Methamphetamine-induced spectrin proteolysis in the rat striatum.
Methamphetamine (METH) is a widely abused psychostimulant. Multiple high doses of METH cause long-term toxicity to dopamine (DA) and serotonin (5-HT) nerve terminals in the brain, as evidenced by decreases in DA and 5-HT content, decreases in tyrosine and tryptophan hydroxylase activities, decreases in DA and 5-HT re-uptake sites, and nerve terminal degeneration. Multiple high doses of METH are known to elicit a rapid increase in DA release and hyperthermia. Although METH also produces a delayed and sustained rise in glutamate, no studies have shown whether METH produces structural evidence of excitotoxicity in striatum, or identified the receptors that mediate this toxicity directly, independent of alterations in METH-induced hyperthermia. These experiments investigated whether METH can cause excitotoxicity as evidenced by cytoskeletal protein breakdown in a glutamate receptor-dependent manner. METH increased calpain-mediated spectrin proteolysis in the rat striatum 5 and 7 days after METH administration without affecting caspase 3-dependent spectrin breakdown. This effect was completely blocked with the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, GYKI 52466, but not the NMDA receptor antagonist, MK-801. However, AMPA or NMDA receptor antagonism did not attenuate the METH-induced depletions of the dopamine transporter (DAT). Independent mechanisms involved in mediating spectrin proteolysis and DAT protein loss are discussed.
Staszewski
Robert D
RD
Laboratory of Neurochemistry, Department of Pharmacology, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Yamamoto
Bryan K
BK
D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology; D015153:Blotting, Western / Q000379:methods; D001831:Body Temperature / Q000187:drug effects; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D004347:Drug Interactions; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology*; D008970:Molecular Weight; D051381:Rats; D017207:Rats, Sprague-Dawley; D013049:Spectrin / Q000378:metabolism*; D013997:Time Factors
D000697:Central Nervous System Stimulants; D050483:Dopamine Plasma Membrane Transport Proteins; D018691:Excitatory Amino Acid Antagonists; C061950:GYKI 52466; D013049:Spectrin; D001569:Benzodiazepines; D008694:Methamphetamine