PMID- 17012607
OWN - NLM
STAT- MEDLINE
DCOM- 20070212
LR  - 20161124
IS  - 0022-3565 (Print)
IS  - 0022-3565 (Linking)
VI  - 320
IP  - 1
DP  - 2007 Jan
TI  - Roles of norepinephrine, free Fatty acids, thyroid status, and skeletal muscle 
      uncoupling protein 3 expression in sympathomimetic-induced thermogenesis.
PG  - 274-80
AB  - Thyroid hormone (TH) plays a fundamental role in thermoregulation, yet the 
      molecular mediators of its effects are not fully defined. Recently, skeletal 
      muscle (SKM) uncoupling protein (UCP) 3 was shown to be an important mediator of 
      the thermogenic effects of the widely abused sympathomimetic agents 
      3,4-methylenedioxymethamphetamine (MDMA; Ecstasy) and methamphetamine. Expression 
      of UCP3 is regulated by TH. Activation of UCP3 is indirectly regulated by 
      norepinephrine (NE) and is dependent upon the availability of free fatty acids 
      (FFAs). We hypothesized that UCP3 may be a molecular link between TH and 
      hyperthermia, requiring increased levels of both NE and FFAs to accomplish the 
      thermogenic effect. Here, we demonstrate that MDMA (40 mg/kg s.c.) significantly 
      increases plasma FFA levels 30 min after treatment. Pharmacologically increasing 
      NE levels through the inhibition of phenylethanolamine N-methyltransferase with 
      +/-2,3-dichloro-alpha-methylbenzylamine potentiated the hyperthermic effects of a 
      20 mg/kg dose of MDMA. Using Western blots and regression analysis, we further 
      illustrated that chronic hyperthyroidism in rats potentiates the hyperthermic 
      effects of MDMA and increases levels of SKM UCP3 protein in a linear fashion 
      according to levels of circulating plasma TH. Conversely, chronic hypothyroidism 
      results in a hypothermic response to MDMA that is directly proportionate to 
      decreased UCP3 expression. Acute TH supplementation did not change the skeletal 
      muscle UCP3 expression levels or temperature responses to MDMA. These findings 
      suggest that, although MDMA-induced hyperthermia appears to result from increased 
      NE and FFA levels, susceptibility is ultimately determined by TH regulation of 
      UCP3-dependent thermogenesis.
FAU - Sprague, Jon E
AU  - Sprague JE
AD  - The Department of Pharmaceutical and Biomedical Sciences, The Raabe College of 
      Pharmacy, Ohio Northern University, Ada, Ohio, USA.
FAU - Yang, Xianmei
AU  - Yang X
FAU - Sommers, Joni
AU  - Sommers J
FAU - Gilman, Tracy L
AU  - Gilman TL
FAU - Mills, Edward M
AU  - Mills EM
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20060929
PL  - United States
TA  - J Pharmacol Exp Ther
JT  - The Journal of pharmacology and experimental therapeutics
JID - 0376362
RN  - 0 (Fatty Acids, Nonesterified)
RN  - 0 (Ion Channels)
RN  - 0 (Mitochondrial Proteins)
RN  - 0 (Sympathomimetics)
RN  - 0 (Ucp3 protein, rat)
RN  - 0 (Uncoupling Protein 3)
RN  - KE1SEN21RM (N-Methyl-3,4-methylenedioxyamphetamine)
RN  - Q51BO43MG4 (Thyroxine)
RN  - X4W3ENH1CV (Norepinephrine)
SB  - IM
MH  - Animals
MH  - Fatty Acids, Nonesterified/*blood
MH  - Ion Channels/*analysis
MH  - Male
MH  - Mitochondrial Proteins/*analysis
MH  - Muscle, Skeletal/*chemistry
MH  - N-Methyl-3,4-methylenedioxyamphetamine/pharmacology
MH  - Norepinephrine/*physiology
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Sympathomimetics/*pharmacology
MH  - Thermogenesis/*drug effects
MH  - Thyroid Gland/*physiology
MH  - Thyroxine/blood
MH  - Uncoupling Protein 3
EDAT- 2006/10/03 09:00
MHDA- 2007/02/13 09:00
CRDT- 2006/10/03 09:00
PHST- 2006/10/03 09:00 [pubmed]
PHST- 2007/02/13 09:00 [medline]
PHST- 2006/10/03 09:00 [entrez]
AID - jpet.106.107755 [pii]
AID - 10.1124/jpet.106.107755 [doi]
PST - ppublish
SO  - J Pharmacol Exp Ther. 2007 Jan;320(1):274-80. doi: 10.1124/jpet.106.107755. Epub 
      2006 Sep 29.