Inhibitors of Na(+)/H(+) and Na(+)/Ca(2+) exchange potentiate methamphetamine-induced dopamine neurotoxicity: possible role of ionic dysregulation in methamphetamine neurotoxicity.
Although the neurotoxic potential of methamphetamine (METH) is well established, underlying mechanisms have yet to be identified. In the present study, we sought to determine whether ionic dysregulation was a feature of METH neurotoxicity. In particular, we reasoned that if METH impairs the function of Na(+)/H(+) and/or Na(+)/Ca(2+) antiporters by compromising the inward Na(+) gradient [via prolonged DA transporter (DAT) activation and Na(+)/K(+) ATPase inhibition], then amiloride (AMIL) and other inhibitors of Na(+)/H(+) and/or Na(+)/Ca(2+) exchange would potentiate METH neurotoxicity. To test this hypothesis, mice were treated with METH alone or in combination with AMIL or one of its analogs; 1 week later, the animals were killed for studies of dopamine (DA) neuronal integrity. AMIL markedly potentiated the toxic effect of METH on DA neurons. Potentiation was not caused by increased core temperature, enhanced DAT activity or higher METH brain levels. The DAT inhibitor, WIN-35,428, protected completely against METH-induced DA neurotoxicity in AMIL pretreated animals, suggesting that the potentiating effects of AMIL require a METH/DAT interaction. Findings with METH and AMIL were extended to six other AMIL analogs (MIA, EIPA, DIMA, BENZ, BEP, DiCBNZ), another species (rats), and neuronal type (5-HT neurons). These results support the notion that ionic dysregulation may play a role in METH neurotoxicity.
Callahan
B T
BT
Department of Neurology and Psychiatry, Johns Hopkins Medical Institutions, Baltimore, Maryland 21224, USA.
Cord
B J
BJ
Yuan
J
J
McCann
U D
UD
Ricaurte
G A
GA
D000584:Amiloride / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D015306:Biogenic Monoamines / Q000378:metabolism; D001831:Body Temperature / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects; D004232:Diuretics / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000378:metabolism / Q000633:toxicity*; D004791:Enzyme Inhibitors / Q000633:toxicity*; D008297:Male; D008694:Methamphetamine / Q000378:metabolism / Q000633:toxicity*; D051379:Mice; D020258:Neurotoxicity Syndromes / Q000378:metabolism* / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors*; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
D015306:Biogenic Monoamines; D004232:Diuretics; D018765:Dopamine Uptake Inhibitors; D004791:Enzyme Inhibitors; D019831:Sodium-Calcium Exchanger; D017923:Sodium-Hydrogen Exchangers; D008694:Methamphetamine; D000584:Amiloride; D004298:Dopamine