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Methamphetamine-induced hyperthermia and lethal toxicity: role of the dopamine and serotonin transporters.
Eur J Pharmacol. 2007 Oct 31; 572(2-3):120-8.EJ

Abstract

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.

Authors+Show Affiliations

Department of Biological Psychiatry, Tohoku University Graduate School of Medicine, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17673199

Citation

Numachi, Yohtaro, et al. "Methamphetamine-induced Hyperthermia and Lethal Toxicity: Role of the Dopamine and Serotonin Transporters." European Journal of Pharmacology, vol. 572, no. 2-3, 2007, pp. 120-8.
Numachi Y, Ohara A, Yamashita M, et al. Methamphetamine-induced hyperthermia and lethal toxicity: role of the dopamine and serotonin transporters. Eur J Pharmacol. 2007;572(2-3):120-8.
Numachi, Y., Ohara, A., Yamashita, M., Fukushima, S., Kobayashi, H., Hata, H., Watanabe, H., Hall, F. S., Lesch, K. P., Murphy, D. L., Uhl, G. R., & Sora, I. (2007). Methamphetamine-induced hyperthermia and lethal toxicity: role of the dopamine and serotonin transporters. European Journal of Pharmacology, 572(2-3), 120-8.
Numachi Y, et al. Methamphetamine-induced Hyperthermia and Lethal Toxicity: Role of the Dopamine and Serotonin Transporters. Eur J Pharmacol. 2007 Oct 31;572(2-3):120-8. PubMed PMID: 17673199.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Methamphetamine-induced hyperthermia and lethal toxicity: role of the dopamine and serotonin transporters. AU - Numachi,Yohtaro, AU - Ohara,Arihisa, AU - Yamashita,Motoyasu, AU - Fukushima,Setsu, AU - Kobayashi,Hideaki, AU - Hata,Harumi, AU - Watanabe,Hidekazu, AU - Hall,F Scott, AU - Lesch,Klaus-Peter, AU - Murphy,Dennis L, AU - Uhl,George R, AU - Sora,Ichiro, Y1 - 2007/06/27/ PY - 2007/02/01/received PY - 2007/06/04/revised PY - 2007/06/07/accepted PY - 2007/8/4/pubmed PY - 2008/1/15/medline PY - 2007/8/4/entrez SP - 120 EP - 8 JF - European journal of pharmacology JO - Eur J Pharmacol VL - 572 IS - 2-3 N2 - 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. SN - 0014-2999 UR - https://www.unboundmedicine.com/medline/citation/17673199/Methamphetamine_induced_hyperthermia_and_lethal_toxicity:_role_of_the_dopamine_and_serotonin_transporters_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-2999(07)00718-2 DB - PRIME DP - Unbound Medicine ER -