Mild uncoupling of oxidative phosphorylation has been reported to reduce generation of
reactive oxygen species (ROS) and therefore may be neuroprotective. We reported previously that the mitochondrial
poison rotenone enhanced currents evoked by
N-methyl-D-aspartate (
NMDA) by a ROS-dependent mechanism in rat midbrain dopamine neurons. Thus,
rotenone, which produces a model of
Parkinson's disease in rodents, may increase the risk of dopamine neuron excitotoxicity. The purpose of this study was to test the hypothesis that oxidative phosphorylation
uncoupling agents would antagonize the effect of
rotenone on
NMDA current. We used patch pipettes to record whole-cell currents under voltage-clamp (-60 mV) in substantia nigra dopamine neurons in slices of rat brain.
Rotenone,
NMDA and
uncoupling agents were added to the brain slice superfusate. Inward currents evoked by
NMDA (30 μM) more than doubled in amplitude after slices were superfused for 30 min with 100 nM
rotenone. Continuous superfusion with the uncoupling agent
carbonyl cyanide-p-trifluoromethoxy-
phenylhydrazone (1-3 nM) or
2,4-dinitrophenol (100 nM) significantly antagonized and delayed the ability of
rotenone to potentiate
NMDA currents.
Coenzyme Q₁₀ (1-10 nM), which has been reported to facilitate
uncoupling protein activity, also antagonized this action of
rotenone. These results suggest that mild uncoupling of oxidative phosphorylation may protect dopamine neurons against injury from mitochondrial
poisons such as
rotenone.