UCP3 and thyroid hormone involvement in methamphetamine-induced hyperthermia.
Here, we determined the extent of hypothalamic-pituitary-thyroid (HPT) axis and uncoupling protein-3 (UCP3) involvement in methamphetamine (METH)-induced hyperthermia. Sprague-Dawley rats treated with METH (40mg/kg, s.c.) responded with a hyperthermic response that peaked 1h post-treatment and was sustained through 2h. After METH treatment, thyroparathyroidectomized (TX) animals developed hypothermia that was sustained for the 3h monitoring period. In TX animals supplemented for 5 days with levothyroxine (100microg/kg, s.c.), METH-induced hypothermia was eliminated and the hyperthermic response was restored. Thyroid hormone levels (T3 and T4), measured in euthyroid animals 1h after METH, remained unchanged. As seen in rats, 1h post-METH (20mg/kg, i.p.) treatment, wild-type (WT) mice developed profound hyperthermia that was sustained for 2h. In marked contrast, UCP3-/- animals developed a markedly blunted hyperthermic response at 1h compared to WT animals. Furthermore, UCP3-/- mice could not sustain this slight elevation in temperature. Two hours post-METH treatment, UCP3-/- animal temperature returned to baseline temperatures. UCP3-/- mice were also completely protected against the lethal effects of METH, whereas 40% of WT mice succumbed to the hyperthermia. These findings suggest that thyroid hormone plays a permissive role in the thermogenic effects induced by METH. Furthermore, the findings indicate that UCP3 plays a major role in the development and maintenance of the hyperthermia induced by METH. The relationship of these results to the hyperthermia induced by 3,4-methylenedioxymethamphetamine (MDMA) is also discussed.
Sprague
Jon E
JE
The Department of Pharmaceutical and Biomedical Sciences, The Raabe College of Pharmacy, Ohio Northern University, Ada, OH 45810, USA. j-sprague@onu.edu
Mallett
Nicole M
NM
Rusyniak
Daniel E
DE
Mills
Edward
E
D000818:Animals; D001831:Body Temperature / Q000187:drug effects*; D002352:Carrier Proteins / Q000502:physiology*; D006979:Hyperthermia, Induced; D007473:Ion Channels; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology*; D051379:Mice; D024101:Mitochondrial Proteins; D018482:Muscle, Skeletal / Q000187:drug effects / Q000502:physiology; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012007:Rectum / Q000187:drug effects / Q000502:physiology; D013963:Thyroid Hormones / Q000502:physiology*; D000071247:Uncoupling Protein 3
D002352:Carrier Proteins; D007473:Ion Channels; D024101:Mitochondrial Proteins; D013963:Thyroid Hormones; C000604393:Ucp3 protein, mouse; C000604394:Ucp3 protein, rat; D000071247:Uncoupling Protein 3; D008694:Methamphetamine; D018817:N-Methyl-3,4-methylenedioxyamphetamine