3-methylglutamic-acid and pyrrolidine-2-4-dicarboxylic-acid

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.

Topics: Amino Acid Transport System X-AG; Animals; Anxiety; Biological Transport; Brain; Cocaine; Dicarboxylic Acids; Dopamine; Dose-Response Relationship, Drug; Excitatory Amino Acids; Glutamic Acid; Male; Methamphetamine; Mice; Mice, Inbred ICR; Motor Activity; Neurotransmitter Uptake Inhibitors; Pyrrolidines; Stereotyped Behavior; Stress, Physiological