|Budget Amount *help
¥2,100,000 (Direct Cost : ¥2,100,000)
Fiscal Year 1994 : ¥900,000 (Direct Cost : ¥900,000)
Fiscal Year 1993 : ¥1,200,000 (Direct Cost : ¥1,200,000)
A series of experiments was conducted to examine the role of glutamate in the behavioral and neurotoxic effects of methamphetamine (MA). Rats treated with MA accoding to an escalating dose schedule (2.5,5,7.5 and 10.0 mg/kg, sc, twice a day on days 1,3,5 and 7, respectively) indicated behavioral sensitization. Pretreatment with either a noncompetitive (MK-801,0.5 mg/kg, ip) or a competitive (D-CPP-ene, 20 mg/kg, ip) NMDA antagonist prior to MA administration prevented the development of behavioral sensitization.
On the other hand, rats treated with four injections of MA (5.0 or 7.5 mg/kg, sc, at 2 hr intervals) caused significant decrements (40-60% of control values) in levels of DA in the striatum and 5-HT in various brain regions. These decreases in DA and 5-HT were prevented by pretreatment with MK-801 or D-CPP-ene. Microdialysis studies revealed that the toxic dose of MA significantly increased levels of glutamate in the striatum.
Effects of Nitric Oxide (NO) syntase inhibition on MA-induced behavior and behavioral sensitization were also examined. Nw-nitro-L-arginine methyl ester, an inhibitor of NO synthase, significantly decreased the level of locomotion and stereotypy. In addition, the inhibitor reduced the degree of sensitization to sterotypy stimulating effect of MA.
These results suggest that the glutamatergic system plays an important role for MA-induced behavioral sensitization and neurotoxicity.