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Application of in vitro [(35)S]GTPγ-S autoradiography in studies of growth hormone effects on opioid receptors in the male rat brain
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.
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.
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.

Place, publisher, year, edition, pages
2013. Vol. 90, 100-106 p.
National Category
Medical and Health Sciences
Research subject
Pharmaceutical Science
Identifiers
URN: urn:nbn:se:uu:diva-185621DOI: 10.1016/j.brainresbull.2012.09.008ISI: 000314446100014PubMedID: 23063719OAI: oai:DiVA.org:uu-185621DiVA: diva2:572262
Available from: 2012-11-27 Created: 2012-11-27 Last updated: 2017-12-07Bibliographically approved
In thesis
1. The Impact of Growth Hormone and Gamma-Hydroxybutyrate (GHB) on Systems Related to Cognition
Open this publication in new window or tab >>The Impact of Growth Hormone and Gamma-Hydroxybutyrate (GHB) on Systems Related to Cognition
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Drug dependence is a serious and increasing problem in our society, especially among adolescents. The use of the large variety of substances available can result in a range of physiological and psychological adverse effects on individuals and negative consequences on the society overall. Several different types of drugs induce neurotoxicological damages, which in turn can generate impairment in for example the reward system and affect cognitive parameters.

 The drug gamma-hydroxybutyrate (GHB) is usually considered a harmless compound among abusers, but has now shown to be highly addictive. Furthermore, GHB can cause memory impairments in both humans and animals. On the contrary, growth hormone (GH) and its main mediator insulin-like growth factor 1 (IGF-1) have recently been suggested to improve memory and learning in several studies. The hormones exhibit certain neuroprotective capabilities and have also previously been demonstrated to reverse opioid induced apoptosis in hippocampal cells. These effects and the fact that GHB is shown to increase GH secretion, which attracted considerable attention among body builders, led us to initiate studies on GHB and its impact on relevant systems in the central nervous system (CNS). Thus, the main purpose of the present investigation was to elucidate some of the underlying mechanisms that could account for the effects exerted by GH and GHB in the CNS.

We found that a) GH affects the density and functionality of GABAB-receptors and opioid receptors in the male rat brain, b) GHB induces cognitive deficits and down-regulates GABAB-receptors, c) GHB treatment creates an imbalance between the endogenous opioids Met-enkaphalin-Arg6Phe7 (MEAP) and dynorphin B and increases the levels of MEAP in regions of the brain that are associated with drug dependence, and d) GHB affects the expression of IGF-1 receptors but not the plasma levels of IGF-1. In conclusion, the present work demonstrates that GH interacts with both opioid and GABAB-receptors in the male rat CNS and that GHB has an impact on brain regions associated with cognition and the development of dependence. These observations may be of relevance in many aspects related to addiction and might be translated into humans.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. 74 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 168
Keyword
Growth Hormone, Gamma-Hydroxybutyrate, GABAB, Opioids, Insulin-like growth factor 1, Rats, Central Nervous System, Autoradiography, Radioimmunoassay, ELISA, Water Maze, Open Field
National Category
Pharmaceutical Sciences
Research subject
Biological Research on Drug Dependence
Identifiers
urn:nbn:se:uu:diva-185631 (URN)978-91-554-8552-8 (ISBN)
Public defence
2013-01-18, B21, BMC, Husargatan 3, Uppsala, 09:15 (Swedish)
Opponent
Supervisors
Available from: 2012-12-20 Created: 2012-11-27 Last updated: 2013-02-11Bibliographically approved
2. Growth Hormone and Anabolic Androgenic Steroids: Effects on Neurochemistry and Cognition
Open this publication in new window or tab >>Growth Hormone and Anabolic Androgenic Steroids: Effects on Neurochemistry and Cognition
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
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:nbn:se:uu:diva-206069 (URN)978-91-554-8732-4 (ISBN)
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

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Johansson, JennyGrönbladh, AlfhildNyberg, FredHallberg, Mathias

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