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Nandrolone-induced hippocampal phosphorylation of NMDA receptor subunits and ERKs
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Biological Research on Drug Dependence.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Biological Research on Drug Dependence.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Biological Research on Drug Dependence.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. (Lindholm)
2007 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 357, no 4, 1028-1033 p.Article in journal (Refereed) Published
Abstract [en]

The age-related decline in gonadal steroids is associated with changes in mood and memory function. It appears that normal physiological concentrations of the steroids are required for adequate synaptic plasticity. However, the effects of high levels of androgens subsequent to misuse of anabolic androgenic steroids (AAS) are largely unknown. In this study, rats were given i.m. nandrolone as a single dose or daily for 14 days and the effects on synaptic components in hippocampal synaptoneurosomes were measured 24h after the last injection. Western blot analysis revealed that a single injection of AAS increased phosphorylation of the NMDA receptor subunits NR2A and NR2B and ERK1/2, while the levels of phosphorylated CaMKIIalpha were unaltered. No changes were seen in other synaptic proteins tested, i.e., BDNF, Arc, TUC-4, and beta-tubulin III. Daily administration of nandrolone for 2 weeks did not affect the content of any of the proteins tested. From this in vivo study, it is concluded that important synaptic components respond to a single high dose of nandrolone, an effect that may influence synapse function.

Place, publisher, year, edition, pages
2007. Vol. 357, no 4, 1028-1033 p.
Keyword [en]
Anabolic androgenic steroids, Nandrolone, Phosphorylation, ERK, NMDA receptor subunits, Hippocampus, Rat, Western blot
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-11166DOI: 10.1016/j.bbrc.2007.04.037ISI: 000246648400033PubMedID: 17451646OAI: oai:DiVA.org:uu-11166DiVA: diva2:38934
Available from: 2008-01-18 Created: 2008-01-18 Last updated: 2017-12-11Bibliographically approved
In thesis
1. The Impact of Drugs of Abuse on the Neuroproteome: Application of Immunoblotting and LC-MS-based Proteomics
Open this publication in new window or tab >>The Impact of Drugs of Abuse on the Neuroproteome: Application of Immunoblotting and LC-MS-based Proteomics
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Qualitative and quantitative analysis of proteins can be based either on immunological or on mass spectrometry-utilizing methods. In this thesis, different approaches of protein analysis were applied to elucidate the impact of drugs of abuse on the rat brain.

Androgens have been reported to affect mood, anxiety and memory function. The hippocampus plays an important role in memory formation, and studies have reported androgen-induced alteration in hippocampal dendritic spine density. The process of memory and learning requires synaptic plasticity, which depends on key components of signaling pathways, e.g. the ERK and the NMDA receptor. Often, misuse of anabolic androgenic steroids (AAS) leads to administration of supratherapeutical doses with partly unknown impact on the brain.

Rapid and subchronic effects of high AAS doses on proteins of a synapse-enriched rat hippocampal preparation (synaptoneurosomes) were investigated using the immunoblot technique and mass spectrometry. A single high dose of the AAS nandrolone decanoate was found to increase the in vivo phosphorylation of both NMDA receptor subunits and ERKs 24 h after administration. Subchronic treatment with multiple doses showed no effect. A subsequent study focused on rapid effects of the free nandrolone. The phosphorylation of the NMDA receptor subunit GluN2B and ERK1 was found diminished after 2 h and restored after 6 h. This suggests a biphasic impact of nandrolone on signaling components. Moreover, this study aimed to elucidate whether the effects were mediated via the androgen receptor (AR). The AR antagonist flutamide abolished AAS-induced effects. Determination of the CaMKIIα and ephrinB2 proteins, being a potential link of the analogous phosphorylation of NMDA receptor and ERK, could be excluded. Proteins involved in synaptogenesis were not found to be altered. A mass spectrometry-based study was conducted to screen for phosphoproteins and their potential alteration 2 h after a single dose of nandrolone. This analysis identified several proteins with known and not yet described phosphorylation sites. A differential analysis of the identified phosphoproteins was performed.

In a fourth study, quantitative MS-based peptidomics were applied to investigate endogenous neuropeptides in the mesolimbic system during morphine withdrawal. Moreover, strain-dependence was investigated. In accordance to earlier reports, comparable regulation was observed of proenkephalin-, prodynorphin- and preprotachykinin-derived neuropeptides levels.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2010. 67 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 121
Identifiers
urn:nbn:se:uu:diva-120303 (URN)978-91-554-7749-3 (ISBN)
Public defence
2010-04-28, B41, BMC, Husargatan 3, Uppsala, Sweden, 09:15 (English)
Opponent
Supervisors
Available from: 2010-04-06 Created: 2010-03-11 Last updated: 2011-05-05Bibliographically approved

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Rossbach, Uwe L. W.Le Grevès, Pierre

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