Lasting alterations in drug biodistribution in the animal brain regions after repeated administration of methamphetamine or cocaine

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In animals, a long-term behavioral sensitization to methamphetamine (MAP) has been confirmed after chronic MAP (reverse tolerance phenomenon). To date, it is suggested that lasting enhancemnt of MAP-induced increase in dopamine (DA) release in the striatum and nucleus accumbens relates to induction and manifestation of the brain vulnerability to psychotic relapses. According to the exchange diffusion model (Fischer and Cho, 1979) regarding the MAP-induced release of DA at nerve terminals, it seems possible to provide a working hypothesis that that subchronic MAP administration may produce an enduring change at the presynaptic cell membrane of the nerve terminal, which may in turn cause an increase in MAP uptake (by DA transporter) with a subsequent increase in DA release to the synaptic cleft. To confirm this hypothesis, we examined the changes in biodistribution of [^<125>I]RTI 55 (an analogue of cocaine) in the MAP-, and cocaine-sensitized rat brain. In MAP-sensitized rat, radioactivity of [^<125>I]RTI 55 increased significantly more in the frontal cortex, striatum, nucleus accumbens, thalamus, amygdala, hippocampus, ventral tegmental area, substantia nigra, cerebellum and pons. In cocaine-sensitized rat, radioactivity of [^<125>I]RTI 55 decreased significantly more in the same brain area. [^<123>I]IMP study showed these changes not due to alterations in metabolism or cerebral blood flow. Dopamine transporter has a structure similar to those of the other monoamine transporters. It seems possible that MAP and cocaine may bind to the 5-HT and noradrenaline transporters as well as DA transporter. Accordingly, it is concluded that subchronic administration of MAP or cocaine may cause a lasting change at the presynaptic cell membrane (including monoamine transporters) of the nerve terminal, though the direction of the changes of MAP- and cocaine-sensitized rats were controversial. This study comfirmed the hypothesis which lsubchronic MAP and cocain