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Trace amines depress D(2)-autoreceptor-mediated responses on midbrain dopaminergic cells.

ABSTRACT: 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 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. EXPERIMENTAL APPROACH: 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. KEY 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 AND IMPLICATIONS: 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.

SUBMITTER: Ledonne A

PROVIDER: S-EPMC2938821 | biostudies-other | 2010 Jul

REPOSITORIES: biostudies-other

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Trace amines depress D(2)-autoreceptor-mediated responses on midbrain dopaminergic cells.

Ledonne Ada A Federici Mauro M Giustizieri Michela M Pessia Mauro M Imbrici Paola P Millan Mark J MJ Bernardi Giorgio G Mercuri Nicola B NB

British journal of pharmacology 20100701 6

<h4>Background and purpose</h4>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) dopaminerg ...[more]

PMID: 20590640

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Project description:Human pluripotent stem cells can be differentiated into midbrain dopaminergic (mDA) neurons by directing cells through a floor plate progenitor stage. The developmental identity of mDA neurons produced using floor plate protocols is similar to substantia nigra neurons, and this has improved the ability to model Parkinson's disease (PD) in a dish. Combined with the unlimited growth potential of pluripotent stem cells, mDA neural progenitor cell production can provide a scalable source of human dopaminergic (DA) neurons for diverse applications. However, due to the complexity and length of the protocols and inherent differences between cell lines, considerable variability of the final population of neurons is often observed. One solution to this problem is to cryopreserve committed mDA neural progenitor cells in a ready-to-use format. Creating a bank of cryopreserved mDA neural progenitor cells poised for neuronal differentiation could significantly improve reproducibility and facilitate collaborations. Here we have compared six (6) different commercial cryopreservation media and different freezing conditions for mDA neural progenitor cells differentiated from human embryonic stem cell (hESC) lines. Significant differences in cell recovery were observed at 24 h post-thawing, but no differences were observed immediately upon thawing. The presence of ROCK inhibitors improved cell recovery at 24 h for all cryopreservation media tested. A faster cooling rate of 1-2°C/min was significantly better than 0.5°C/min for all conditions tested, while rapid thawing at 37°C was not always superior to slow thawing at 4°C. Importantly, cryopreservation of mDA neural progenitor cells did not alter their potential to resume differentiation into mDA neurons. Banks of cryopreserved committed mDA neural progenitor cells provide a method to generate human DA neurons with reduced batch-to-batch variability, and establish a mechanism to share lineage-primed cells for collaborative research.

Dataset Information

Trace amines depress D(2)-autoreceptor-mediated responses on midbrain dopaminergic cells.

Publications

Trace amines depress D(2)-autoreceptor-mediated responses on midbrain dopaminergic cells.

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