Binge ethanol administration enhances the MDMA-induced long-term 5-HT neurotoxicity in rat brain.
BACKGROUND
Ecstasy abuse commonly occurs in hot, overcrowded environments in combination with alcohol. Around 90% of ecstasy users take ethanol; over 70% of these users also often drink alcohol at hazardous levels.


OBJECTIVE
We wished to examine whether binge ethanol administration enhanced the long-lasting 5-HT neurotoxicity induced by 3,4-methylenedioxymethamphetamine (MDMA) in rats maintained at high ambient temperature and the role of acetaldehyde.


METHODS
Rats were treated with a 4-day ethanol regimen leading to plasma ethanol levels of around 450 mg/dl. On day 5, rats were placed at 30 degrees C and administered MDMA (5 mg/kg). Rectal temperature and hydroxyl radical formation were measured immediately before and up to 6 h after MDMA. 5-HT concentration and 5-HT transporter density were determined 7 days later. A group of rats received cyanamide (50 mg/kg) on days 1 and 3 of the 4-day-ethanol inhalation.


RESULTS
In ethanol treated rats, MDMA produced a hyperthermic response similar to that observed in controls but enhanced the loss of 5-HT concentration and 5-HT transporter density in the hippocampus. Cyanamide elevated the plasma acetaldehyde concentration fivefold to sevenfold, reduced the MDMA-induced hyperthermia and increased the neuronal damage with neurotoxicity also appearing in the cortex. MDMA increased hydroxyl radical production in the hippocampus, the effect being more marked in rats pre-exposed to ethanol.


CONCLUSIONS
Binge ethanol administration enhances the MDMA-induced long-term 5-HT neurotoxicity by a mechanism not related to changes in acute hyperthermia but probably involving hydroxyl radical formation. The magnitude of this effect is more pronounced after increasing plasma acetaldehyde levels by aldehyde dehydrogenase inhibition.
Izco
María
M
Departamento de Farmacologia, Facultad de Medicina, Universidad Complutense, Madrid, 28040, Spain.
Orio
Laura
L
O'Shea
Esther
E
Colado
M Isabel
MI
D000079:Acetaldehyde / Q000378:metabolism; D000435:Alcoholic Intoxication / Q000150:complications; D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002492:Central Nervous System Depressants / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000378:metabolism; D003484:Cyanamide / Q000494:pharmacology; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000431:Ethanol / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000378:metabolism; D005334:Fever / Q000139:chemically induced / Q000378:metabolism; D006358:Hot Temperature; D017665:Hydroxyl Radical / Q000378:metabolism; D019570:Inhalation Exposure; D008297:Male; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000633:toxicity*; D020258:Neurotoxicity Syndromes / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D051381:Rats; D012701:Serotonin / Q000378:metabolism*; D018490:Serotonin Agents / Q000633:toxicity*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D020230:Serotonin Syndrome / Q000378:metabolism; D013997:Time Factors
D002492:Central Nervous System Depressants; D004791:Enzyme Inhibitors; D018490:Serotonin Agents; D050486:Serotonin Plasma Membrane Transport Proteins; D012701:Serotonin; D017665:Hydroxyl Radical; D000431:Ethanol; D003484:Cyanamide; D000444:Aldehyde Dehydrogenase; D000079:Acetaldehyde; D018817:N-Methyl-3,4-methylenedioxyamphetamine