[Changes of the dopamine uptake sites in the rat striatum induced by repeated methamphetamine administration: a neurochemical approach to a mechanism of relapse in amphetamine psychosis].

We investigated the effects of repeated administrations of methamphetamine on the dopamine uptake sites in the rat striatum, by using an increasing dose paradigm of methamphetamine (2.5, 5, 7.5, 10 mg/kg sc x 2, every other day for a week) which has been established to produce behavioral sensitization in methamphetamine-induced behavior. A significant decrease in the Bmax value of [3H] GBR12935 binding and in the Vmax value of [3H] dopamine uptake was demonstrated in rats sacrificed 7 days after the final methamphetamine administration, and it was also shown that the Bmax value of [3H] GBR12935 binding was reduced in the dose dependent manner. Moreover, repeated administrations of methamphetamine significantly reduced the [3H] GBR12935 binding sites in the rat striatum even 30 days after the drug discontinuation. These data suggest that repeated administrations of methamphetamine induces a long lasting decrease of the dopamine uptake sites in the rat striatum. For an understanding of neurochemical basis of these findings, we investigated the effects of pharmacological manipulations in the presynaptic dopaminergic system by the pretreatment of alpha-methyl-p-tyrosine, reserpine or amfonelic acid and the blockade of postsynaptic dopamine receptor by a pretreatment of SCH23390 or YM-09151-2, on decrease in the dopamine uptake sites following the repeated administration of methamphetamine in the rat striatum. While pretreatment of alpha-methyl-p-tyrosine or amfonelic acid prevented a reduction in the dopamine uptake sites, pretreatment of reserpine accelerated this reduction. These data suggest that presynaptic newly synthesised dopamine plays an important role in the methamphetamine-induced decrease in the dopamine uptake sites. Pretreatment of SCH23390 or YM-09151-2 protected the dopamine uptake sites from reductive effect of repeated methamphetamine administration. Because there was no presynaptic dopaminergic mechanism understanding this result, some other neronal networks, which communicate with dopaminergic system, might make a reasonable explanation of this result.