The significance of rotational behavior and sensitivity of striatal dopamine receptors in hemiparkinsonian rats: A comparative study of lactacystin and 6-OHDA.
A growing body of evidence indicates that impairment of the ubiquitin-proteasome (UPS) system in the substantia nigra (SN) plays an important role in the pathogenesis of Parkinson's disease (PD). The aim of our study was to compare two unilateral rat models, one produced by intranigral administration of the UPS inhibitor lactacystin or the other induced by 6-OHDA, in terms of their effect on the amphetamine- and apomorphine-induced rotational behavior, striatal dopamine (DA) D1 and D2 receptor sensitivity and tissue levels of DA and its metabolites. We found that these models did not differ in the intensity of ipsilateral rotations induced by amphetamine. In contrast, apomorphine produced contralateral rotations only in 6-OHDA-lesioned rats, and, depending on the dose, it induced either no or moderate ipsilateral rotations in the lactacystin-lesioned group. In addition, lactacystin induced a strong reduction in the tissue DA level and its metabolites in the lesioned striatum and SN when measured three weeks after the administration which was aggravated six weeks post-lesion, reaching the level comparable to the 6-OHDA group. Binding of [3H]raclopride to D2 receptors was increased in the lesioned striatum in both investigated (PD) models six weeks after lesion. In turn, binding of [3H]SCH23390 to the striatal D1 receptors was not changed in the lactacystin group but was increased bilaterally in the 6-OHDA group. The present results add a new value to the study of DA receptor sensitivity and are discussed in the context of the validity of the lactacystin model as a suitable model of Parkinson's disease.
Institute of Pharmacology, Polish Academy of Sciences, Department of Neuropsychopharmacology, 31-343 Kraków, Smętna Street 12, Poland. Electronic address: koniecz@if-pan.krakow.pl.
Jolanta
J
Konieczny
Institute of Pharmacology, Polish Academy of Sciences, Department of Neuropsychopharmacology, 31-343 Kraków, Smętna Street 12, Poland.
Anna
A
Czarnecka
Institute of Pharmacology, Polish Academy of Sciences, Department of Neuropsychopharmacology, 31-343 Kraków, Smętna Street 12, Poland.
Tomasz
T
Lenda
Institute of Pharmacology, Polish Academy of Sciences, Department of Neuropsychopharmacology, 31-343 Kraków, Smętna Street 12, Poland.
Kinga
K
Kamińska
Institute of Pharmacology, Polish Academy of Sciences, Department of Neurochemistry, 31-343 Kraków, Smętna Street 12, Poland.
Lucyna
L
Antkiewicz-Michaluk
D000111:Acetylcysteine / Q000031:analogs & derivatives; D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D001552:Benzazepines / Q000494:pharmacology; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D007839:Functional Laterality / Q000502:physiology; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology*; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000378:metabolism*; D065842:Pars Compacta / Q000187:drug effects / Q000378:metabolism*; D020891:Raclopride / Q000494:pharmacology; D017208:Rats, Wistar; D017447:Receptors, Dopamine D1 / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D012399:Rotation
D001552:Benzazepines; D000697:Central Nervous System Stimulants; C000607792:DRD2 protein, rat; D015259:Dopamine Agents; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; C534628:SCH 23390; C067713:lactacystin; D020891:Raclopride; D016627:Oxidopamine; D000661:Amphetamine; D001058:Apomorphine; D004298:Dopamine; D000111:Acetylcysteine
6-OHDA; amphetamine; apomorphine; dopamine receptors; lactacystin; rotational behavior