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Molecular Mechanisms of Amphetamine Actions in Caenorhabditis elegans

Molecular Mechanisms of Amphetamine Actions in Caenorhabditis elegans Abstract 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 the DA transporter (DAT) cycle and, as a consequence, altering DA signaling. In Caenorhabditis 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 receptor knockout 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 is required for AMPH-induced behaviors and does not require DOP-1 signaling. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Molecular Pharmacology Am. Soc for Pharma & Experimental Therapeutics

Molecular Mechanisms of Amphetamine Actions in Caenorhabditis elegans

Molecular Mechanisms of Amphetamine Actions in Caenorhabditis elegans

Molecular Pharmacology , Volume 78 (1): 151 – Jul 1, 2010

Abstract

Abstract 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 the DA transporter (DAT) cycle and, as a consequence, altering DA signaling. In Caenorhabditis 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 receptor knockout 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 is required for AMPH-induced behaviors and does not require DOP-1 signaling.

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References (47)

Publisher
Am. Soc for Pharma & Experimental Therapeutics
Copyright
Copyright © Molecular Pharmacology
ISSN
0026-895X
eISSN
1521-0111
DOI
10.1124/mol.109.062703
pmid
20410438
Publisher site
See Article on Publisher Site

Abstract

Abstract 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 the DA transporter (DAT) cycle and, as a consequence, altering DA signaling. In Caenorhabditis 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 receptor knockout 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 is required for AMPH-induced behaviors and does not require DOP-1 signaling.

Journal

Molecular PharmacologyAm. Soc for Pharma & Experimental Therapeutics

Published: Jul 1, 2010

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