Altered dopamine and serotonin metabolism in the dopamine-denervated and serotonin-hyperinnervated neostriatum of adult rat after neonatal 6-hydroxydopamine.
3,4-Dihydroxyphenylalanine (L-DOPA), 5-hydroxy-l-tryptophan (5-HTP), dopamine (DA), 5-hydroxytryptamine (5-HT) and their metabolites were measured in the rostral neostriatum of adult rats neonatally lesioned with 6-hydroxydopamine (6-OHDA) after treatment with NSD-1015 (aromatic L-amino acid decarboxylase inhibitor), pargyline (monoamine oxidase inhibitor) or probenecid (blocker of acidic metabolite efflux). Binding experiments with DA and 5-HT transporter ligands allowed us to relate observed changes to the number of DA and 5-HT terminals. One and 3 months after the lesions were made, DA, 3,4-dihydroxyphenylacetic acid (DOPAC)- and homovanillic acid (HVA)-content as well as [3H]N-[1-(2-benzo(b)-thiophenyl)cyclohexyl]piperidine ([3H]BTCP) binding were lowered to 1% to 2% of control values, reflecting a permanent DA denervation. After 1 month, 5-HT content was increased by 96% and 5-hydroxyindole-3-acetic acid (5-HIAA) was increased by 50% in the presence of control levels of [3H]citalopram binding, suggesting that there was an increased amount of 5-HT per neostriatal 5-HT terminal. At 3 months, 5-HT content had increased by 205%, 5-HIAA remained increased by 50% and [3H]citalopram binding had reached 170% of control values, indicating a persistent increase in 5-HT content within an excessive number of 5-HT terminals (hyperinnervation). At both survival times, neostriatal L-DOPA accumulation after NSD-1015 was low, but ratios of L-DOPA to DA and of L-DOPA to [3H]BTCP were greatly elevated. 5-HTP accumulation was increased, but ratios of 5-HTP to 5-HT were lower than control, despite unchanged ratios of 5-HTP to [3H]citalopram.(ABSTRACT TRUNCATED AT 250 WORDS)
Molina-Holgado
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Département de Physiologie, Faculté de Médecine, Université de Montréal, Quebec, Canada.
Dewar
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Descarries
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Reader
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D000818:Animals; D000831:Animals, Newborn; D002352:Carrier Proteins / Q000378:metabolism; D003714:Denervation; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins; D005260:Female; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D026901:Membrane Transport Proteins; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism*; D009419:Nerve Tissue Proteins; D016627:Oxidopamine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins
D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D008996:Monoamine Oxidase Inhibitors; D009419:Nerve Tissue Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; C493232:Slc6a4 protein, rat; D012701:Serotonin; D016627:Oxidopamine; D004298:Dopamine