title: Early increase in dopamine release in the ipsilateral striatum after unilateral intranigral administration of lactacystin produces spontaneous contralateral rotations in rats.
abstract: Since the discovery of the role of the ubiquitin-proteasome system (UPS) in the pathogenesis of Parkinson's disease, UPS inhibitors, such as lactacystin have been used to investigate the relationship between UPS impairment and degeneration of dopamine (DA) neurons. However, mostly long-term neurotoxic effects of lactacystin have been studied in animal models. Therefore, the aim of our study was to investigate behavioral and biochemical changes related to the DA system during the first week following unilateral intranigral injection of lactacystin to rats. We found that lactacystin produced early spontaneous contralateral rotations which were inhibited by combined administration of DA D1 and D2 receptor antagonists. Simultaneously, an increase in the extracellular level of DA and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanilic acid (HVA) was found in the ipsilateral striatum. In contrast, one week after lesion, when turning behavior was no longer visible, a decrease in the extracellular level of DA, DOPAC and HVA was demonstrated. It was accompanied by a substantial reduction in the tissue levels of DA and its metabolites in the lesioned substantia nigra and striatum. We concluded that unilateral intranigral administration of lactacystin produces an early increase in DA neurotransmission which precedes a decrease in the striatal and nigral tissue DA content. It is manifested by the appearance of spontaneous contralateral rotations and an elevation of the extracellular DA level in the ipsilateral striatum. Since similar behavior was previously observed after intranigral administration of rotenone and MPP(+) but not 6-hydroxydopamine (6-OHDA), it may indicate a common mechanism of action shared by these neurotoxins.
authors.affiliation: Department of Neuropsychopharmacology, Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Street, 31-343 Krakow, Poland. Electronic address: koniecz@if-pan.krakow.pl.
authors.forename: J
authors.initials: J
authors.lastname: Konieczny
authors.affiliation: Department of Neuropsychopharmacology, Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Street, 31-343 Krakow, Poland.
authors.forename: T
authors.initials: T
authors.lastname: Lenda
authors.affiliation: Department of Neuropsychopharmacology, Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Street, 31-343 Krakow, Poland.
authors.forename: A
authors.initials: A
authors.lastname: Czarnecka
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D002491:Central Nervous System Agents / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects* / Q000502:physiology; D004298:Dopamine / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000494:pharmacology; D007839:Functional Laterality / Q000187:drug effects* / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism; D006220:Haloperidol / Q000494:pharmacology; D006719:Homovanillic Acid / Q000378:metabolism; D008297:Male; D009068:Movement / Q000187:drug effects* / Q000502:physiology; D020734:Parkinsonian Disorders; D017208:Rats, Wistar; D011954:Receptors, Dopamine / Q000378:metabolism; D012399:Rotation; D013378:Substantia Nigra / Q000187:drug effects / Q000502:physiology
chemical_list: D001552:Benzazepines; D002491:Central Nervous System Agents; D018492:Dopamine Antagonists; D011954:Receptors, Dopamine; C534628:SCH 23390; D015102:3,4-Dihydroxyphenylacetic Acid; C067713:lactacystin; D018698:Glutamic Acid; D000661:Amphetamine; D006220:Haloperidol; D004298:Dopamine; D000111:Acetylcysteine; D006719:Homovanillic Acid
keywords: Parkinson’s disease; dopamine; lactacystin; microdialysis; rotational behavior; substantia nigra