Effect of repeated treatment with high doses of selegiline on behaviour, striatal dopaminergic transmission and tyrosine hydroxylase mRNA levels.
The anti-parkinsonian drug selegiline is a monoamine oxidase B (MAO-B) inhibitor and a potential neuroprotective agent which facilitates dopaminergic transmission. Its metabolites (-)-amphetamine and (-)-metamphetamine might contribute to the pharmacological effects as they are also able to increase dopaminergic transmission and in addition might lead to behavioural sensitization after repeated administration. We investigated the effects of acute and repeated treatment with a high dose of selegiline on dopamine overflow in the striatum as well as on behaviour and on tyrosine hydroxylase (TH) mRNA levels in midbrain. Two experiments were performed. In the first one, rats were implanted with microdialysis probes into the striatum and received daily injections of selegiline (10 mg/kg, i.p.) for 1 or 8 days or a single dose of saline. In vivo microdialysis was carried out on days 1, 8 or 17 (after withdrawal of 9 days) to measure dopamine overflow. Motility was measured at the same time. In the second experiment, rats were injected daily with selegiline (10 mg/kg, i.p.) or saline over a time period of 6 weeks or only once before the brains were processed for in situ hybridization with a (35)S-radiolabelled probe for TH. Repeated treatment led to higher levels in motility scores than acute administration after administration of the same dose, indicating behavioural sensitization, which was still manifest after an interruption of 9 days in the supply of selegiline. In contrast, acute administration of selegiline increased dopamine levels to a similar degree as the same dose after subchronic treatment, with or without interruption of 9 days. The dopamine metabolite DOPAC was reduced by more than 50% after acute administration of selegiline and even more so on day 8 by the same dose, after repeated administration. The basal concentrations of dopamine (before challenge with selegiline) were not altered by the repeated administration, whereas the basal concentrations of DOPAC were decreased by more than 80% by the repeated administration of selegiline, suggesting a decrease in dopamine turnover. Acute administration did not have any influence on TH mRNA levels, whereas chronic treatment significantly reduced TH mRNA levels in substantia nigra and ventral tegmental area. In conclusion, repeated administration of selegiline leads to behavioural sensitization independent of altered dopamine levels. In addition, it leads to a decrease, probably due to a down-regulation, of dopamine turnover and tyrosine hydroxylase.
Themann
C
C
Institute of Pharmacology and Toxicology, Faculty of Pharmacy, University of Marburg, Ketzerbach 63, 35032 Marburg, Germany.
Alvarez Fischer
D
D
Gross
S
S
Westermann
R
R
Weihe
E
E
Kuschinsky
K
K
Schäfer
H
H
Ferger
B
B
D000818:Animals; D000978:Antiparkinson Agents / Q000008:administration & dosage*; D003342:Corpus Striatum / Q000187:drug effects* / Q000201:enzymology; D004298:Dopamine / Q000378:metabolism*; D004334:Drug Administration Schedule; D017403:In Situ Hybridization; D007274:Injections, Intraperitoneal; D008297:Male; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012642:Selegiline / Q000008:administration & dosage*; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism*
D000978:Antiparkinson Agents; D012333:RNA, Messenger; D012642:Selegiline; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine