Trace amines depress D(2)-autoreceptor-mediated responses on midbrain dopaminergic cells.
OBJECTIVE
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 sigma receptors. Here, we have investigated the effects of two TAs, tyramine (TYR) and beta-phenylethylamine (beta-PEA), on electrophysiological responses of substantia nigra pars compacta (SNpc) dopaminergic cells to the D(2) receptor agonist, quinpirole.


METHODS
Electrophysiological recordings of D(2) 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 D(2) receptors and GIRK channels.


RESULTS
TYR and beta-PEA reversibly reduced D(2) 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 TA(1) receptors and they could not be reproduced by the selective TA(1) agonist, o-phenyl-3-iodotyramine (O-PIT). Pretreatment with antagonists of sigma1 and sigma2 receptors did not block TA-induced effects. In GTPgammaS-loaded neurones, the irreversibly-activated GIRK-current was still reversibly reduced by beta-PEA. Moreover, beta-PEA did not affect basal or dopamine-evoked GIRK-currents in Xenopus oocytes.


CONCLUSIONS
TAs reduced dopamine-induced responses on SNpc neurones by acting at sites different from TA(1), sigma-receptors, D(2) 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.
Ledonne
Ada
A
Università della Calabria, Dipartimento Farmaco-biologico, Arcavacata di Rende, Cosenza, Italy.
Federici
Mauro
M
Giustizieri
Michela
M
Pessia
Mauro
M
Imbrici
Paola
P
Millan
Mark J
MJ
Bernardi
Giorgio
G
Mercuri
Nicola B
NB
D000818:Animals; D017660:Autoreceptors / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004594:Electrophysiology; D005260:Female; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009865:Oocytes; D010627:Phenethylamines / Q000494:pharmacology*; D019257:Quinpirole / Q000494:pharmacology; D017448:Receptors, Dopamine D2 / Q000187:drug effects* / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism; D014439:Tyramine / Q000494:pharmacology*; D014982:Xenopus laevis; D000095383:Trace Amine-Associated Receptors
D017660:Autoreceptors; D004298:Dopamine; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D010627:Phenethylamines; D019257:Quinpirole; D017448:Receptors, Dopamine D2; D043562:Receptors, G-Protein-Coupled; D014439:Tyramine; D000095383:Trace Amine-Associated Receptors; C029261:phenethylamine