Clozapine reverses hyperthermia and sympathetically mediated cutaneous vasoconstriction induced by 3,4-methylenedioxymethamphetamine (ecstasy) in rabbits and rats.
Life-threatening hyperthermia occurs in some individuals taking 3,4-methylenedioxymethamphetamine (MDMA, ecstasy). In rabbits, sympathetically mediated vasoconstriction in heat-exchanging cutaneous beds (ear pinnae) contributes to MDMA-elicited hyperthermia. We investigated whether MDMA-elicited cutaneous vasoconstriction and hyperthermia are reversed by clozapine and olanzapine, atypical antipsychotic agents. Ear pinna blood flow and body temperature were measured in conscious rabbits; MDMA (6 mg/kg, i.v.) was administered; and clozapine (0.1-5 mg/kg, i.v.) or olanzapine (0.5 mg/kg, i.v.) was administered 15 min later. One hour after MDMA, temperature was 38.7 +/- 0.5 degrees C in 5 mg/kg clozapine-treated rabbits and 39.0 +/- 0.2 degrees C in olanzapine-treated rabbits, less than untreated animals (41.5 +/- 0.3 degrees C) and unchanged from pre-MDMA values. Ear pinna blood flow increased from the MDMA-induced near zero level within 5 min of clozapine or olanzapine administration. Clozapine-induced temperature and flow responses were dose-dependent. In urethane-anesthetized rabbits, MDMA (6 mg/kg, i.v.) increased ear pinna postganglionic sympathetic nerve discharge to 217 +/- 33% of the pre-MDMA baseline. Five minutes after clozapine (1 mg/kg, i.v.) discharge was reduced to 10 +/- 4% of the MDMA-elicited level. In conscious rats made hyperthermic by MDMA (10 mg/kg, s.c.), body temperature 1 hr after clozapine (3 mg/kg, s.c.) was 36.9 +/- 0.5 degrees C, <38.6 +/- 0.3 degrees C (Ringer's solution-treated) and not different from the pre-MDMA level. One hour after clozapine, rat tail blood flow was 24 +/- 3 cm/sec, greater than both flow in Ringer's solution-treated rats (8 +/- 1 cm/sec) and the pre-MDMA level (17 +/- 1 cm/sec). Clozapine and olanzapine, by interactions with 5-HT receptors or by other mechanisms, could reverse potentially fatal hyperthermia and cutaneous vasoconstriction occurring in some humans after ingestion of MDMA.
Blessing
W W
WW
Centre for Neuroscience, Department of Medicine, Flinders University, Bedford Park, South Australia 5042, Australia. w.w.blessing@flinders.edu.au
Seaman
B
B
Pedersen
N P
NP
Ootsuka
Y
Y
D000758:Anesthesia; D000818:Animals; D014150:Antipsychotic Agents / Q000627:therapeutic use; D001569:Benzodiazepines; D001831:Body Temperature / Q000187:drug effects; D003024:Clozapine / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004423:Ear / Q000098:blood supply; D005334:Fever / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D000077152:Olanzapine; D010890:Pirenzepine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000187:drug effects; D012702:Serotonin Antagonists / Q000627:therapeutic use; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use; D012867:Skin / Q000098:blood supply*; D013564:Sympathetic Nervous System / Q000187:drug effects* / Q000503:physiopathology; D013623:Tail / Q000098:blood supply; D016896:Treatment Outcome; D014661:Vasoconstriction / Q000187:drug effects*; D014851:Wakefulness
D014150:Antipsychotic Agents; D001569:Benzodiazepines; D003024:Clozapine; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D000077152:Olanzapine; D010890:Pirenzepine; D012702:Serotonin Antagonists; D017367:Selective Serotonin Reuptake Inhibitors