Methamphetamine-induced hyperthermia and lethal toxicity: role of the dopamine and serotonin transporters.
We examined the hyperthermic and lethal toxic effects of methamphetamine in dopamine transporter (DAT) and/or serotonin transporter (SERT) knockout (KO) mice. Methamphetamine (45 mg/kg) caused significant hyperthermia even in the mice with a single DAT gene copy and no SERT copies (DAT+/- SERT-/- mice). Mice with no DAT copies and a single SERT gene copy (DAT-/- SERT+/- mice) showed significant but reduced hyperthermia when compared to wild-type mice after methamphetamine. Surprisingly, DAT/SERT double KO mice exhibited a paradoxical hypothermia after methamphetamine. These results demonstrate that methamphetamine exerts a hyperthermic effect via DAT, or via SERT, in the absence of DAT. The selective norepinephrine transporter blocker (20 mg/kg nisoxetine) caused hyperthermia in DAT/SERT double KO mice, suggesting that the norepinephrine system is not responsible for methamphetamine-induced paradoxical hypothermia in the double KO mice. DAT gene deletion in mice strikingly increased LD50 of methamphetamine by 1.7-1.8 times that of wild-type mice, suggesting that the lethal toxic effect of methamphetamine is mainly dependent on DAT. Moreover, dissociation between hyperthermic and lethal toxic effects of methamphetamine in DAT single KO mice and DAT/SERT double KO mice suggest that hyperthermia is not a prerequisite for methamphetamine-induced lethality. Methamphetamine (45 mg/kg) significantly increased mRNA of interleukin-1beta, which is the major endogenous pyrogen, in the hypothalamus of wild-type mice but not in DAT/SERT double KO mice, which provides a partial mechanism of methamphetamine-induced paradoxical hypothermia. These results suggest that DAT and SERT are key molecules for hyperthermic and lethal toxic effects of methamphetamine.
Numachi
Yohtaro
Y
Department of Biological Psychiatry, Tohoku University Graduate School of Medicine, Japan.
Ohara
Arihisa
A
Yamashita
Motoyasu
M
Fukushima
Setsu
S
Kobayashi
Hideaki
H
Hata
Harumi
H
Watanabe
Hidekazu
H
Hall
F Scott
FS
Lesch
Klaus-Peter
KP
Murphy
Dennis L
DL
Uhl
George R
GR
Sora
Ichiro
I
D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D000697:Central Nervous System Stimulants / Q000506:poisoning / Q000633:toxicity*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D005260:Female; D005334:Fever / Q000139:chemically induced* / Q000378:metabolism; D005473:Fluoxetine / Q000031:analogs & derivatives / Q000633:toxicity; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000235:genetics; D007928:Lethal Dose 50; D008297:Male; D008694:Methamphetamine / Q000506:poisoning / Q000633:toxicity*; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000096:biosynthesis; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000502:physiology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000506:poisoning / Q000633:toxicity
D000697:Central Nervous System Stimulants; D050483:Dopamine Plasma Membrane Transport Proteins; D005473:Fluoxetine; D053583:Interleukin-1beta; D008694:Methamphetamine; D012333:RNA, Messenger; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; C011386:nisoxetine