Abstract
GABAergic and dopaminergic pathways are co-localized in several areas of the central nervous system and recently several reports have shown co-release of both neurotransmitters. The GABA-A receptor (β and ρ1 subunits) is modulated by dopamine (DA) and, interestingly, GABAρ1 can be modulated by several biogenic amines. Here we explored the effects of the metabolites of the dopaminergic pathway and other structural analogues of DA on GABAρ1 and the DA gated ion channel (LGC-53) from Caenorhabditis elegans expressed in Xenopus laevis oocytes. Our findings show an antagonistic effect of the metabolite 3-Methoxytyramine (3-MT, IC50 = 285 ± 30 µM) with similar potency compared to DA on induced GABA currents; however, it was inactive on LGC-53. The structural DA analogues and metabolites, 3, 4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 2-phenylethylamine (β-PEA) and 4-amino-1-butanol (4-AM-1-OH), antagonized GABAρ1 currents, whereas β-PEA acted as partial agonists on LGC-53, indicating that the putative binding sites of both receptors may share structural characteristics. These results suggest that the DA metabolites 3-MT, DOPAC and HVA modulate GABAρ1 and possibly affect the activity of the receptors that include this subunit in vivo.
Highlights
Γ-Aminobutyric acid (GABA) is the most abundant inhibitory neurotransmitter in the central nervous system (CNS), and its co-localization with other neurotransmitter pathways has been fully demonstrated
LGC-53 is activated by DA but not by serotonin (5HT), octopamine, tyramine or histamine, yet it is sensitive to modulators of mammalian metabotropic DA receptors such as haloperidol, risperidone and spiperone[21]
We report the negative modulation of GABAρ1 by DA metabolites: 3-methoxytyramine (3-MT), 3, 4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and structural DA analogues 2-phenylethylamine (β-PEA) and 4-amino-1-butanol (4-AM-1-OH)
Summary
Γ-Aminobutyric acid (GABA) is the most abundant inhibitory neurotransmitter in the central nervous system (CNS), and its co-localization with other neurotransmitter pathways has been fully demonstrated. The second component does not desensitize after prolonged exposure to the agonist, is insensitive to bicuculline[4,5] and the (1,2,5,6-Tetrahydropyridin-4-yl) methylphosphinic acid (TPMPA) is a competitive antagonist[6]; is abundantly expressed in retina and has been found in several areas of the brain; for example, the cerebellum[7], hippocampus[8] and striatum[9]. This GABA receptor is formed by ρ subunits (ρ1–ρ3) and is commonly known as GABA-C10,11. These characteristics make this receptor suitable for comparative functional and structural studies
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