Abstract
Amphetamine is a highly addictive psychostimulant, which is thought to generate its effects by promoting release of dopamine through reverse activation of dopamine transporters. However, some amphetamine-mediated behaviors persist in dopamine transporter knock-out animals, suggesting the existence of alternative amphetamine targets. Here we demonstrate the identification of a novel amphetamine target by showing that in Caenorhabditis elegans, a large fraction of the behavioral effects of amphetamine is mediated through activation of the amine-gated chloride channel, LGC-55. These findings bring to light alternative pathways engaged by amphetamine, and urge rethinking of the molecular mechanisms underlying the effects of this highly-addictive psychostimulant.
Highlights
Amphetamine affects Caenorhabditis elegans behavior by acting on dopamine transporter (DAT) residual effects are present in DAT knockouts
We demonstrate the identification of a novel amphetamine target by showing that in Caenorhabditis elegans, a large fraction of the behavioral effects of amphetamine is mediated through activation of the aminegated chloride channel, LGC-55
Amphetamine Induces Behavioral Effects in Dopamine Transporter Knock-out Animals—Previously, we reported that Amphinduced DA release through the DAT inhibits C. elegans swimming [21]
Summary
Amphetamine affects Caenorhabditis elegans behavior by acting on dopamine transporter (DAT) residual effects are present in DAT knockouts. We demonstrate the identification of a novel amphetamine target by showing that in Caenorhabditis elegans, a large fraction of the behavioral effects of amphetamine is mediated through activation of the aminegated chloride channel, LGC-55 These findings bring to light alternative pathways engaged by amphetamine, and urge rethinking of the molecular mechanisms underlying the effects of this highly-addictive psychostimulant. In vivo and in vitro studies showed that mice overexpressing the metabotropic trace amine-associated receptor type I are hyposensitive to Amph [18], and in vitro studies showed these receptors are directly activated by Amph [19] Taken together, these data suggest that in addition to their interaction with the DAT, Amph produces a number of its behavioral effects through multiple, poorly defined mechanisms. Our work identifies a novel target of the psychostimulant amines in C. elegans and urges consideration of the existence of similar channels in mammals
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