The effects of central aromatic amino acid DOPA decarboxylase inhibition on the motor actions of L-DOPA and dopamine agonists in MPTP-treated primates.
1. Endogenous L-DOPA may act as a neuromodulator contributing to the production of motor activity. We now investigate the effects of the centrally acting aromatic amino acid dopa decarboxylase (AADC) inhibitor NSD-1015 (3-hydroxybenzyl hydrazine) on the motor actions of L-DOPA and dopamine agonist drugs in MPTP treated common marmosets. 2. Pretreatment with NSD-1015 (10 - 50 mg kg(-1); i.p.) worsened baseline motor deficits in MPTP-treated common marmosets. Similarly, it abolished L-DOPA (5 - 18 mg kg(-1) s.c.) induced locomotor activity and reversal of disability. NSD-1015 pretreatment inhibited dopamine formation and elevated L-DOPA levels in plasma. 3. The increase in locomotor activity and improvement in disability produced by the administration of the D-1 agonist A-86929 (0.03 - 0. 04 mg kg(-1) s.c.) or the D-2 agonist quinpirole (0.05 - 0.3 mg kg(-1) i.p.) was abolished by NSD-1015 (25 mg kg(-1) i.p.) pretreatment. While the effects of a low dose combination of A-86929 (0.04 mg kg(-1) s.c.) and quinpirole (0.05 mg kg(-1) i.p.) were inhibited by NSD-1015 (25 mg kg(-1) i.p.), there was little effect on the action of a high dose combination of these drugs (0.08 mg kg(-1) A-86929 and 0.1 mg kg(-1) quinpirole). 4. Following central AADC inhibition with NSD-1015 (25 mg kg(-1) i.p.), locomotor behaviour induced by administration of high dose combinations of A-86929 (0.08 mg kg(-1) s.c.) and quinpirole (0.1 mg kg(-1) i.p.) was unaffected by L-DOPA (5 mg kg(-1) s.c.) pretreatment. 5. These results do not support a role for endogenous L-DOPA in spontaneous or drug induced locomotor activity. Rather, they strengthen the argument for the importance of endogenous dopaminergic tone in the motor actions of dopamine agonists.
Treseder
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Neurodegenerative Disease Research Centre, Hodgkin Building, Division of Pharmacology & Therapeutics, Guy's, King's and St Thomas' School of Biomedical Sciences, King's College, London, SE1 1UL, UK.
Jackson
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Jenner
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D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology*; D015102:3,4-Dihydroxyphenylacetic Acid / Q000097:blood; D000818:Animals; D065105:Aromatic Amino Acid Decarboxylase Inhibitors; D001522:Behavior, Animal / Q000187:drug effects; D002144:Callithrix; D004298:Dopamine / Q000097:blood; D018491:Dopamine Agonists / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006834:Hydrazines / Q000494:pharmacology*; D007980:Levodopa / Q000097:blood / Q000494:pharmacology*; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D015363:Quinolones / Q000494:pharmacology; D019257:Quinpirole / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology; D014443:Tyrosine / Q000031:analogs & derivatives / Q000097:blood / Q000187:drug effects
D065105:Aromatic Amino Acid Decarboxylase Inhibitors; D018491:Dopamine Agonists; D004791:Enzyme Inhibitors; D006834:Hydrazines; D015363:Quinolones; D013876:Thiophenes; D015102:3,4-Dihydroxyphenylacetic Acid; D019257:Quinpirole; D014443:Tyrosine; D007980:Levodopa; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; C004297:3-hydroxybenzylhydrazine; C095427:A 86929; C008404:3-methoxytyrosine; D004298:Dopamine