Trace amines depress D₂-autoreceptor-mediated responses on midbrain dopaminergic cells

Background and purpose: Although trace amines (TAs) are historically considered 'false neurotransmitters' on the basis of their ability to induce catecholamine release, there is evidence that they directly affect neuronal activity via TA receptors, ligand-gated receptor channels and/or σ receptors. Here, we have investigated the effects of two TAs, tyramine (TYR) and β-phenylethylamine (β-PEA), on electrophysiological responses of substantia nigra pars compacta (SNpc) dopaminergic cells to the D₂ receptor agonist, quinpirole. Experimental approach: Electrophysiological recordings of D₂ receptor-activated G-protein-gated inward rectifier K⁺ channel (GIRK) currents were performed on dopaminergic cells from midbrain slices of mice and on Xenopus oocytes expressing D₂ receptors and GIRK channels. Key results: TYR and β-PEA reversibly reduced D₂ receptor-activated GIRK currents in a concentration-dependent manner on SNpc neurones. The inhibitory effect of TAs was still present in transgenic mice with genetically deleted TA₁ receptors and they could not be reproduced by the selective TA₁ agonist, o-phenyl-3- iodotyramine (O-PIT). Pretreatment with antagonists of σ1 and σ2 receptors did not block TA-induced effects. In GTPγS-loaded neurones, the irreversibly-activated GIRK-current was still reversibly reduced by β-PEA. Moreover, β-PEA did not affect basal or dopamine-evoked GIRK-currents in Xenopus oocytes. Conclusions and implications: TAs reduced dopamine-induced responses on SNpc neurones by acting at sites different from TA₁, σ-receptors, D₂ receptors or GIRK channels. Although their precise mechanism of action remains to be identified, TAs, by antagonizing the inhibitory effects of dopamine, may render dopaminergic neurones less sensitive to autoreceptor feedback inhibition and hence enhance their sensitivity to stimulation.