DIFFERENTIAL TOXIC EFFECTS OF METHAMPHETAMINE (METH) AND METHYLENEDIOXYMETHAMPHETAMINE (MDMA) IN MULTIDRUG-RESISTANT (MDR1A) KNOCKOUT MICE

The toxic effects of methamphetamine (METH) (2.5, 5.0 and 10.0 mg/kg) and methylenedioxymethamphetamine (MDMA) (5.0, 10.0 and 20.0 mg/kg) on dopaminergic systems were assessed in the striatum and of the nucleus accumbens in mdr1a wild-type and knockout mice. METH caused significa nt dose-dependent decreases of dopamine (DA) and DA transporters (DAT) in the striatum and the nucleus accumbens (NAc) of both wild-type and knockout mice. The lowest doses of METH (2.5 mg/kg) caused only small changes in the wild-type, but marked decreases in the mdr1a knockout mice. The two higher doses (5 mg/kg and 10 mg/kg) caused similar chang es in both strains of mice. In contrast to METH, MDMA caused greater p ercentage decreases in DAT in the wild-type mice. For example, the low est dose (5 mg/kg) caused significant decreases in DAT in the NAc of w ild-type but not of mdr1a knockout mice. The highest dose (20 mg/kg) c aused similar changes in both the strains. These results suggest that METH and MDMA interact differentially with P-glycoproteins. These obse rvations document, for the first time, a role for these proteins in th e entry of METH and MDMA into the brain via the blood-brain barrier, w ith P-glycoprotein possibly facilitating the entry of MDMA but interfe ring with that of METH into the brain. (C) 1997 Elsevier Science B.V.