Rotenone potentiates NMDA currents in substantia nigra dopamine neurons.
Rotenone is a pesticide that produces a rodent model of Parkinson's disease. Although much evidence suggests that oxidative stress mediates the toxicity of rotenone on dopamine neurons, rotenone can also potentiate glutamate excitotoxicity. We used whole-cell patch pipettes to investigate actions of rotenone on currents evoked by N-methyl-d-aspartate (NMDA) in dopamine neurons in slices of rat midbrain. After superfusing the slice for 20-30 min, rotenone (100 nM) caused a 162% increase in the average amplitude of inward current evoked by 30 microM NMDA. This effect of rotenone was mimicked by the sodium pump inhibitor strophanthidin (10 microM) and was abolished when pipettes contained an ATP regeneration solution. Although strophanthidin also significantly increased the amplitude of inward currents evoked by (+/-)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA; 10 microM), rotenone failed to potentiate AMPA currents. Because rotenone potentiated NMDA- but not AMPA-dependent currents, this suggests that rotenone acts selectively to augment NMDA receptor function. Furthermore, the failure of rotenone to mimic strophanthidin suggests that rotenone does not inhibit sodium pump activity. Our results suggest that an excitotoxic mechanism might contribute to rotenone neurotoxicity.
Wu
Yan-Na
YN
Department of Neurology, Oregon Health & Science University, Portland, OR 97239, USA.
Johnson
Steven W
SW
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000528:radiation effects; D016202:N-Methylaspartate / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects*; D018408:Patch-Clamp Techniques / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D012402:Rotenone / Q000494:pharmacology*; D013327:Strophanthidin / Q000494:pharmacology; D013378:Substantia Nigra / Q000166:cytology*; D014475:Uncoupling Agents / Q000494:pharmacology*; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
D018690:Excitatory Amino Acid Agonists; D014475:Uncoupling Agents; D012402:Rotenone; D016202:N-Methylaspartate; D013327:Strophanthidin; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid