Impact of L-dopa on striatal acetylcholine release: effects of 6-hydroxydopamine.
We investigated the effects of the dopamine (DA) precursor L-dihydroxyphenylalanine (L-DOPA) on electrically evoked acetylcholine (ACh) overflow from rat striatal slices. Some animals were pretreated 1 to 2 months earlier with 6-hydroxydopamine, (6-OHDA), a catecholamine neurotoxin, so as to selectively destroy DA terminals (98.6% striatal DA depletion). Although the addition of L-DOPA (10 microM) produced a 37% inhibition of ACh overflow in slices from lesioned rats, it failed to affect ACh overflow in slices from intact animals. In contrast, ACh overflow from intact slices exposed to L-DOPA and to the DA uptake inhibitor nomifensine (1 microM) was 22% greater than in the presence of nomifensine without L-DOPA. ACh overflow from slices prepared from lesioned rats was 45% greater with both drugs than in the presence of nomifensine by itself. Superfusion with the aromatic L-amino acid decarboxylase (AADC) inhibitor NSD-1055 (250 microM) abolished the inhibitory effects of L-DOPA, as did L-sulpiride (1 microM), an inhibitor of DA receptors of the D2 subtype. These results suggest that inhibition of ACh overflow by L-DOPA is mediated by DA formed from exogenous L-DOPA which then acts on D2 receptors. They further indicate that the net impact of the loss of nigrostriatal terminals is an increased dopaminergic inhibition of striatal cholinergic interneurons in response to exogenous L-DOPA. This appears to result in large part from a lesion-induced reduction in high-affinity reuptake of DA formed from exogenous L-DOPA.
Jackson
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Department of Behavioral Neuroscience, University of Pittsburgh, Pennsylvania.
Abercrombie
E D
ED
Zigmond
M J
MJ
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism*; D004298:Dopamine / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology; D005110:Extracellular Space / Q000378:metabolism; D007980:Levodopa / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D009474:Neurons / Q000502:physiology; D009627:Nomifensine / Q000494:pharmacology; D016627:Oxidopamine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000502:physiology
D017448:Receptors, Dopamine D2; D015102:3,4-Dihydroxyphenylacetic Acid; D009627:Nomifensine; D007980:Levodopa; D016627:Oxidopamine; D000109:Acetylcholine; D004298:Dopamine