Tyramine excites rat subthalamic neurons in vitro by a dopamine-dependent mechanism

Tyramine, an endogenous ligand for mammalian trace amine-associated receptors, may act as a neuromodulator that regulates neuronal activity in basal ganglia. Using whole-cell patch recordings of subthalamic nucleus (STN) neurons in rat brain slices, we found that bath application of tyramine evoked an inward current in voltage-clamp in over 60% of all STN neurons. The inward current induced by tyramine was mimicked by the D₂-like dopamine receptor agonist quinpirole, but was only partially blocked by the D₂-like receptor antagonist sulpiride. In contrast, the D₁-like receptor agonist SKF38393 evoked no current in STN neurons. Inward current evoked by tyramine was significantly reduced by the catecholamine uptake inhibitor nomifensine, and by exhausting catecholamines in the brain via pretreatment with reserpine. Tyramine also reduced the amplitude of GABA_A receptor-mediated IPSCs that were evoked by focal electrical stimulation of the slice. Inhibition of IPSCs by tyramine was mimicked by quinpirole and was blocked by sulpiride but not by SCH23390, a D₁ receptor antagonist. Moreover, tyramine-induced inhibition of IPSCs was reduced in slices pretreated with reserpine, and this inhibition could be restored by briefly superfusing the slice with dopamine. These results suggest that tyramine acts as an indirect dopamine agonist in the STN. Although inhibition of IPSCs is mediated by D₂-like receptors, the dopamine-dependent inward currents evoked by tyramine do not fit a typical dopamine receptor pharmacological profile.