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Gamma-Hydroxybutyrate (GHB) elevates Met-enkephalin-Arg6Phe7 (MEAP) levels in the frontal cortex of 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.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Gamma-hydroxybutyrate (GHB) has increased in popularity among adolescents during recent years. Predominantly it is used as a recreational drug, but frequently also as an anabolic agent due to its ability of releasing growth hormone. The fact that GHB has been reported to be highly addictive and can cause cognitive deficiencies has become a major concern. In this study, we investigated the impact of GHB treatment in rats on the levels of the endogenous opioid peptides Met-enkephalin-Arg6Phe7 (MEAP) and Dynorphin B (DYNB) in various regions of the brain and on the levels of insulin-like growth factor 1 (IGF-1) in plasma. Furthermore, spontaneous explorative behavior and locomotor activity after GHB administration was analyzed in an Open field (OF). The results demonstrated that treatment with GHB did not affect the parameters that were assessed in the OF, nor did it affect the plasma levels of IGF-1. Regarding the opioid peptide levels, the GHB treated rats demonstrated increased immunoreactive (ir) MEAP but not DYNB levels in the frontal cortex, while no significant alterations were observed in caudate putamen, hypothalamus, nucleus accumbens, amygdala, hippocampus and periaqueductal grey. Moreover, in control rats the levels of ir MEAP and ir DYNB seemed well-balanced in many regions and the peptide levels correlated in amygdala, hippocampus and hypothalamus. However, in the GHB-treated animals no such correlation was observed. In conclusion, GHB treatment created an imbalance regarding the opioids MEAP/DYNB and increased the levels of MEAP significantly in regions of the brain that are of importance for the development of drug dependence.

National Category
Pharmaceutical Sciences
Research subject
Biological Research on Drug Dependence
Identifiers
URN: urn:nbn:se:uu:diva-185422OAI: oai:DiVA.org:uu-185422DiVA: diva2:572266
Funder
Swedish Research Council
Available from: 2012-11-27 Created: 2012-11-23 Last updated: 2013-02-11
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

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Johansson, JennyBrolin, ErikaGrönbladh, Alfhild

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