Differential regional effects of methamphetamine on dopamine transport.
Multiple high-dose methamphetamine administrations cause long-lasting (>1 week) deficits in striatal dopaminergic neuronal function. This stimulant likewise causes rapid (within 1 h) and persistent (at least 48 h) decreases in activities of striatal: 1) dopamine transporters, as assessed in synaptosomes; and 2) vesicular monoamine transporter -2 (VMAT-2), as assessed in a non-membrane-associated (referred to herein as cytoplasmic) vesicular subcellular fraction. Importantly, not all brain areas are vulnerable to methamphetamine-induced long-lasting deficits. Similarly, the present study indicates that methamphetamine exerts differential acute effects on monoaminergic transporters according to brain region. In particular, results revealed that in the nucleus accumbens, methamphetamine rapidly, but reversibly (within 24 h), decreased plasmalemmal dopamine transporter function, without effect on plasmalemmal dopamine transporter immunoreactivity. Methamphetamine also rapidly and reversibly (within 48 h) decreased cytoplasmic VMAT-2 function in this region, with relatively little effect on cytoplasmic VMAT-2 immunoreactivity. In contrast, methamphetamine did not alter either dopamine transporter or VMAT-2 activity in the hypothalamus. Noteworthy, the nucleus accumbens and hypothalamus did not display the persistent long-lasting striatal dopamine depletions caused by the stimulant. Taken together, these data suggest that deficits in plasmalemmal and vesicular monoamine transporter activity lasting greater than 24-48 h may be linked to the long-lasting dopaminergic deficits caused by methamphetamine and appear to be region specific.
Chu
Pei-Wen
PW
Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT 84112, USA.
Seferian
Kristi S
KS
Birdsall
Elisabeth
E
Truong
Jannine G
JG
Riordan
James A
JA
Metcalf
Cameron S
CS
Hanson
Glen R
GR
Fleckenstein
Annette E
AE
D015102:3,4-Dihydroxyphenylacetic Acid / Q000032:analysis; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D050493:Vesicular Monoamine Transport Proteins / Q000032:analysis
D050483:Dopamine Plasma Membrane Transport Proteins; D050493:Vesicular Monoamine Transport Proteins; D015102:3,4-Dihydroxyphenylacetic Acid; D008694:Methamphetamine; D004298:Dopamine