title: Brain excitatory amino acid transporters (EAATs) and treatment of methamphetamine toxicity.
abstract: 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.
authors.affiliation: Department of Legal Medicine, Kyoto University Graduate School of Medicine, Faculty of Medicine, Yoshidakonoe-cho, Sakyo-ko, Kyoto 606-8501, Japan.
authors.forename: Tamaki
authors.initials: T
authors.lastname: Hayase
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Keiichi
authors.initials: K
authors.lastname: Yamamoto
mesh_terms: 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
chemical_list: 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