Locomotor response to L-DOPA in reserpine-treated rats following central inhibition of aromatic L-amino acid decarboxylase: further evidence for non-dopaminergic actions of L-DOPA and its metabolites.
L-DOPA is the most widely used treatment for Parkinson's disease. The anti-parkinsonian and pro-dyskinetic actions of L-DOPA are widely attributed to its conversion, by the enzyme aromatic L-amino acid decarboxylase (AADC), to dopamine. We investigated the hypothesis that exogenous L-DOPA can induce behavioural effects without being converted to dopamine in the reserpine-treated rat-model of Parkinson's disease. A parkinsonian state was induced with reserpine (3 mg/kg s.c.). Eighteen hours later, the rats were administered L-DOPA plus the peripherally acting AADC inhibitor benserazide (25 mg/kg), with or without the centrally acting AADC inhibitor NSD1015 (100 mg/kg). L-DOPA/benserazide alone reversed reserpine-induced akinesia (4158+/-1125 activity counts/6 h, cf vehicle 1327+/-227). Addition of NSD1015 elicited hyperactive behaviour that was approximately 7-fold higher than L-DOPA/benserazide (35755+/-5226, P<0.001). The hyperactivity induced by L-DOPA and NSD1015 was reduced by the alpha(2C) antagonist rauwolscine (1 mg/kg) and the 5-HT(2C) agonist MK212 (5 mg/kg), but not by the D2 dopamine receptor antagonist remoxipride (3 mg/kg) or the D1 dopamine receptor antagonist SCH23390 (1 mg/kg). These data suggest that L-DOPA, or metabolites produced via routes not involving AADC, might be responsible for the generation of at least some L-DOPA actions in reserpine-treated rats.
Alachkar
Amal
A
Department of Pharmacology, Faculty of Pharmacy, University of Aleppo, Aleppo, Syria P.O. Box 8119, Syrian Arab Republic. a.alachkar@alepuniv.com
Brotchie
Jonathan M
JM
Jones
Owen T
OT
D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D065105:Aromatic Amino Acid Decarboxylase Inhibitors; D001142:Aromatic-L-Amino-Acid Decarboxylases / Q000378:metabolism*; D001545:Benserazide / Q000494:pharmacology; D001923:Brain Chemistry / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D015259:Dopamine Agents / Q000378:metabolism / Q000494:pharmacology; D004338:Drug Combinations; D004409:Dyskinesia, Drug-Induced / Q000201:enzymology* / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006834:Hydrazines / Q000494:pharmacology; D006948:Hyperkinesis / Q000139:chemically induced / Q000201:enzymology / Q000503:physiopathology; D007980:Levodopa / Q000378:metabolism* / Q000494:pharmacology*; D008297:Male; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012110:Reserpine / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology
D018759:Adrenergic Uptake Inhibitors; D000317:Adrenergic alpha-Antagonists; D065105:Aromatic Amino Acid Decarboxylase Inhibitors; D015259:Dopamine Agents; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D006834:Hydrazines; D017366:Serotonin Receptor Agonists; C005177:benserazide, levodopa drug combination; D007980:Levodopa; D001545:Benserazide; D012110:Reserpine; C004297:3-hydroxybenzylhydrazine; D001142:Aromatic-L-Amino-Acid Decarboxylases