Hypothalamic-pituitary-thyroid axis and sympathetic nervous system involvement in hyperthermia induced by 3,4-methylenedioxymethamphetamine (Ecstasy).
An acute and potentially life-threatening complication associated with the recreational use of the 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) is hyperthermia. In the present study, Sprague-Dawley rats treated with MDMA (40 mg/kg s.c.) responded with a significant increase (maximal at 1 h) in rectal and skeletal muscle temperatures that lasted for at least 3 h post-treatment. Hypophysectomized (HYPO) and thyroparathyroidectomized (TX) animals treated with MDMA (40 mg/kg s.c.) did not become hyperthermic and in fact displayed a significant hypothermia. The HYPO and TX animals were also resistant to the serotonergic neurotoxic effects of MDMA assessed by serotonin measurements 4 to 7 days later in the striatum and hippocampus. MDMA (40 mg/kg s.c.) induced a significant increase in thyroxine levels 1 h post-treatment. Thyroid hormone replacement in TX animals returned the hyperthermic response seen after MDMA. Prazosin, an alpha(1)-antagonist (0.2 mg/kg i.p.), administered 30 min before MDMA significantly attenuated the MDMA-induced increase in rectal temperature, but had no effect on skeletal muscle temperature. Cyanopindolol, a beta(3)-antagonist (4 mg/kg s.c.), administered 30 min before MDMA (40 mg/kg s.c.) significantly attenuated the increase in skeletal muscle temperature, but had no effect on the rise in rectal temperature. The combination of prazosin and cyanopindolol resulted in an abolishment of MDMA-induced hyperthermia. The mechanisms of thermogenesis induced by MDMA seem to result from an interaction between the hypothalamic-pituitary-thyroid axis and the sympathetic nervous system, wherein mechanisms leading to core and skeletal muscle hyperthermia after MDMA exposure seem to be differentially regulated by alpha(1)- and beta(3)-adrenergic receptors.
Sprague
Jon E
JE
The Department of Pharmaceutical and Biomedical Sciences, The Raabe College of Pharmacy, Ohio Northern University, Ada, Ohio 45810, USA. j-sprague@onu.edu
Banks
Matthew L
ML
Cook
Valerie J
VJ
Mills
Edward M
EM
D015104:3,4-Methylenedioxyamphetamine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D004347:Drug Interactions; D005334:Fever / Q000139:chemically induced / Q000503:physiopathology*; D007016:Hypophysectomy; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects* / Q000503:physiopathology; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects / Q000502:physiology; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000494:pharmacology*; D020258:Neurotoxicity Syndromes; D010869:Pindolol / Q000031:analogs & derivatives* / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012007:Rectum / Q000187:drug effects / Q000502:physiology; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D013564:Sympathetic Nervous System / Q000187:drug effects* / Q000503:physiopathology; D013961:Thyroid Gland / Q000187:drug effects / Q000503:physiopathology; D013974:Thyroxine / Q000494:pharmacology
D000317:Adrenergic alpha-Antagonists; D012702:Serotonin Antagonists; C016575:3,4-methylenedioxyphenethylamine; D012701:Serotonin; D015104:3,4-Methylenedioxyamphetamine; C047975:cyanopindolol; D010869:Pindolol; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D013974:Thyroxine; D011224:Prazosin