The central aromatic amino acid DOPA decarboxylase inhibitor, NSD-1015, does not inhibit L-DOPA-induced circling in unilateral 6-OHDA-lesioned-rats.
The centrally acting aromatic amino acid dopa decarboxylase (AADC) inhibitor, 3-hydroxybenzyl hydrazine (NSD-1015), is widely used to study the neurotransmitter-like actions of L-DOPA. However, the effects of NSD-1015 on L-DOPA-induced motor activity are unclear as both increases and decreases have been reported. We now investigate the effects of NSD-1015 on L-DOPA-induced contralateral circling behaviour in 6-OHDA-lesioned rats and on striatal levels of L-DOPA, 3-O-methyl-DOPA (3-OMD), dopamine, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) using microdialysis techniques. NSD-1015 (50-200 mg/kg i.p.) inhibited AADC activity both in the liver and striatum of normal rats. Administration of NSD-1015 (50-200 mg/kg i.p.), delayed the onset of circling produced by administration of L-DOPA (25 mg/kg i.p.) and carbidopa (12.5 mg/kg i. p.), suggesting blockade of central AADC activity. However, the duration of the L-DOPA-induced circling was prolonged and overall no inhibition of circling behaviour occurred. L-DOPA (25 mg/kg i.p.) plus carbidopa (12.5 mg/kg i.p.) increased extracellular levels of L-DOPA, 3-OMD, dopamine, DOPAC and HVA in the 6-OHDA-lesioned striatum. Pretreatment of rats with the central AADC inhibitor, NSD-1015 (100 mg/kg i.p.), potentiated the increase in dialysate levels of L-DOPA and 3-OMD. However, it did not reduce striatal dopamine levels in the 6-OHDA-lesioned hemisphere, which were elevated following L-DOPA administration. The increases in DOPAC and HVA levels were abolished by NSD-1015 pretreatment. These results suggest that, while NSD-1015 blocks central AADC activity, it also acts as a monoamine oxidase inhibitor so maintaining striatal dopamine concentration by reducing dopamine metabolism. NSD-1015, therefore, may not be an appropriate tool for the study of brain AADC activity and for assessing the neuromodulatory role of L-DOPA.
Treseder
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SA
Neurodegenenerative Disease Research Centre, Division of Pharmacology & Therapeutics, Guy's, King's and St Thomas' School of Biomedical Sciences, King's College, London, Guy's Campus, London, SE1 1UL, UK.
Rose
S
S
Jenner
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P
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D065105:Aromatic Amino Acid Decarboxylase Inhibitors; D001522:Behavior, Animal / Q000187:drug effects*; D015306:Biogenic Monoamines / Q000378:metabolism; D001921:Brain / Q000201:enzymology*; D003342:Corpus Striatum / Q000378:metabolism; D004295:Dihydroxyphenylalanine / Q000031:analogs & derivatives / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology; D004338:Drug Combinations; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006220:Haloperidol / Q000494:pharmacology; D006719:Homovanillic Acid / Q000378:metabolism; D006834:Hydrazines / Q000494:pharmacology*; D007980:Levodopa / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D008474:Medial Forebrain Bundle / Q000187:drug effects / Q000473:pathology; D016627:Oxidopamine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013239:Stereotyped Behavior / Q000187:drug effects*; D014443:Tyrosine / Q000031:analogs & derivatives
D065105:Aromatic Amino Acid Decarboxylase Inhibitors; D015306:Biogenic Monoamines; D015259:Dopamine Agents; D018492:Dopamine Antagonists; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D006834:Hydrazines; D015102:3,4-Dihydroxyphenylacetic Acid; D014443:Tyrosine; D007980:Levodopa; D004295:Dihydroxyphenylalanine; D016627:Oxidopamine; C004297:3-hydroxybenzylhydrazine; D006220:Haloperidol; C008404:3-methoxytyrosine; D004298:Dopamine; D006719:Homovanillic Acid