Methamphetamine alters vesicular monoamine transporter-2 function and potassium-stimulated dopamine release.
This report demonstrates that a repeated 'challenge' high-dose methamphetamine (METH) injection regimen rapidly decreases striatal K(+)-stimulated dopamine (DA) release concurrent with decreases in both synaptosomal membrane-associated (referred to herein as membrane-associated) and previously reported decreases in non-synaptosomal membrane-associated (presumably cytoplasmic) vesicular DA uptake and content. Resembling previously reported effects involving cytoplasmic vesicles wherein uptake was decreased 48 h after treatment, the decrease in membrane-associated uptake persisted 72 h. Cytoplasmic and membrane-associated vesicular DA uptakes were decreased 7 days after the challenge regimen. A single METH injection also rapidly decreased K(+)-stimulated DA release, membrane-associated DA content, and membrane-associated DA uptake; however, unlike after the challenge regimen, the decrease in uptake recovered by 24 h. Pre-treatment with the D(2) receptor antagonist, eticlopride, did not attenuate the decrease in membrane-associated uptake as assessed 1 h after either a single or challenge treatment. However, eticlopride attenuated the decrease in membrane-associated uptake caused by the challenge regimen as assessed 24 h later. These data reveal complex effects of METH on vesicular function that vary according to the vesicle population under study, dosing regimen, and time after treatment. These may contribute to both the decrease in K(+)-stimulated DA release and the persistent dopaminergic deficits caused by METH.
Chu
Pei-Wen
PW
Interdepartmental Program in Neuroscience, University of Utah, Salt Lake City, Utah 84112, USA.
Hadlock
Gregory C
GC
Vieira-Brock
Paula
P
Stout
Kristen
K
Hanson
Glen R
GR
Fleckenstein
Annette E
AE
D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000648:ultrastructure; D004298:Dopamine / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004347:Drug Interactions; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology*; D011188:Potassium / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012457:Salicylamides / Q000494:pharmacology; D013347:Subcellular Fractions / Q000187:drug effects; D013997:Time Factors; D050493:Vesicular Monoamine Transport Proteins / Q000378:metabolism*
D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors; D012457:Salicylamides; C493454:Slc18a2 protein, rat; D050493:Vesicular Monoamine Transport Proteins; D008694:Methamphetamine; C045989:eticlopride; D011188:Potassium; D004298:Dopamine