title: Decreased behavioral response to intranigrally administered GABAA agonist muscimol in the lactacystin model of Parkinson's disease may result from partial lesion of nigral non-dopamine neurons: comparison to the classical neurotoxin 6-OHDA.
abstract: Lactacystin is a selective UPS inhibitor recently used to destroy dopamine (DA) neurons in animal models of Parkinson's disease (PD). However, both in vitro and in vivo studies show discrepancies in terms of the sensitivity of non-DA neurons to its toxicity. Therefore, our study was aimed to examine the toxic effect of intranigral administration of lactacystin on DA and non-DA neurons in the rat substantia nigra (SN), compared to the classic neurotoxin 6-OHDA. Tissue DA levels in the striatum and SN and GABA levels in the SN were also examined. Moreover, behavioral response of nigral GABAA receptors to locally administered muscimol was evaluated in these two PD models. We found that both lactacystin and 6-OHDA induced a strong decrease in DA level in the lesioned striatum and SN but only lactacystin slightly reduced GABA levels in the SN. A stereological analysis showed that both neurotoxins highly decreased the number of DA neurons in the SN, while only lactacystin moderately reduced the number of non-DA ones. Finally, in the lactacystin group, the number of contralateral rotations after intranigrally administrated muscimol was decreased in contrast to the increased response in the 6-OHDA model. Our study proves that, although lactacystin is not a fully selective to DA neurons, these neurons are much more vulnerable to its toxicity. Partial lesion of nigral non-DA neurons in this model may explain the decreased behavioral response to the GABAA agonist muscimol.
authors: Department of Neuropsychopharmacology, Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Street, 31-343 Kraków, Poland. Electronic address: koniecz@if-pan.krakow.pl.
authors: Jolanta
authors: J
authors: Konieczny
authors: Department of Neuropsychopharmacology, Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Street, 31-343 Kraków, Poland.
authors: Anna
authors: A
authors: Czarnecka
authors: Department of Neuropsychopharmacology, Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Street, 31-343 Kraków, Poland.
authors: Kinga
authors: K
authors: Kamińska
authors: Department of Neuropsychopharmacology, Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Street, 31-343 Kraków, Poland.
authors: Tomasz
authors: T
authors: Lenda
authors: Department of Toxicology and Occupational Health Protection, Medical University of Silesia, 18 Medyków Street, 40-752 Katowice Ligota, Poland.
authors: Przemysław
authors: P
authors: Nowak
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000111:Acetylcysteine / Q000031:analogs & derivatives*; D000818:Animals; D002452:Cell Count; D003342:Corpus Striatum / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D004298:Dopamine / Q000031:analogs & derivatives / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D058785:GABA-A Receptor Agonists / Q000494:pharmacology*; D006719:Homovanillic Acid / Q000378:metabolism; D008124:Locomotion / Q000187:drug effects / Q000502:physiology; D008297:Male; D009118:Muscimol / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000473:pathology* / Q000502:physiology; D016627:Oxidopamine; D010300:Parkinson Disease; D020734:Parkinsonian Disorders / Q000473:pathology* / Q000503:physiopathology; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000378:metabolism; D013378:Substantia Nigra / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology
chemical_list: D058785:GABA-A Receptor Agonists; D011963:Receptors, GABA-A; D015102:3,4-Dihydroxyphenylacetic Acid; C067713:lactacystin; D009118:Muscimol; D016627:Oxidopamine; C001746:3-methoxytyramine; D004298:Dopamine; D000111:Acetylcysteine; D006719:Homovanillic Acid
keywords: 6-OHDA; Dopamine; GABA; Lactacystin; Muscimol; Substantia nigra