Mithramycin protects against dopaminergic neurotoxicity in the mouse brain after administration of methamphetamine.
The present study was undertaken to examine the effects of mithramycin, an inhibitor of transcription factor Specificity protein (Sp)-1, on the behavioral changes and dopaminergic neurotoxicity in the mouse striatum after administration of methamphetamine (METH). Pretreatment with mithramycin (75, 150 or 300 microg/kg) did not alter acute hyperlocomotion in mice after a single administration of METH (3 mg/kg). However, the development of behavioral sensitization in mice after repeated administration of METH (3 mg/kg/day, once daily for 5 days) was significantly blocked by pretreatment with mithramycin (300 microg/kg). Furthermore, pretreatment with mithramycin (300 microg/kg) significantly attenuated the hyperthermia in mice after repeated administration of METH (3 mg/kgx3, 3-h intervals). Moreover, the combination of pretreatment and subsequent administration of mithramycin (75, 150 or 300 microg/kg) significantly attenuated the reductions of dopamine (DA), its major metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) and DA transporter (DAT) in the striatum after repeated administration of METH (3 mg/kgx3, 3-h intervals), and these attenuations were dose dependent. These findings suggest that mithramycin attenuates the development of behavioral sensitization and dopaminergic neurotoxicity in mice after repeated administration of METH. Therefore, mithramycin could have potential for the treatment of METH abusers, particularly since this drug has been approved by the Food and Drug Administration in the United States. In the future, however, another Sp1 inhibitors with fewer side effects might be more appropriate.
Hagiwara
Hiroko
H
Chiba University Center for Forensic Mental Health, Inohana, Japan.
Iyo
Masaomi
M
Hashimoto
Kenji
K
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005334:Fever / Q000139:chemically induced / Q000517:prevention & control; D006948:Hyperkinesis / Q000139:chemically induced / Q000517:prevention & control; D007150:Immunohistochemistry; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology*; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D018696:Neuroprotective Agents / Q000008:administration & dosage; D008926:Plicamycin / Q000008:administration & dosage*; D011500:Protein Synthesis Inhibitors / Q000008:administration & dosage
D050483:Dopamine Plasma Membrane Transport Proteins; D018696:Neuroprotective Agents; D011500:Protein Synthesis Inhibitors; D015102:3,4-Dihydroxyphenylacetic Acid; D008694:Methamphetamine; D008926:Plicamycin; D004298:Dopamine