TY - JOUR T1 - Molecular Mechanisms of Amphetamine Actions in <em>C. elegans</em> JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.109.062703 SP - mol.109.062703 AU - Lucia Carvelli AU - Dawn S Matthies AU - Aurelio Galli Y1 - 2010/01/01 UR - http://molpharm.aspetjournals.org/content/early/2010/04/21/mol.109.062703.abstract N2 - Amphetamine (AMPH) poses a serious hazard to public health. Defining the molecular targets of AMPH is essential to developing treatments for psychostimulant abuse. AMPH elicits its behavioral effects primarily by increasing extracellular dopamine (DA) levels through the reversal of DA transporter (DAT) cycle and, as a consequence, altering DA signaling. In C. elegans, an excess of synaptic DA results in a loss of motility in water, termed Swimming-Induced Paralysis (SWIP). Here we demonstrate that AMPH produces SWIP in a time- and dose-dependent manner in wild-type (wt) animals, but has a reduced ability to generate SWIP in DAT knock out worms (dat-1). To determine whether D1-like and/or D2-like receptors are involved in AMPH-induced SWIP, we performed experiments in DOP-1 and DOP-4, and DOP-2, and DOP-3 knock out animals, respectively. AMPH administration resulted in a reduced ability to induce SWIP in animals lacking DOP-3, DOP-4 and DOP-2 receptors. In contrast, in worms lacking DOP-1 receptors AMPH-induced SWIP occurred at wt levels. Using microamperometry on C. elegans DA neurons, we determined that in contrast to wt cells, AMPH failed to promote DA efflux in dat-1 DA neurons. These data suggest that DA efflux is critical to sustaining SWIP behavior by signaling through DOP-3, DOP-4, and DOP-2. In a double mutant lacking both DAT-1 and DOP-1 expression, we found no ability of AMPH to induce SWIP or DA efflux. This result supports the paradigm that DA efflux through C. elegans DAT (DAT-1) is required for AMPH-induced behaviors and does not require DOP-1 signaling.The American Society for Pharmacology and Experimental Therapeutics ER -