Phenobarbital and dizocilpine can block methamphetamine-induced neurotoxicity in mice by mechanisms that are independent of thermoregulation.
Body temperature profiles observed during methamphetamine (METH) exposure are known to affect dopamine and tyrosine hydroxylase (TH) levels in the striatum of mice; hyperthermia potentiates depletion while hypothermia is protective against depletions. In the current study, the doses of METH were sufficiently great that significant dopamine and TH depletions occurred even though hypothermia occurred. Four doses, administered at 2 h intervals, of 15 mg/kg (4x15 mg/kg) D-METH significantly decreased TH and dopamine levels to 50% of control in mice becoming hypothermic during dosing in a 13 degrees C environment. Phenobarbital or dizocilpine during METH exposure blocked the depletions while diazepam did not. Phenobarbital and dizocilpine did not block depletions by altering the hypothermic profiles from that observed during METH only exposure. Here we show that phenobarbital and dizocilpine can block measures of METH neurotoxicity by non-thermoregulatory mechanisms.
Bowyer
J F
JF
Division of Neurotoxicology, National Center for Toxicological Research, Jefferson, AR 72079, USA. jbowyer@nctr.fda.gov
Holson
R R
RR
Miller
D B
DB
O'Callaghan
J P
JP
D000818:Animals; D001833:Body Temperature Regulation / Q000187:drug effects* / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000008:administration & dosage*; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents / Q000633:toxicity*; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage*; D008297:Male; D008694:Methamphetamine / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D010634:Phenobarbital / Q000008:administration & dosage*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D015259:Dopamine Agents; D018691:Excitatory Amino Acid Antagonists; D008694:Methamphetamine; D016291:Dizocilpine Maleate; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine; D010634:Phenobarbital