Naslov
CNS consequences of 5-LOX inhibition defficiency

Autori
Manev, R. ; Imbesi, M. ; Zavoreo, Iris ; Kurtuncu, M. ; Uz, T. ; Dimitrijevic, Nikola ; Manev, Hari

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
XXIVth CINP Congress: Chicago USA 9– 13 July 2006 The International Journal of Neuropsychopharmacology, Volume 9, Supplement S1, / - Chicago (IL) : Cambridge University Press, 2006, 128-128

Skup
XXIVth CINP Congress

Mjesto i datum
Chicago (IL), Sjedinjene Američke Države, 09.07.2006. - 13.07.2006

Vrsta sudjelovanja
Poster

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
5-LOX; inhibition; cocaine abuse

Sažetak
Statement of the study: 5-Lipoxygenase (5-LOX), an enzyme involved in the synthesis of leukotrienes, is typically considered in relation to its role in inflammation and atherosclerosis. Recent findings of behavioral alterations and reduced amyloid-related brain pathology in 5-LOX-deficient mice suggest a role for 5-LOX and its metabolites in brain functioning. Furthermore, it was suggested that pharmacological 5-LOX inhibition increases the phosphorylation of hippocampal GluR1 subunits of glutamate/AMPA receptors. This phosphorylation is crucial for the regulation of AMPA receptor membrane insertion and may contribute to the development of behavioral cocaine sensitization, which is associated with the increased surface expression of GluR1. The membrane insertion of GluR1 is influenced by the activity of extracellular signal-regulated kinase 1 and 2 (ERK1/2). ERK activation is typically assayed as an increased amount of phospho ERK1/2 proteins. Methods: In this study, we used primary cultures of mouse striatal neurons to investigate the effects of the 5-LOX inhibitor MK-886 on Glur1 and ERK phosphorylation and we used 5-LOX-deficient mice to investigate the consequences of a 5-LOX deficiency on the development of locomotor cocaine sensitization. Western blot assay revealed a significant increase of GluR1 phosphorylation after a 30 min incubation of cultures with MK-886 that had returned to control values by the end of 6 hours of treatment. In contrast, the same schedule of MK-886 treatment produced a significant reduction of ERK1 and ERK2 phosphorylation in 30 min, and these reduced phosphorylation values had returned to control levels by the end of 6-hour treatment. Cocaine hydrochloride (20 mg/kg) was administered intraperitoneally and locomotor activity was measured in automated mouse activity cages. Repeated injections of saline did not produce differential effects on the locomotor activity of wild-type or 5-LOX-deficient mice. In contrast, after the first cocaine injection, the increase in locomotor activity was already significantly greater in 5-LOX-deficient mice than in wild-type mice. This difference remained until the fourth injection. Conclusion: Since pharmacological inhibition of 5-LOX increased GluR1 phosphorylation, it is possible that the increased cocaine responsiveness observed in mice with a disrupted 5-LOX gene, is mediated by altered GluR1 functioning. Considering that 5-LOX gene polymorphism may cause significant functional consequences in humans, it would be interesting to investigate whether a 5-LOX polymorphism contributes to cocaine abuse.

Izvorni jezik
Engleski

Znanstvena područja
Kliničke medicinske znanosti

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