title: Ambient temperature effects on 3,4-methylenedioxymethamphetamine-induced thermodysregulation and pharmacokinetics in male monkeys.
abstract: Changes in ambient temperature are known to alter both the hyperthermic and the serotonergic consequences of 3,4-methylenedioxymethamphetamine (MDMA). Metabolism of MDMA has been suggested to be a requisite for these neurotoxic effects, whereas the hyperthermic response is an important contributing variable. The aim of the present study was to investigate the interaction between ambient temperature, MDMA-induced thermodysregulation, and its metabolic disposition in monkeys. MDMA (1.5 mg/kg i.v.) was administered noncontingently at cool (18 degrees C; n = 5), room (24 degrees C; n = 7), and warm (31 degrees C; n = 7) ambient temperatures. For 240 min following MDMA administration, core temperature was recorded and blood samples were collected for analysis of MDMA and its metabolites 3,4-dihydroxymethamphetamine (HHMA), 3,4-dihydroxyamphetamine, and 3,4-methylenedioxyamphetamine (MDA). A dose of 1.5 mg/kg MDMA induced a hypothermic response at 18 degrees C, a hyperthermic response at 31 degrees C, and did not significantly change core temperature at 24 degrees C. Regardless of ambient temperature, plasma MDMA concentrations reached maximum within 5 min, and HHMA was a major metabolite. Curiously, the approximate elimination half-life (t(1/2)) of MDMA at 18 degrees C (136 min) and 31 degrees C (144 min) was increased compared with 24 degrees C (90 min) and is most likely because of volume of distribution changes induced by core temperature alterations. At 18 degrees C, there was a significantly higher MDA area under the concentration-time curve (AUC) and a trend for a lower HHMA AUC compared with 24 degrees C and 31 degrees C, suggesting that MDMA disposition was altered. Overall, induction of hypothermia in a cool environment by MDMA may alter its disposition. These results could have implications for MDMA-induced serotonergic consequences.
authors.affiliation: Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Banks
authors.forename: Jon E
authors.initials: JE
authors.lastname: Sprague
authors.forename: David F
authors.initials: DF
authors.lastname: Kisor
authors.forename: Paul W
authors.initials: PW
authors.lastname: Czoty
authors.forename: David E
authors.initials: DE
authors.lastname: Nichols
authors.forename: Michael A
authors.initials: MA
authors.lastname: Nader
mesh_terms: D015104:3,4-Methylenedioxyamphetamine / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D003846:Deoxyepinephrine / Q000031:analogs & derivatives / Q000097:blood; D005334:Fever / Q000139:chemically induced / Q000378:metabolism*; D006213:Hallucinogens / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D008252:Macaca fascicularis; D008297:Male; D018490:Serotonin Agents / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D013696:Temperature
chemical_list: D006213:Hallucinogens; D018490:Serotonin Agents; C069512:alpha-methylepinine; D015104:3,4-Methylenedioxyamphetamine; C023492:alpha-methyldopamine; D003846:Deoxyepinephrine