L-DOPA exacerbates amphetamine-induced dopamine depletion.
Administration of L-DOPA to Parkinson patients has been suggested to exacerbate "functional denervation" of the nigrostriatal system. Therefore, experiments were conducted to determine if L-DOPA combined with the DOPA decarboxylase inhibitor, Ro4-4602 (benserazide hydrochloride) would potentiate amphetamine-induced neurotoxicity. Mice received two injections of saline or benserazide + L-DOPA (25.0 or 100.0 mg/kg) interspersed with four injections of amphetamine (15.0 mg/kg) at 2-h intervals. Significant depletion of striatal dopamine, DOPAC, and HVA was evident 1 wk following amphetamine administered with or without 25.0 mg/kg L-DOPA + benserazide, whereas 100.0 mg/kg L-DOPA + benserazide potentiated amphetamine-induced depletion of striatal dopamine (17 vs 28% of control values). This enhanced toxicity may be consequent to increased dopamine turnover following L-DOPA (360 vs 231%), a situation akin to that observed in compromised dopaminergic nigrostriatal systems of parkinsonian patients. Furthermore, striatal 5-HT was not altered by amphetamine alone, whereas concurrent administration of L-DOPA/ benserazide depleted 5-HT to 82% of control values. No changes were evident in the frontal cortex following amphetamine with or without concurrent L-DOPA/benserazide; however, L-DOPA/benserazide administered alone reduced 5-HT and 5-HT turnover to 58% of control values.
Myers
C S
CS
Psychology Department, Rutgers University, New Brunswick, NJ 08903, USA.
Witten
M
M
Yu
Y L
YL
Wagner
G C
GC
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D065105:Aromatic Amino Acid Decarboxylase Inhibitors; D001545:Benserazide / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D003342:Corpus Striatum / Q000378:metabolism; D003913:Dextroamphetamine / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D004357:Drug Synergism; D005625:Frontal Lobe / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D006719:Homovanillic Acid / Q000378:metabolism; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D007980:Levodopa / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009928:Organ Specificity; D012701:Serotonin / Q000378:metabolism
D065105:Aromatic Amino Acid Decarboxylase Inhibitors; D015102:3,4-Dihydroxyphenylacetic Acid; D012701:Serotonin; D007980:Levodopa; D006897:Hydroxyindoleacetic Acid; D001545:Benserazide; D003913:Dextroamphetamine; D004298:Dopamine; D006719:Homovanillic Acid