The pharmacology of the acute hyperthermic response that follows administration of 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') to rats.
1. The pharmacology of the acute hyperthermia that follows 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') administration to rats has been investigated. 2. MDMA (12.5 mg kg(-1) i.p.) produced acute hyperthermia (measured rectally). The tail skin temperature did not increase, suggesting that MDMA may impair heat dissipation. 3. Pretreatment with the 5-HT(1/2) antagonist methysergide (10 mg kg(-1)), the 5-HT(2A) antagonist MDL 100,907 (0.1 mg kg(-1)) or the 5-HT(2C) antagonist SB 242084 (3 mg kg(-1)) failed to alter the hyperthermia. The 5-HT(2) antagonist ritanserin (1 mg kg(-1)) was without effect, but MDL 11,939 (5 mg kg(-1)) blocked the hyperthermia, possibly because of activity at non-serotonergic receptors. 4. The 5-HT uptake inhibitor zimeldine (10 mg kg(-1)) had no effect on MDMA-induced hyperthermia. The uptake inhibitor fluoxetine (10 mg kg(-1)) markedly attenuated the MDMA-induced increase in hippocampal extracellular 5-HT, also without altering hyperthermia. 5. The dopamine D(2) antagonist remoxipride (10 mg kg(-1)) did not alter MDMA-induced hyperthermia, but the D(1) antagonist SCH 23390 (0.3 - 2.0 mg kg(-1)) dose-dependently antagonized it. 6. The dopamine uptake inhibitor GBR 12909 (10 mg kg(-1)) did not alter the hyperthermic response and microdialysis demonstrated that it did not inhibit MDMA-induced striatal dopamine release. 7. These results demonstrate that in vivo MDMA-induced 5-HT release is inhibited by 5-HT uptake inhibitors, but MDMA-induced dopamine release may not be altered by a dopamine uptake inhibitor. 8. It is suggested that MDMA-induced hyperthermia results not from MDMA-induced 5-HT release, but rather from the increased release of dopamine that acts at D(1) receptors. This has implications for the clinical treatment of MDMA-induced hyperthermia.
Mechan
Annis O
AO
Pharmacology Research Group, School of Pharmacy, De Montfort University, The Gateway, Leicester LE1 9RH.
Esteban
Blanca
B
O'Shea
Esther
E
Elliott
J Martin
JM
Colado
M Isabel
MI
Green
A Richard
AR
D015104:3,4-Methylenedioxyamphetamine / Q000031:analogs & derivatives / Q000633:toxicity; D000208:Acute Disease; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D001831:Body Temperature / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D018492:Dopamine Antagonists / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D005334:Fever / Q000139:chemically induced*; D006213:Hallucinogens / Q000633:toxicity*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008784:Methysergide / Q000494:pharmacology; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000633:toxicity*; D018696:Neuroprotective Agents / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism; D017330:Remoxipride / Q000494:pharmacology; D016713:Ritanserin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology
D015104:3,4-Methylenedioxyamphetamine; D001552:Benzazepines; D004298:Dopamine; D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors; D006213:Hallucinogens; D008784:Methysergide; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D018696:Neuroprotective Agents; D010879:Piperazines; D010880:Piperidines; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin; D017330:Remoxipride; D016713:Ritanserin; D012702:Serotonin Antagonists; D017367:Selective Serotonin Reuptake Inhibitors; C066169:alpha-phenyl-1-(2-phenylethyl)-4-piperidinemethanol; C043425:vanoxerine