Effects of haloperidol and cocaine pretreatments on brain distribution and kinetics of [11C]methamphetamine in methamphetamine sensitized dog: application of PET to drug pharmacokinetic study.

Repeated administration of methamphetamine (MAP) causes behavioral sensitization in animals. We previously reported that the maximum accumulation level of [11C]MAP in the MAP-sensitized dog brain was 1.4 times higher than that in the control. In behavioral studies, haloperidol (a dopamine D2 receptor antagonist) prevents MAP-induced behavioral sensitization, and cocaine (a dopamine reuptake blocker) has the cross-behavioral sensitization with MAP. In the present study, to elucidate the relation between the MAP-induced behavioral sensitization and the pharmacokinetics of MAP, we investigated the effects of haloperidol and cocaine pretreatments on brain regional distribution and kinetics of [11C]MAP using positron emission tomography (PET). A significant increase of [11C]MAP uptake into the sensitized dog brain was prevented by haloperidol and cocaine pretreatments. These pharmacokinetic changes were not due to the changes in the rate of MAP metabolism. These results suggest haloperidol and cocaine can change the cerebral pharmacokinetic profile of MAP in the behavioral-sensitized dog. The variations of MAP-accumulation may affect the development or expression of MAP-induced behavioral sensitization.