Rapid and differential losses of in vivo dopamine transporter (DAT) and vesicular monoamine transporter (VMAT2) radioligand binding in MPTP-treated mice

The dose- and time-dependent changes of in vivo radioligand binding to the neuronal membrane dopamine transporter (DAT) and vesicular monoamine transp orter type 2 (VMAT2) were examined in mouse brain after MPTP( 1-methyl-4-ph enyl-1,2,3,6-tetrahydropyridine) administrations. Regional brain distributi on studies were done in male C57BL/6 mice using simultaneous injections of d-threo-[H-3]methylphenidate (DAT) and (+)-alpha-[C-11]dihydrotetrabenazine (VMAT2). Single (55 mg/kg i.p.) or multiple (4 x 10 mg/kg i.p., I-hour int ervals) administration of MPTP caused significant reductions in [3H]methylp henidate and [C-11] dihydrotetrabenazine specific striatal binding, measure d 14 days later. The single high dose of MPTP produced greater losses of [C -11]dihydrotetrabenazine binding than did the multiple MPTP dosing regimen. Using the single high dose of R MPTP, changes of in vivo binding of the tw o radioligands were determined at 1, 3, and 14 days after neurotoxin inject ion. At 1 day, there are large losses of [H-3] methylphenidate binding (DAT ) but no changes in [C-11] dihydrotetrabenazine binding to the VMAT2 site i n the striatum. At 3 and 14 days, there were >50% losses of binding of both bot radioligands, but significantly (P < 0.001) greater losses of VMAT2 bi nding of [11C]dihydrotetrabenazine. These studies indicate that the losses of the neuronal membrane and vesicular transporters are not always equal, a nd do not occur in the same time frame? after administration of the neuroto xin MPTP. (C) 2000 Wiley-Liss, Inc.