[Effects of antagonists of NMDA receptor on methamphetamine-induced decrease in the dopamine uptake sites in the rat...

In humans, repeated use of methamphetamine produces hypersensitivity to the psychotogenic effects of methamphetamine that persists for months to years after the discontinuation of methamphetamine administration. Methamphetamine-induced psychosis has been thought to be a useful experimental model for schizophrenia. A possible involvement of the glutamate system in the hypersensitivity including behavioral sensitization or reverse tolerance is recognized in an animal model for methamphetamine psychosis. We investigated the effects of antagonists of N-methyl-D-aspartate (NMDA) receptor on methamphetamine-induced decrease in dopamine (DA) uptake sites in the rat striatum and on the behavioral sensitization. Repeated administrations of escalating doses of methamphetamine (2.5, 5, 7.5, 10mg/kg s. c. x 2, every other day for a week) decreased DA uptake sites to about 75% of the control in the striatum assayed by binding with [3H]GBR 12935. Co-administration of MK-801, a non-competitive antagonist of NMDA receptor, and methamphetamine significantly prevented the methamphetamine-induced decrease in striatal [3H]GBR 12935 binding in a dose dependent manner. Administration of MK-801 alone did not affect the [3H]GBR 12935 binding. Furthermore, co-administration of SDZ EAA494, a competitive antagonist of NMDA receptor, and methamphetamine also prevented the methamphetamine-induced decrease in the striatal [3H]GBR 12935 binding in a dose dependent manner. In methamphetamine-pretreated rats, the methamphetamine challenge (2.5mg/kg) after a 7-day-drug-free period produced an initial elevation in locomotion lasting for 10-30 min which was followed by a precipitous drop in the locomotion activity to very low levels for approximately 50-70 min. During the period of reduced locomotor activity, methamphetamine-pretreated rats showed intense focused stereotyped behavior. In contrast, animals treated with both MK-801 and methamphetamine showed neither the progressive enhancement of the locomotor activity nor the stereotyped behavior induced by the drug. Pretreatment with MK-801 blocked the development of the methamphetamine-induced behavioral sensitization. These results suggest an involvement of excitatory amino acids in neurochemical effects of methamphetamine on the dopamine system in the striatum.