The effects of 2-deoxyglucose (2-DG), an inhibitor of the uptake and use of glucose, on ATP loss caused by the neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were determined in the mouse brain. 2-DG alone had no effect on brain ATP levels, but when administered 30 min before MPTP exposure, 2-DG significantly enhanced MPTP-induced ATP reduction. This was reflected as an increase in ATP loss in the striatum (from 15 to 27%) as well as a significant decrease in ATP in the cerebellar cortex, an area of the brain that was not affected after exposure to MPTP alone. In mice pretreated with 2-DG, striatal ATP levels remained significantly decreased for > 8 h after MPTP administration. In contrast, ATP levels in the cerebellar cortex returned to normal values within 4 h from MPTP exposure. Mazindol, a catecholamine uptake blocker, completely protected against MPTP-induced loss of striatal ATP in the absence of 2-DG, but it only partially prevented striatal ATP decrease after administration of both 2-DG and MPTP; mazindol was also ineffective in protecting against ATP loss caused by 2-DG and MPTP in the cerebellar cortex. 2-DG/MPTP-induced ATP loss appeared to be associated with the presence of the 1-methyl-4-phenylpyridinium (MPP+) metabolite because (1) the pattern of ATP recovery in the striatum and cerebellar cortex appeared to reflect the pattern of MPP+ clearance from these areas of the brain (i.e., significant MPP+ levels persisted longer in the striatum than in the cerebellar cortex), and (2) ATP decrease was completely prevented by blocking the conversion of MPTP to MPP+ with the monoamine oxidase B inhibitor deprenyl.(ABSTRACT TRUNCATED AT 250 WORDS)