The effect of long-term repeated exposure to 3,4-methylenedioxymethamphetamine on cardiovascular and thermoregulatory changes.
BACKGROUND
3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") disrupts thermoregulation in rats and can lead to life-threatening hyperthermia in humans. MDMA administration can also lead to long-term neurotoxicity in animals and possibly humans.


OBJECTIVE
The purpose of the current study was to extend previous results on the acute effects of MDMA on behavioral thermoregulation to a repeated dosing regime, simulating regular weekend use of ecstasy, on measures of thermoregulation and heart rate (HR).


METHODS
Sprague-Dawley rats with telemetry implants were administered 40 micromol/kg MDMA on three consecutive days each week for 1 or 6 weeks before being confined to an elevated ambient temperature (TA) (HOT; 30+/-1 degrees C) or an area at room temperature (ROOM; 21.5+/-1.5 degrees C) for 30 min. After the final drug administration, rats were placed in a thermal gradient for 4 h to allow behavioral thermoregulation.


RESULTS
HOT rats showed higher core temperature (TC), HR, and locomotor activity than ROOM rats during confinement to a set TA (P<0.001). HR responses to MDMA over 6 weeks at both TAs progressively decreased with repeated dosing (P<0.05). TC was significantly higher in both 6-week groups compared to the 1-week groups (P<0.05) at the end of time in the gradient. Cortical concentrations of dihydroxyphenylacetic acid (DOPAC; P<0.05) and 5-hydroxyindole acetic acid (5-HIAA; P<0.001) decreased significantly irrespective of TA, while concentrations of dopamine and 5-HT did not change.


CONCLUSIONS
Long-term treatment with MDMA resulted in apparent tolerance to the effects of the drug on HR, dysregulation of TC in thermal gradient, and depletion of cortical DOPAC and 5-HIAA.
Jaehne
Emily Joy
EJ
Discipline of Pharmacology, School of Medical Sciences, Level 5 Medical School North, University of Adelaide, Adelaide, SA, 5005, Australia. emily.jaehne@adelaide.edu.au
Salem
Abdallah
A
Irvine
Rodney James
RJ
D015102:3,4-Dihydroxyphenylacetic Acid / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D015104:3,4-Methylenedioxyamphetamine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001833:Body Temperature Regulation / Q000187:drug effects*; D002540:Cerebral Cortex / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000032:analysis / Q000737:chemistry / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D006339:Heart Rate / Q000187:drug effects*; D006358:Hot Temperature; D006801:Humans; D006897:Hydroxyindoleacetic Acid / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D006979:Hyperthermia, Induced / Q000295:instrumentation / Q000379:methods; D007274:Injections, Intraperitoneal; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000032:analysis / Q000737:chemistry / Q000378:metabolism; D013686:Telemetry; D013997:Time Factors
D015102:3,4-Dihydroxyphenylacetic Acid; D012701:Serotonin; D015104:3,4-Methylenedioxyamphetamine; D006897:Hydroxyindoleacetic Acid; C051800:3,4-methylenedioxyethamphetamine; D004298:Dopamine