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Anabolic androgenic steroids and central monoaminergic systems: Supratherapeutic doses of nandrolone decanoate affect dopamine and serotonin
Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Supratherapeutic doses of anabolic androgenic steroids (AASs) are administered, not only as performance-enhancing drugs in the world of sports, but also in order to modify behaviour. AAS abusers are at risk of developing serious physical and psychological side effects such as dependence and aggressive behaviour. The aim of this thesis was to investigate the impact of supratherapeutic doses of nandrolone decanoate after subchronic administration on dopamine and serotonin pathways involved in drug dependence and aggression, in the male rat brain.

Adult male Sprague-Dawley rats received intramuscular injections of nandrolone decanoate (3 or 15 mg/kg) or vehicle once daily for 14 days. Nandrolone decanoate pre-exposure abolished the effect of amphetamine on the 3,4-dihydroxyphenylacetic acid (DOPAC) tissue level in the hypothalamus and on the DOPAC/dopamine ratio in the hypothalamus and the hippocampus. A significant decrease of the basal extracellular DOPAC and homovanillic acid (HVA) levels could be detected in the nucleus accumbens, which remained low during the first hour following the amphetamine challenge. Nandrolone decanoate significantly reduced the activity of both monoamine oxidase A and B (MAO-A and -B) in the caudate putamen and amygdala. The gene transcript levels of MAO-B, and the dopamine D1 and D4 receptors were altered in limbic regions. No changes in transcriptional levels could be detected among the serotonin receptor genes examined. However, the density of the serotonin transporter protein was elevated in a range of aggression-related brain regions.

Taken together, subchronic administration of nandrolone decanoate causes dopaminergic and serotonergic dysregulations in distinct brain regions. These areas of the brain are involved in the development of drug dependence and expression of impulsive and aggressive behaviours. These results may contribute to explain some of the behavioural changes often reported in AAS abusers, such as polydrug use and impaired impulse control.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2008. , 68 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 77
Keyword [en]
Pharmacology, anabolic androgenic steroids, nandrolone decanoate, dopamine, serotonin, rat, central nervous system
National Category
Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:uu:diva-9208ISBN: 978-91-554-7259-7 (print)OAI: oai:DiVA.org:uu-9208DiVA: diva2:172399
Public defence
2008-09-26, B22, BMC, Husargatan, Uppsala, 13:00
Opponent
Supervisors
Available from: 2008-09-05 Created: 2008-09-05Bibliographically approved
List of papers
1. Effects on rat brain dopamine and DOPAC levels after sub-chronic nandrolone administration followed by an amphetamine challenge
Open this publication in new window or tab >>Effects on rat brain dopamine and DOPAC levels after sub-chronic nandrolone administration followed by an amphetamine challenge
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2006 In: Pharmacologyonline, ISSN 1827-8620, Vol. 3, 99-108 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-97440 (URN)
Available from: 2008-09-05 Created: 2008-09-05Bibliographically approved
2. Altered extracellular levels of DOPAC and HVA in the rat nucleus accumbens shell in response to sub-chronic nandrolone administration and a subsequent amphetamine challenge
Open this publication in new window or tab >>Altered extracellular levels of DOPAC and HVA in the rat nucleus accumbens shell in response to sub-chronic nandrolone administration and a subsequent amphetamine challenge
2007 (English)In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 412, no 2, 168-172 p.Article in journal (Refereed) Published
Abstract [en]

Associated with acts of violence and polydrug use, abuse of anabolic androgenic steroids (AAS) is an increasing problem in society. The aim of the present study was to elucidate whether sub-chronic treatment with the AAS nandrolone decanoate affects dopamine release and dopamine metabolism in the rat nucleus accumbens shell, before and after an amphetamine challenge. Male Sprague–Dawley rats received daily i.m. injections of nandrolone decanoate (15 mg/kg) or vehicle for 14 days. On day 15, the animals were anaesthetized and a microdialysis probe was implanted into the nucleus accumbens shell. Extracellular fluid was collected 1 h before and 3 h after a single amphetamine injection (5 mg/kg). The samples were then analyzed regarding the content of dopamine, and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), using HPLC with electrochemical detection. Two weeks of nandrolone decanoate administration caused a significant decrease of the basal DOPAC and HVA levels, which remained low during the first hour following the amphetamine challenge. Dopamine levels did not differ significantly between groups, neither after the nandrolone pre-treatment nor the amphetamine challenge. In conclusion, these novel findings indicate that AAS alter the metabolism of dopamine in a brain region involved in the development of drug dependence.

Keyword
Anabolic androgenic steroids, Dopamine, Microdialysis, Nandrolone decanoate, Nucleus accumbens
National Category
Pharmaceutical Sciences Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-97441 (URN)10.1016/j.neulet.2006.11.001 (DOI)000244268500016 ()17123707 (PubMedID)
Available from: 2008-09-05 Created: 2008-09-05 Last updated: 2011-02-16Bibliographically approved
3. Reduced activity of monoamine oxidase in the rat brain following repeated nandrolone decanoate administration
Open this publication in new window or tab >>Reduced activity of monoamine oxidase in the rat brain following repeated nandrolone decanoate administration
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2008 (English)In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1219, 103-110 p.Article in journal (Refereed) Published
Abstract [en]

Anabolic androgenic steroids (AAS) are known as doping agents within sports and body-building, but are currently also abused by other groups in society in order to promote increased courage and aggression. We previously showed that 14 days of daily intramuscular injections of the AAS nandrolone decanoate (15 mg/kg) reduced the extracellular levels of the dopaminergic metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the nucleus accumbens shell using microdialysis. The aim of the present study was to investigate whether the same dose regimen of nandrolone decanoate may affect the activities of the dopamine-metabolizing enzymes monoamine oxidases A and B (MAO-A and MAO-B). A radiometric assay was used to determine the activities of MAO-A and MAO-B in rat brain tissues after 14 days of daily i.m. nandrolone decanoate injections at the doses 3 and 15 mg/kg. Gene transcript contents of MAO-A, MAO-B and cathecol-O-methyltransferase (COMT) were measured with quantitative real-time reverse transcription PCR. 3 mg/kg of nandrolone decanoate significantly reduced the activity of both MAO-A and -B in the caudate putamen. 15 mg/kg of nandrolone decanoate significantly reduced the activity of MAO-A in the amygdala and increased the gene transcript level of MAO-B in the substantia nigra. In conclusion, imbalanced MAO activities may contribute to explain the impulsive and aggressive behaviour often described in AAS abusers. The reduced MAO activities observed are in line with our previously presented findings of decreased extracellular levels of DOPAC and HVA in the rat brain, indicating decreased monoaminergic activity following repeated AAS administration.

Keyword
Anabolic androgenic steroid, Monoamine oxidase, Nandrolone decanoate
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-97442 (URN)10.1016/j.brainres.2008.05.014 (DOI)000257907000011 ()18539264 (PubMedID)
Available from: 2008-09-05 Created: 2008-09-05 Last updated: 2011-12-02Bibliographically approved
4. The anabolic androgenic steroid nandrolone decanoate affects mRNA expression of dopaminergic but not serotonergic receptors
Open this publication in new window or tab >>The anabolic androgenic steroid nandrolone decanoate affects mRNA expression of dopaminergic but not serotonergic receptors
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2008 (English)In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1240, 221-228 p.Article in journal (Refereed) Published
Abstract [en]

The abuse of anabolic androgenic steroids (AASs) at supratherapeutic doses is a problem not only in the world of sports, but also among non-athletes using AASs to improve physical appearance and to become more bold and courageous. Investigations of the possible neurochemical effects of AAS have focused partially on the monoaminergic systems, which are involved in aggressive behaviours and the development of drug dependence. In the present study, we administered nandrolone decanoate (3 or 15 mg/kg/day for 14 days) and measured mRNA expression of dopaminergic and serotonergic receptors, transporters and enzymes in the male rat brain using quantitative real-time polymerase chain reaction. Expression of the dopamine D1-receptor transcript was elevated in the amygdala and decreased in the hippocampus while the transcript level of the dopamine D4-receptor was increased in the nucleus accumbens. No changes in transcriptional levels were detected among the serotonin-related genes examined in this study. The altered mRNA expression of the dopamine receptors may contribute to some of the behavioural changes often reported in AAS abusers of increased impulsivity, aggression and drug-seeking.

Keyword
Anabolic androgenic steroid, Dopamine receptor, Nandrolone decanoate, Serotonin receptor, Quantitative real-time PCR
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-97443 (URN)10.1016/j.brainres.2008.09.003 (DOI)000261415600025 ()18809391 (PubMedID)
Available from: 2008-09-05 Created: 2008-09-05 Last updated: 2011-12-02Bibliographically approved
5. Nandrolone decanoate increases serotonin transporter density in rat brain
Open this publication in new window or tab >>Nandrolone decanoate increases serotonin transporter density in rat brain
Manuscript (Other academic)
Identifiers
urn:nbn:se:uu:diva-97444 (URN)
Available from: 2008-09-05 Created: 2008-09-05 Last updated: 2010-01-13Bibliographically approved

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