Serotonergic activation after 2-week intrastriatal infusion of L-dopa and slow recovery of circling in rats with unilateral nigral lesions.
A unilateral 6-hydroxydopamine (6-OHDA)-lesioned rat model of Parkinson's disease was used to determine an effective dose to abolish circling behaviour of the continuous intrastriatal infusions of L-dopa via osmotic minipumps into the lesioned striatum. This 2-week L-dopa treatment evoked a dose-dependent decrease in the contralateral rotations induced by acute intraperitoneal L-dopa and carbidopa that was sustained at least for 10 weeks. The minimum effective dose of intrastriatal L-dopa was 3 microg/hr. Striatal [3H]-spiperone binding was significantly increased by the 6-OHDA lesion, reflecting a permanent, lesion-induced, up-regulation of dopamine D2 receptors. Furthermore, striatal dopamine and its metabolites as well as the level of tyrosine hydroxylase were significantly reduced by 6-OHDA. None of these parameters were restored by the 2-week L-dopa infusions but, unexpectedly, the rotational response did not become normalized after discontinuation of L-dopa infusions. Nigral 6-OHDA lesions suppressed ipsilateral striatal 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) concentrations, and 5-HT uptake sites while tryptophan hydroxylase was not changed in the striatum. When studying the cause of the sustained circling behaviour, we found that intrastriatal L-dopa infusion dose-dependently elevated striatal tryptophan hydroxylase much above the levels of intact side and 5-HT uptake sites to the level of intact side, but the striatal 5-HT levels exhibited no significant recovery while 5-HIAA levels were partially restored. These data support the view that a long-term ipsilateral activation of the serotonergic innervation occurs after L-dopa infusions into the lesioned striata.
Kääriäinen
Tiina M
TM
Department of Pharmacology and Toxicology, University of Kuopio, Kuopio, Finland. Tiina.Kaariainen@uku.fi
García-Horsman
J Arturo
JA
Piltonen
Marjo
M
Huotari
Marko
M
Männistö
Pekka T
PT
D000818:Animals; D000978:Antiparkinson Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D015918:Infusion Pumps, Implantable; D007980:Levodopa / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D016627:Oxidopamine; D010300:Parkinson Disease / Q000188:drug therapy*; D051381:Rats; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D013378:Substantia Nigra / Q000473:pathology; D014365:Tryptophan Hydroxylase / Q000187:drug effects / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D000978:Antiparkinson Agents; D017448:Receptors, Dopamine D2; D012701:Serotonin; D007980:Levodopa; D006897:Hydroxyindoleacetic Acid; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D014365:Tryptophan Hydroxylase; D004298:Dopamine