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Acute 19-nortestosterone transiently suppresses hippocampal MAPK pathway and the phosphorylation of the NMDA receptor
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
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2010 (English)In: Molecular and Cellular Endocrinology, ISSN 0303-7207, E-ISSN 1872-8057, Vol. 314, no 1, 143-149 p.Article in journal (Refereed) Published
Abstract [en]

High doses of anabolic androgenic steroid are associated with changes in personality, e.g. increased aggression and irritability, behavioural changes that may be linked to structural changes in the hippocampus. In this in vivo study we demonstrate acute effects of a single injection of 19-nortestosterone on proteins that play a major role in molecular plasticity at synaptic connections. The steroid rapidly and transiently decreased total and phosphorylated NMDA receptor GluN2B subunit levels and phosphorylated extracellular signal-regulated kinase 1 in rat hippocampal synaptoneurosomes. Pretreatment with the androgen receptor antagonist flutamide prevented these effects suggesting an androgen receptor mediated mode of action. However, flutamide alone stimulated the phosphorylation of both extracellular signal-regulated kinase 1 and 2. EphrinB2 and phosphorylated translation initiation factor 4E, two proteins that act on synaptic plasticity through NMDA receptor and/or mitogen-activated protein kinase pathways, were not affected by any of the treatment regimens. This study demonstrates rapid in vivo effects of an anabolic androgenic steroid on two key elements in hippocampal synaptic plasticity.

Place, publisher, year, edition, pages
Ireland: Elsevier , 2010. Vol. 314, no 1, 143-149 p.
Keyword [en]
Anabolic androgenic steroids, Phosphorylation, ERK, NMDA receptor, Hippocampus, Synaptoneurosomes
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-120301DOI: 10.1016/j.mce.2009.07.027ISI: 000272101700017OAI: oai:DiVA.org:uu-120301DiVA: diva2:303087
Available from: 2010-03-11 Created: 2010-03-11 Last updated: 2017-12-12Bibliographically 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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