EFFECT OF D-AMPHETAMINE ON THE EXTRACELLULAR CONCENTRATIONS OF GLUTAMATE AND DOPAMINE IN IPRINDOLE-TREATED RATS

A single administration of D-amphetamine and iprindole has been report ed to produce selective, long-lasting decreases in brain dopamine (DA) content because of axon terminal degeneration. It has been found that the noncompetitive glutamate (GLU) antagonist, MK 801, blocks D-amphe tamine-induced DA depletion in iprindole-treated rats. In the present study, the effect Of D-amphetamine (9.2 mg/kg) and iprindole (10 mg/kg ) on the extracellular concentrations of DA and GLU was determined in the striatum of awake, freely moving rats by the use of in vivo microd ialysis. D-Amphetamine significantly increased DA and GLU efflux in th e striatum of iprindole-treated rats as compared to the vehicle-treate d group. The increase in the extracellular concentration of GLU occurr ed 4-6 hr following drug administration. The concentration of DA was d ecreased significantly in the striatum of D-amphetamine and iprindole- treated rats 7 days following administration as compared to the vehicl e-treated group. Inhibition of tyrosine hydroxylase after alpha-methyl paratyrosine (150 mg/kg) administration attenuated D-amphetamine-induc ed DA and GLU release. The DA antagonist, haloperidol (1 mg/kg), block ed D-amphetamine-induced GLU release without affecting the increase in the extracellular concentration of DA produced by the combination Of D-amphetamine and iprindole. Both alpha-methylparatyrosine and haloper idol blocked the depletion of DA in the striatum 7 days after D-amphet amine and iprindole as compared to the vehicle group. In addition, adm inistration of MK-801 (2 mg/kg) 2 hr after D-amphetamine significantly attenuated the long-term (7 day) decrease in striatal DA content prod uced by the combination Of D-amphetamine and iprindole. These data pro vide direct evidence that amphetamine increases the extracellular conc entration of GLU in iprindole-treated rats. Moreover, these data are s uggestive that the acute increase in GLU efflux contributes to the lon g-term damage to DA axon terminals produced by high dose amphetamine a dministration.