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Electrophysiological Effects of Trace Amines on Mesencephalic Dopaminergic Neurons

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Electrophysiological Effects of Trace Amines on Mesencephalic Dopaminergic Neurons

Ada Ledonne et al. Front Syst Neurosci.

Abstract

Trace amines (TAs) are a class of endogenous compounds strictly related to classic monoamine neurotransmitters with regard to their structure, metabolism, and tissue distribution. Although the presence of TAs in mammalian brain has been recognized for decades, until recently they were considered to be by-products of amino acid metabolism or as "false" neurotransmitters. The discovery in 2001 of a new family of G-protein-coupled receptors (GPCRs), namely trace amines receptors, has re-ignited interest in TAs. In particular, two members of the family, trace amine receptor 1 (TA(1)) and trace amine receptor 2 (TA(2)), were shown to be highly sensitive to these endogenous compounds. Experimental evidence suggests that TAs modulate the activity of catecholaminergic neurons and that TA dysregulation may contribute to neuropsychiatric disorders, including schizophrenia, attention deficit hyperactivity disorder, depression and Parkinson's disease, all of which are characterized by altered monoaminergic networks. Here we review recent data concerning the electrophysiological effects of TAs on the activity of mesencephalic dopaminergic neurons. In the context of recent data obtained with TA(1) receptor knockout mice, we also discuss the mechanisms by which the activation of these receptors modulates the activity of these neurons. Three important new aspects of TAs action have recently emerged: (a) inhibition of firing due to increased release of dopamine; (b) reduction of D2 and GABA(B) receptor-mediated inhibitory responses (excitatory effects due to disinhibition); and (c) a direct TA(1) receptor-mediated activation of GIRK channels which produce cell membrane hyperpolarization. While the first two effects have been well documented in our laboratory, the direct activation of GIRK channels by TA(1) receptors has been reported by others, but has not been seen in our laboratory (Geracitano et al., 2004). Further research is needed to address this point, and to further characterize the mechanism of action of TAs on dopaminergic neurons.

Keywords: dopaminergic neurons; neuropsychiatric disorders; trace amine receptor 1; tyramine; β-phenylethylamine.

Figures

Figure 1
Figure 1
Biosynthetic and catabolic enzymatic pathways of endogenous TAs (β-PEA and tyramine) and dopamine. The aromatic amino acids phenylalanine and tyrosine represent common precursors of TAs and dopamine. TAs are directly produced by decarboxylation by l-aromatic amino acid decarboxylase (AADC), while dopamine derives from l-DOPA, which is synthesized from tyrosine by tyrosine hydroxylase (TH). The catabolism is mainly via monoamine oxidase (MAO), with the production of phenyl acetic acid (PAA), hydroxyphenyl acetic acid (HPA), and dihydroxyphenyl acetic acid (DOPAC) from β-PEA, tyramine, and dopamine, respectively.
Figure 2
Figure 2
Electrophysiological effects of TAs on mesencephalic dopaminergic neurons. (A) β-PEA produces a reversible hyperpolarization and inhibition of spontaneous firing in mesencephalic dopaminergic neurons. (B) The TAs-induced inhibition of firing is mediated by indirect activation of D2 autoreceptors, subsequent to the release of newly synthesized dopamine. The effect was absent in dopaminergic neurons treated with an inhibitor of DA synthesis (carbidopa, 300 μM for 30 min) and was blocked by a D2 receptor antagonist, sulpiride (1 μM; data not shown). (C) The amplitude of electrically evoked inhibitory postsynaptic potentials (IPSPs) mediated by GABAB receptors is reduced by bath application of β-PEA (100 μM) and TYR (100 μM). (D) TAs reduce the outward currents produced by pressure application of the GABAB agonist, baclofen (arrows) in a reversible manner. (E) Negative modulatory effects of TAs on the D2-autoreceptors-mediated responses. The quinpirole-induced GIRK channel activation is reduced by both β-PEA and TYR in a reversible and concentration-dependent manner. (F) The D2/GIRK-mediated outward current evoked by TAs is not mediated by the activation of TA1 receptors, since it was present in TA1 receptor knockout mice.

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