Brain excitatory amino acid transporters (EAATs) and treatment of methamphetamine toxicity.
Based on the phenomenon of the abnormally increased transport of brain excitatory amino acids induced by the increased release of dopamine (DA) in the brain, the effects of intraperitoneal L-trans-pyrrolidine-2,4-dicarboxylic acid (PDC), a non-selective excitatory amino acid transporter (EAAT) inhibitor, and (+/-)-threo-3-methylglutamic acid (MG), a specific EAAT2 inhibitor, were examined against methamphetamine (MA) and cocaine (COC) toxicity in mice. The MA (5 mg/kg)-increased activity counts, which included counts of both ambulatory and stereotyped behaviors, were attenuated by 10 and 20 mg/kg of PDC, but the COC (40 mg/kg)-increased activity counts were attenuated only by 20 mg/kg PDC. PDC (20 mg/kg) significantly attenuated both the mortality rate and the seizure score in acute MA (18 mg/kg) toxicity, but attenuated only the seizure score in acute COC (75 mg/kg) toxicity. PDC and MG (repeated doses of 5 and 10 mg/kg) attenuated the mortality rate (significant attenuation in the PDC group) and seizure score against repeated MA (12 mg/kg) toxicity, but had no effect on repeated COC (60 mg/kg) toxicity. Furthermore, MA (5 mg/kg) and COC (40 mg/kg) induced stressor-like and anxiogenic effects, the former of which were attenuated by PDC only (10 and 20 mg/kg in the MA group and 20 mg/kg in the COC group), and the latter of which were attenuated by both PDC and MG (for both drugs, 10 and 20 mg/kg in the MA group and 20 mg/kg in the COC group). Therefore, it was concluded that not only EAAT2 but also the other EAATs contributed to the occurrence of the MA-induced effects and part of the COC-induced effects, and that a non-selective EAAT inhibitor notably blocked the behavioral effects accompanying the MA-induced over-release of DA.
Hayase
Tamaki
T
Department of Legal Medicine, Kyoto University Graduate School of Medicine, Faculty of Medicine, Yoshidakonoe-cho, Sakyo-ko, Kyoto 606-8501, Japan.
Yamamoto
Yoshiko
Y
Yamamoto
Keiichi
K
D027322:Amino Acid Transport System X-AG / Q000037:antagonists & inhibitors* / Q000502:physiology*; D000818:Animals; D001007:Anxiety / Q000188:drug therapy; D001692:Biological Transport; D001921:Brain / Q000378:metabolism*; D003042:Cocaine / Q000633:toxicity; D003998:Dicarboxylic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D004298:Dopamine / Q000378:metabolism / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D018846:Excitatory Amino Acids / Q000378:metabolism*; D018698:Glutamic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D008694:Methamphetamine / Q000633:toxicity*; D051379:Mice; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000187:drug effects; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology* / Q000627:therapeutic use; D013239:Stereotyped Behavior / Q000187:drug effects; D013312:Stress, Physiological / Q000188:drug therapy
C425779:3-methylglutamic acid; D027322:Amino Acid Transport System X-AG; D003998:Dicarboxylic Acids; D018846:Excitatory Amino Acids; D014179:Neurotransmitter Uptake Inhibitors; D011759:Pyrrolidines; D018698:Glutamic Acid; D008694:Methamphetamine; C083486:pyrrolidine-2,4-dicarboxylic acid; D003042:Cocaine; D004298:Dopamine