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.