showed that dopamine evoked an inward current with an estimated slope conductance of 0.45 nS with an Erev of −57 mV. Moreover, this inward current was completely blocked by the trace amine-associated receptor 1 (TAAR1) antagonist EPPTB. These results suggest that dopamine activates a TAAR1-dependent non-selective cation current that is regulated by AMPK.