title: Amphetamine potentiates the effects of β-phenylethylamine through activation of an amine-gated chloride channel.
abstract: β-Phenylethylamine (βPEA) is a trace amine present in the CNS of all animals tested to date. However, its function is still not fully understood. βPEA has been suggested to function as a neurotransmitter and/or to mimic the effect of amphetamine (Amph). In support of the latter is the observation that βPEA and Amph produce similar but not identical behaviors. Here, we show that βPEA, like Amph, activates the dopamine transporter and the amine-gated chloride channel LGC-55 to generate behaviors in Caenorhabditis elegans. However, although Amph-induced behaviors occurred gradually during 10 min of treatment, βPEA induced maximal effects within 1 min. In vitro data demonstrate that βPEA activates the LGC-55 more efficiently than Amph (Km = 9 and 152 μm, respectively) and generates saturating currents that are 10 times larger than those produced by Amph. These results suggest that activation of LGC-55 mostly accounts for the behavioral effects reached after 1 min of treatment with βPEA. Importantly, our in vitro and in vivo data show that Amph increases the effects induced by βPEA on the LGC-55, indicating that Amph potentiates the effects generated by the biogenic amine βPEA. Together, our data not only identify a new target for βPEA, but also offer a novel mechanism of action of Amph. In addition, our results highlight C. elegans as a powerful genetic model for studying the effects of biogenic and synthetic amines both at the molecular and behavioral levels.
authors.affiliation: Department of Pharmacology, Physiology, and Therapeutics, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota 58202-9037, and Department of Physiology and Biophysics, University of Miami, Miller School of Medicine, Miami, Florida 33136.
authors.forename: Bryan D
authors.initials: BD
authors.lastname: Safratowich
authors.forename: Murad
authors.initials: M
authors.lastname: Hossain
authors.forename: Laura
authors.initials: L
authors.lastname: Bianchi
authors.forename: Lucia
authors.initials: L
authors.lastname: Carvelli
mesh_terms: D000588:Amines / Q000378:metabolism / Q000494:pharmacology*; D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D018118:Chloride Channels / Q000235:genetics / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D009865:Oocytes; D010627:Phenethylamines / Q000494:pharmacology*; D011619:Psychotropic Drugs / Q000494:pharmacology*; D017982:Receptors, Biogenic Amine; D011954:Receptors, Dopamine / Q000378:metabolism
chemical_list: D000588:Amines; D029742:Caenorhabditis elegans Proteins; D000697:Central Nervous System Stimulants; D018118:Chloride Channels; C532156:DAT-1 protein, C elegans; D050483:Dopamine Plasma Membrane Transport Proteins; C542018:LGC-55 protein, c elegans; D010627:Phenethylamines; D011619:Psychotropic Drugs; D017982:Receptors, Biogenic Amine; D011954:Receptors, Dopamine; C029261:phenethylamine; D000661:Amphetamine; D004298:Dopamine
keywords: Caenorhabditis elegans; amphetamine; dopamine transporter; ligand-gated ion channels; β-phenylethylamine