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Growth Hormone and Anabolic Androgenic Steroids: Effects on Neurochemistry and Cognition
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Growth hormone (GH) stimulates growth and metabolism but also displays profound effects on the central nervous system (CNS). GH affects neurogenesis and neuroprotection, and has been shown to counteract drug-induced apoptosis in the brain. Anabolic androgenic steroids (AAS), mainly abused for their anabolic and performance-enhancing properties, can cause several adverse effects, such as cardiovascular complications, sterility, depression, and aggression. GH and AAS are both believed to interact with several signaling systems in the CNS. The aim of this thesis was to further investigate the impact of GH and AAS on neurochemistry and cognitive functions. Recombinant human GH (rhGH) and the steroid nandrolone decanoate (ND) were administered, separately and in combination with each other, to male rats.

The results demonstrated that administration of GH improved spatial memory, assessed in a water maze test. Furthermore, GH induced alterations of the GABAB receptor mRNA expression, density, and functionality in the brain, for example in regions associated with cognition. GH also altered the mu opioid peptide (MOP) receptor, but not the delta opioid peptide (DOP) receptor functionality in the brain. Thus, some of the GH effects on cognition may involve effects on the GABAB receptors and MOP receptors. ND, on the contrary, seemed to induce impairments of memory and also altered the GABAB receptor mRNA expression in the brain. Furthermore, ND lowered the IGF-1 plasma concentrations and attenuated the IGF-1, IGF-2, and GHR mRNA expression in the pituitary. In addition, significant effects of GH and ND were found on plasma steroid concentrations, organ weight, as well as body weight.

In conclusion, this thesis contributes with further knowledge on the cognitive and neurochemical consequences of GH and ND use. The findings regarding ND are worrying considering the common use of AAS among adolescents. GH improves memory functions and affects signaling systems in the brain associated with cognition, hence the hypothesis that GH can reverse drug-induced impairments is further strengthened.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. , 73 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 175
Keyword [en]
Growth hormone, anabolic androgenic steroids, nandrolone decanoate, insulin-like growth factor, GABAB, opioids, memory, water maze, autoradiography, central nervous system, rats
National Category
Pharmaceutical Sciences
Research subject
Biological Research on Drug Dependence
Identifiers
URN: urn:nbn:se:uu:diva-206069ISBN: 978-91-554-8732-4 (print)OAI: oai:DiVA.org:uu-206069DiVA: diva2:643425
Public defence
2013-10-11, B21, Biomedical center, Husargatan 3, Uppsala, 09:15 (Swedish)
Opponent
Supervisors
Available from: 2013-09-20 Created: 2013-08-27 Last updated: 2014-01-22
List of papers
1. GH (Growth hormone) improves spatial memory and reverses certain anabolic androgenic steroid-induced effects in intact rats
Open this publication in new window or tab >>GH (Growth hormone) improves spatial memory and reverses certain anabolic androgenic steroid-induced effects in intact rats
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2013 (English)In: Journal of Endocrinology, ISSN 0022-0795, E-ISSN 1479-6805, Vol. 216, no 1, 31-41 p.Article in journal (Refereed) Published
Abstract [en]

Growth hormone (GH) has previously been shown to promote cognitive functions in GH deficient rodents. In this study we report effects of GH on learning and memory in intact rats pretreated with the anabolic androgenic steroid nandrolone. Male Wistar rats received nandrolone decanoate (15 mg/kg) or peanut oil every third day for three weeks and were subsequently treated with recombinant human GH (1.0 IU/kg) or saline for ten consecutive days. During the GH/saline treatment spatial learning and memory were tested in the Morris water maze (MWM). Also, plasma levels of insulin-like growth factor 1 (IGF1) were assessed and the gene expression of the GH receptor, Igf1, and Igf2 in hippocampus and frontal cortex was analyzed. The results demonstrated a significant positive effect of GH on memory functions and increased gene expression of Igf1 in the hippocampus was found in the animals treated with GH. In addition, GH was demonstrated to increase the body weight gain and was able to attenuate the reduced body weight seen in nandrolone treated animals. In general, the rats treated with nandrolone alone did not exhibit any pronounced alteration in memory compared to controls in the MWM, and in many cases GH did not induce any alteration. Regarding target zone crossings, considered to be associated to spatial memory, the difference between GH and steroid treated animals was significant and administration of GH improved this parameter in the latter group. In conclusion, GH improves spatial memory in intact rats and can reverse certain effects induced by AAS (anabolic androgenic steroid).

National Category
Neurosciences
Research subject
Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-185657 (URN)10.1530/JOE-12-0315 (DOI)000313718300008 ()23092877 (PubMedID)
Available from: 2012-11-27 Created: 2012-11-27 Last updated: 2017-12-07Bibliographically approved
2. Administration of growth hormone and nandrolone decanoate alters mRNA expression of the GABAB receptor subunits as well as GH receptor, IGF-1, and IGF-2 in rat brain
Open this publication in new window or tab >>Administration of growth hormone and nandrolone decanoate alters mRNA expression of the GABAB receptor subunits as well as GH receptor, IGF-1, and IGF-2 in rat brain
(English)Article in journal (Refereed) Submitted
Abstract [en]

Objective: The illicit use of anabolic androgenic steroids (AAS), especially among young adults, is of major concern. Among AAS users it is common to combine the AAS nandrolone decanoate (ND), with intake of growth hormone (GH) and a connection between gonadal steroids and the GH system has been suggested. Both AAS and GH affect functions in the brain, for example those associated with the hypothalamus and pituitary, and several GH actions are mediated by growth factors such as insulin-like growth factor 1 (IGF-1) and insulin-like growth factor 2 (IGF-2). The GABAergic system is implicated in actions induced by AAS and previous studies have provided evidence for a link between GH and GABAB receptors in the brain. Our aim was to examine the impact of a combined administration of AAS and GH on expression of GABAB receptors and important GH mediators in rat brain

Design: In the present study, male rats were administered a high dose of ND every third day during three weeks, and subsequently the rats were given recombinant human GH (rhGH) during ten days. Quantitative PCR (qPCR) was used to analyze gene expression in hypothalamus, anterior pituitary, caudate putamen, nucleus accumbens, and amygdala.

Results: In the pituitary gland, the expression of GABAB receptor subunits was affected differently by the steroid treatment; the GABAB1 mRNA expression was decreased whereas a distinct elevation of the GABAB2 expression was found. Administration of ND also caused a decrease of GHR, IGF-1, and IGF-2 mRNA expression in the pituitary while the corresponding expression in the hypothalamus, caudate putamen, nucleus accumbens, and amygdala was unaffected. The rhGH administration did not alter the GABAB2 expression but increased the GABAB1 gene expression in the hypothalamus as compared the AAS treated group.

Conclusions: These results provide new insights on the impact of ND and GH on the brain and highlight the interaction of these hormones with systems influencing GABAB receptor expression. The physiological significance of the observed effects of these hormones is discussed.

National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-205916 (URN)
Available from: 2013-08-27 Created: 2013-08-25 Last updated: 2014-01-22Bibliographically approved
3. Recombinant Human Growth Hormone Affects the Density and Functionality of GABAB receptors in the Male Rat Brain
Open this publication in new window or tab >>Recombinant Human Growth Hormone Affects the Density and Functionality of GABAB receptors in the Male Rat Brain
2013 (English)In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 97, no 3, 203-211 p.Article in journal (Refereed) Published
Abstract [en]

The beneficial effects of growth hormone (GH) on memory and learning have previously been confirmed in both humans and in animal models. An important role of GABA(B) receptors for multiple forms of learning and memory has also been reported. In this study, we examined the effect of GH on the density and functionality of the metabotropic GABA(B) receptors in the rat brain. Male Sprague-Dawley rats (n = 24) divided into 3 groups were injected twice daily with recombinant human GH (0.07 or 0.7 IU/kg) for 7 days. The effects of the hormone were determined by quantitative autoradiography and by GABA(B) stimulated [(35)S]-GTPγS binding using the selective GABA(B) receptor agonist baclofen. The results demonstrate moderate but significant alterations in both receptor density and functionality in a number of brain regions. For example, a dose-dependent upregulation of GABA(B) receptors was found in the cingulate cortex, primary motor cortex and caudate putamen, whereas attenuation in the receptor density was encountered in, for example, the medial geniculate nucleus. Although the GH-induced effects on the GABA(B) receptor in brain areas associated with cognition were fairly pronounced, they were significant and we propose that the physiological responses observed after GH administration at least partly can be mediated through a mechanism involving GABA(B) receptors.

National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-182071 (URN)10.1159/000339821 (DOI)000318463400001 ()22710737 (PubMedID)
Available from: 2012-10-03 Created: 2012-10-03 Last updated: 2017-12-07Bibliographically approved
4. Application of in vitro [(35)S]GTPγ-S autoradiography in studies of growth hormone effects on opioid receptors in the male rat brain
Open this publication in new window or tab >>Application of in vitro [(35)S]GTPγ-S autoradiography in studies of growth hormone effects on opioid receptors in the male rat brain
2013 (English)In: Brain Research Bulletin, ISSN 0361-9230, E-ISSN 1873-2747, Vol. 90, 100-106 p.Article in journal (Refereed) Published
Abstract [en]

Chronic treatment with opiates may inhibit cell growth and trigger apoptosis. On the contrary, growth hormone (GH) has been demonstrated to stimulate neurogenesis and counteract apoptosis. We recently demonstrated that recombinant human GH (rhGH) may reverse opiate-induced apoptosis in cells derived from prenatal mouse hippocampus. Thus, GH might be able to prevent the impaired cognitive capabilities that may occur in both humans and other mammals in connection to chronic opiate treatment. In order to explore the mechanism by which GH exerts its beneficial effects we here examined the impact of GH treatment on the levels of delta and mu opioid peptide (DOP and MOP, respectively) receptors in the male rat brain. The rats were treated with rhGH (Genotropin(®)) at two different doses (0.07 and 0.7IU/kg), twice daily, during 7 days. Following decapitation, the levels of DOP and MOP receptor functionality were determined using [(35)S]GTPγS autoradiography. The results demonstrate that rhGH affects the levels of the MOP receptor functionality in certain areas of the brain. These alterations were seen in e.g. amygdala and thalamus, i.e. regions that recently have been implicated in learning and memory. The activity level of DOP receptors was not affected. Thus, the data support that the beneficial effect of GH on counteracting apoptosis might involve a direct or indirect effect on the MOP but not the DOP receptor.

National Category
Medical and Health Sciences
Research subject
Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-185621 (URN)10.1016/j.brainresbull.2012.09.008 (DOI)000314446100014 ()23063719 (PubMedID)
Available from: 2012-11-27 Created: 2012-11-27 Last updated: 2017-12-07Bibliographically approved
5. The impact of nandrolone decanoate and growth hormone on biosynthesis of steroids in rats
Open this publication in new window or tab >>The impact of nandrolone decanoate and growth hormone on biosynthesis of steroids in rats
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2013 (English)In: Steroids, ISSN 0039-128X, E-ISSN 1878-5867, Vol. 78, no 12-13, 1192-1199 p.Article in journal (Refereed) Published
Abstract [en]

Growth hormone (GH) and anabolic androgenic steroids (AAS) are commonly used in sports communities. Several studies have suggested an association between GH and AAS. We have investigated the impact of GH in rats treated with nandrolone decanoate (ND). Male Wistar rats received ND (15 mg/kg) every third day during three weeks and were subsequently treated with recombinant human GH (1.0 IU/kg) for ten consecutive days. Plasma samples were collected and peripheral organs (i.e. heart, liver, testis and thymus) were dissected and weighed. Concentration of thirteen endogenous steroids was measured in the rat plasma samples using high specificity LC-MS/MS methods. Seven steroids were detected and quantified, and concentrations of estrone, testosterone, and androstenedione were significantly different among the groups, while concentrations of pregnenolone, DHEA, 17- hydroxyprogesterone and corticosterone were not altered. Administration of rhGH alone altered the plasma steroid distribution, and the results demonstrated significantly increased concentrations of plasma estrone as well as decreased concentrations of testosterone and androstenedione in the ND-treated rats. Administration of rhGH to ND-pretreated rats did not reverse the alteration of the steroid distribution induced by ND. Administration of ND decreased the weight of the thymus, and addition of rhGH did not reverse this reduction. However, rhGH administration induced an enlargement of thymus. Taken together, the plasma steroid profile differed in the four groups, i.e. controls, AAS, rhGH and the combination of AAS and rhGH treatment.

Place, publisher, year, edition, pages
Elsevier, 2013
Keyword
Growth hormone, anabolic androgenic steroids, testosterone, androstenedione
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-205915 (URN)10.1016/j.steroids.2013.08.012 (DOI)000327287800006 ()
Available from: 2013-08-27 Created: 2013-08-25 Last updated: 2017-12-06Bibliographically approved

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