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The Impact of Nandrolone Decanoate on Neuropeptidergic Mechanisms

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The Impact of Nandrolone Decanoate on Neuropeptidergic Mechanisms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å finns du här så självklar, Linnea – strålande och fin Livets spirande blomma, du underbara dotter min List of Papers included in the thesis This thesis is based on the following Papers, which are referred to in the text by their Roman numerals: I Magnusson, K., Hallberg, M., Kindlundh Högberg, AMS., Ny- berg, F. (2006) Administration of the anabolic androgenic ster- oid nandrolone decanoate affects substance P endopeptidase- like activity in the rat brain. Peptides, 27(1):114-21 II Magnusson, K., Hallberg, M., Bergquist, J., Nyberg, F. (2007) Enzymatic conversion of dynorphin A in the rat brain is af- fected by administration of nandrolone decanoate. Peptides, 28(4):851-8 III Magnusson, K., Birgner, C., Bergström, L., Nyberg, F., Hall- berg M. (2009) Nandrolone decanoate administration dose- dependently affects the density of kappa opioid peptide recep- tors in the rat brain determined by autoradiography. Neuropep- tides, 43(2):105-11 IV Magnusson, K., Hållner, A., Bazov, I., Clausen, F., Zhou, Q., Nyberg, F. Nandrolone decanoate administration elevates hip- pocampal prodynorphin mRNA expression and impairs Morris water maze performance in male rats. Submitted. Reprints are published with kind permission from Elsevier Ldt./Inc. List of additional Papers Hallberg, M., Magnusson, K., Kindlundh, AMS., Steensland, P., Nyberg, F. (2005) The effect of anabolic androgenic steroids on calcitonin gene-related peptide (CGRP) levels in the rat brain. PharmacologyOnline, 1:178-196 Lindblom, J., Petrovska, R., Hallberg, M., Magnusson, K., Nyberg, F., Uhlén, S. (2005) Nandrolone treatment decreases the α1B-adrenoceptor mRNA level in rat kidney cells. Eur J Pharmacol., 19:527(1-3) Sahlin, C., Lord, A., Magnusson, K., Englund, H., Almeida, CG., Greengard, P., Nyberg, F., Gouras, GK., Lannfelt, L., Nilsson, LN. (2007) The Arctic Alzheimer mutation favors intracellular amyloid-beta production by making amyloid precursor protein less available to alpha-secretase. J Neurochem., 101(3):854-62 Takahashi, K., Hallberg, M., Magnusson, K., Nyberg, F., Watanabe, Y., Långström, B., Bergström, M. (2007) Increase in [11C]vorozole binding to aromatase in the hypothalamus in rats treated with anabolic androgenic ster- oids. Neuroreport, 18(2):171-4 Contents Introduction...................................................................................................11 Anabolic androgenic steroids ...................................................................11 Definition.............................................................................................11 Use in society.......................................................................................11 Testosterone.........................................................................................12 Nandrolone ..........................................................................................13 Administration patterns .......................................................................14 Physiological aspects...........................................................................15 Psychological aspects ..........................................................................15 Pharmacological aspects......................................................................17 The Substance P system ...........................................................................18 The Dynorphinergic system .....................................................................19 The KOP receptor................................................................................20 Processing of neuropeptides.....................................................................20 Enzymatic conversion of Substance P.................................................21 Enzymatic conversion of Dynorphin A(1-17) .....................................22 Methodological aspects ............................................................................24 Radioimmunoassay..............................................................................24 Autoradiography..................................................................................24 Morris water maze ...............................................................................25 TaqMan? real-time polymerase chain reaction ...................................25 Aims..............................................................................................................26 Materials and methods ..................................................................................27 Experimental animal procedures..............................................................27 Enzyme activities .....................................................................................27 Tissue preparation................................................................................27 Assay for measurement of SPE-like activity .......................................27 Assay for measurement of DCE-like activity......................................28 HPLC characterization.........................................................................28 Mass spectrometry characterization.....................................................28 Radioimmunoassay ..................................................................................28 Autoradiography.......................................................................................29 Morris water maze....................................................................................29 RNA isolation and cDNA synthesis.........................................................30 ? TaqMan real-time polymerase chain reaction ........................................31 Statistics ...................................................................................................31 Results and discussion ..................................................................................32 Effects on Substance P conversion (Paper I)............................................32 Effects on Dynorphin A(1-17) conversion (Paper II)...............................34 Effects on the kappa opioid peptide receptor (Paper III) .........................35 Effects on Morris water maze performance (Paper IV) ...........................38 Effects on Prodynorphin gene transcription (Paper IV)...........................41 General considerations .............................................................................42 Nandrolone decanoate administration .................................................42 Summarizing conclusions .............................................................................43 Populärvetenskaplig sammanfattning ...........................................................45 Acknowledgements.......................................................................................47 References.....................................................................................................48 Abbreviations AAS Anabolic androgenic steroid ACE Angiotensin converting enzyme AD Alzheimer’s disease ANOVA Analysis of variance cAMP Cyclic adenosine 3’,5’ monophosphate cDNA Complementary deoxyribonucleic acid CNS Central nervous system CSF Cerebrospinal fluid Ct Threshold cycles DCE Dynorphin converting enzyme DHN Dihydronandrolone DHT Dihydrotestosterone DNA Deoxyribonucleic acid DOP Delta opioid peptide DSM IV Diagnostic and statistical manual of mental disorders, fourth edition Dyn A Dynorphin A(1-17) Dyn B Dynorphin B(1-13) EDTA Ethylenediaminetetraacetic acid FSH Follicle stimulating hormone GABA Gamma amino butyric acid hCG Human chorionic gonadotropin HDL High-density lipoprotein HPLC High performance liquid chromatography i.m. Intramuscular KOP Kappa opioid peptide LDL Low-density lipoprotein LH Luteinizing hormone MOP Mu opioid peptide mRNA Messenger ribonucleic acid MS Mass spectrometry MWM Morris water maze NEP Neutral endopeptidase NK Neurokinin NMDA N-methyl-D-aspartate PAG Periaqueductal gray PC Prohormone convertase PCR Polymerase chain reaction PDYN Prodynorphin RIA Radioimmunoassay RNA Ribonucleic acid s.c. Subcutaneous SEM Standard error of the mean SP Substance P SPE Substance P endopeptidase VTA Ventral tegmental area Introduction Anabolic androgenic steroids Definition “Anabolic androgenic steroids” (AAS) is the designation of the endogenous male sex hormone testosterone and synthetic derivatives of the same. Com- mon effects of all AAS are enhanced tissue building, i.e. anabolic effects, and the development and maintenance of male sexual characteristics, i.e., androgenic effects [1]. Use in society The general belief in today’s society is that the use of AAS is a problem mainly connected to athletes and bodybuilders.
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