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CNS Targets for GH and IGF-1: Emphasis on Their Regulation in Relation to Cognitive Processes
Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The interest for the growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis and its role in the central nervous system (CNS) has grown during the past decade. GH has been associated with psychological functions as sleep, mood, general well-being and learning and memory. The present thesis is a contribution to clarify the functions and mechanisms involved in the actions of GH and IGF-1 in the CNS. A variant of the GH receptor (GHR) gene transcript lacking exon 3 (GHR3-) was cloned from ovine choroid plexus epithelial cells and tissue. The GHR3- transcript has previously only been identified in human tissue. Further, an anatomical study of the localization of GHR mRNA in the rat brain stem and spinal cord was carried out by the use of in situ hybridization. High densities of GHRs were found in areas associated with the regulation of food intake, sleep and nociception, functions known to be influenced by the GH/IGF-1 axis. The interaction with the opioid system was studied by an acute treatment with morphine. The levels of the transcripts for GHR and GHBP in the rat hippocampus and spinal cord were decreased 4 h after the injection of the opiate and restored to normal levels after 24 h. Young and aged rats injected with GH or IGF-1 showed differential gene regulation of subunits of the NMDA subtype of glutamate receptor in the hippocampus. This indicates an age-related difference in the sensitivity to GH/IGF-1 mediated effects on memory functions. Moreover, hypophysectomized rats treated with GH showed improved performance in the Morris water maze, a spatial memory task. The effect was accompanied with an increase in transcripts for NMDA receptor subunits and its associated membrane anchoring PSD-95 protein. Taken together, the results suggest that GH and/or IGF-1 play important roles in mechanisms associated with cognitive functions.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2005. , p. 64
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 2
Keywords [en]
Pharmaceutical pharmacology, Central nervous system, Growth hormone, Insulin-like growth factor-1, Receptor mRNA regulation, N-methyl-D-aspartate receptor mRNA, Morris water maze
Keywords [sv]
Farmaceutisk farmakologi
National Category
Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:uu:diva-4758ISBN: 91-554-6132-8 (print)OAI: oai:DiVA.org:uu-4758DiVA, id: diva2:165652
Public defence
2005-02-11, B41, BMC, Husargatan 3, Uppsala, 13:15
Opponent
Supervisors
Available from: 2005-01-20 Created: 2005-01-20 Last updated: 2018-01-13Bibliographically approved
List of papers
1. Detection of growth hormone receptor mRNA in an ovine choroid plexus epithelium cell line
Open this publication in new window or tab >>Detection of growth hormone receptor mRNA in an ovine choroid plexus epithelium cell line
1995 In: Biochemical and biophysical research communications, ISSN 0006-291, Vol. 217, no 1, p. 349-353Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-92527 (URN)
Available from: 2005-01-20 Created: 2005-01-20Bibliographically approved
2. The exon 3-deleted isoform of the growth hormone receptor mRNA is present in ovine choroid plexus
Open this publication in new window or tab >>The exon 3-deleted isoform of the growth hormone receptor mRNA is present in ovine choroid plexus
Article in journal (Refereed) Submitted
Identifiers
urn:nbn:se:uu:diva-92528 (URN)
Available from: 2005-01-20 Created: 2005-01-20Bibliographically approved
3. Distribution of growth hormone receptor mRNA in the brain stem and spinal cord of the rat
Open this publication in new window or tab >>Distribution of growth hormone receptor mRNA in the brain stem and spinal cord of the rat
2004 (English)In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 130, no 2, p. 419-425Article in journal (Refereed) Published
Abstract [en]

By using in situ hybridization histochemistry the distribution of growth hormone (GH) receptor mRNA was examined in the rat brain stem and spinal cord. Dense labeling was seen in the arcuate nucleus of the hypothalamus, as reported previously, but also in several other areas, including the locus coeruleus, the area postrema, and the commissural part of the nucleus of the solitary tract. Other labeled structures included the superior lateral parabrachial nucleus, the facial, hypoglossal and trigeminal motor nuclei, the nucleus incertus, the dorsal tegmental nucleus, the dorsal raphe nucleus, the nucleus of the trapezoid body, and the superficial layers of the dorsal horn of the spinal cord. These findings provide support for a direct action of GH on brain regions involved in various aspects of homeostatic control. Thus, the distribution of GH receptor mRNA to visceral sensory and motor structures is consonant with a role of GH in the regulation of food intake and energy homeostasis. Its presence in the superficial dorsal horn of the spinal cord indicates a role for GH in the initial processing of fine afferent input, and may help explain the beneficial effects of GH replacement in certain unclear pain conditions.

Keywords
Animals, Appetite Regulation/physiology, Arcuate Nucleus/cytology/metabolism, Area Postrema/cytology/metabolism, Brain Stem/anatomy & histology/*metabolism, Energy Metabolism/physiology, Growth Hormone/*metabolism, Locus Coeruleus/cytology/metabolism, Male, Neurons/*metabolism, Pain/metabolism/physiopathology, RNA; Messenger/*metabolism, Rats, Rats; Sprague-Dawley, Receptors; Somatotropin/*genetics, Research Support; Non-U.S. Gov't, Solitary Nucleus/cytology/metabolism, Spinal Cord/anatomy & histology/*metabolism
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-92529 (URN)10.1016/j.neuroscience.2004.10.003 (DOI)15664698 (PubMedID)
Available from: 2005-01-20 Created: 2005-01-20 Last updated: 2017-12-14Bibliographically approved
4. Morphine decreases the level of the gene transcripts of growth hormone receptor and growth hormone binding protein in the male rat hippocampus and spinal cord
Open this publication in new window or tab >>Morphine decreases the level of the gene transcripts of growth hormone receptor and growth hormone binding protein in the male rat hippocampus and spinal cord
Show others...
2001 In: Neuroscience Letters, ISSN 0304-3940, no 304, p. 69-72Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-92530 (URN)
Available from: 2005-01-20 Created: 2005-01-20Bibliographically approved
5. Growth hormone induces age-dependent alteration in the expression of hippocampal growth hormone receptor and N-methyl-D-aspartate receptor subunits gene transcripts in male rats
Open this publication in new window or tab >>Growth hormone induces age-dependent alteration in the expression of hippocampal growth hormone receptor and N-methyl-D-aspartate receptor subunits gene transcripts in male rats
2002 In: Proceedings of the national academy of science, ISSN 1091-6490, Vol. 99, no 10, p. 7119-7123Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-92531 (URN)
Available from: 2005-01-20 Created: 2005-01-20Bibliographically approved
6. Age-related effects of IGF-1 on the NMDA-, GH- and IGF-1 receptor mRNA transcripts in the rat hippocampus
Open this publication in new window or tab >>Age-related effects of IGF-1 on the NMDA-, GH- and IGF-1 receptor mRNA transcripts in the rat hippocampus
2005 (English)In: Brain Research Bulletin, ISSN 0361-9230, E-ISSN 1873-2747, Vol. 65, no 5, p. 369-374Article in journal (Refereed) Published
Abstract [en]

Insulin-like growth factor-1 (IGF-1) and growth hormone (GH) have been suggested to promote memory and cognitive capabilities. In a recent publication we observed that GH increase the proportion of the NR2B subunit mRNA transcript of the NMDA receptor in rat hippocampus. NR2B has been suggested to be essential for spatial learning and long-term potentiation (LTP). This effect of GH might be IGF-1-mediated or a result of a co-ordination with IGF-1. To test this hypothesis further, we examined the effects of 10 daily s.c. injections of IGF-1 on NMDA receptor subunits (NR1, NR2A, and NR2B), GH receptor (GHR), GH binding protein (GHBP) and type 1 IGF receptor (IGF-1R) gene transcripts in the hippocampus. The NR2B subunit mRNA increased in young (11 weeks) but not in older (14-16 months) rats and the expression of the NR2A mRNA was decreased in both groups. The ratio of NR2B to NR2A is suggested to mirror the potential for synaptic plasticity. In both age groups, IGF-1 treatment resulted in a significant increase of this ratio at transcription level. The GHR mRNA increased in young rats, mimicking the effect of GH, while the IGF-1R mRNA was decreased in the older group of rats after IGF-1 treatment. These results suggest that IGF-1 in many aspects may mediate the actions earlier shown for GH.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-92532 (URN)10.1016/j.brainresbull.2005.01.012 (DOI)15833590 (PubMedID)
Available from: 2005-01-20 Created: 2005-01-20 Last updated: 2017-12-14Bibliographically approved
7. Growth hormone enhances spatial performance and hippocampal levels of NMDA subunit and PSD-95 transcripts in the hypophysectomized rat
Open this publication in new window or tab >>Growth hormone enhances spatial performance and hippocampal levels of NMDA subunit and PSD-95 transcripts in the hypophysectomized rat
Show others...
Article in journal (Refereed) Submitted
Identifiers
urn:nbn:se:uu:diva-92533 (URN)
Available from: 2005-01-20 Created: 2005-01-20Bibliographically approved

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