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Pharmacological and environmental modulations of the rat glutamatergic system
Linköping University, Department of Neuroscience and Locomotion, Geriatrics. Linköping University, Faculty of Health Sciences.
2006 (English)Licentiate thesis, comprehensive summary (Other academic)
Abstract [en]

Glutamate is the principal excitatory neurotransmitter in the central nervous system and it is implicated in neural transmission, learning, memory processes and neuronal plasticity. In the glutamatergic synapse two main components are present; the glutamate receptors and the glutamate transporters. The receptors, the NMDA, AMPA, kainite and the metabotroptic receptors, are responsible for conveying neural transmission, including long term potentiation (LTP), synaptic strengthening and modification. The transporters, located to the neuronal membrane and to the membranes of surrounding astrocytes, regulates the extracellular concentration of glutamate and thereby the duration of the synaptic signal.

Alterations in both receptor and transporter systems have been suggested to be important in the pathogenesis of several acute and chronic nervous system diseases, such as psychosis, mood disorders, epilepsy, Parkinson's disease and Alzheimer's disease. The pathophysiology of these disorders is not yet completely understood and the involvement of glutamate is unclear. In this thesis we have sought to investigate the role of the glutamatergic system in the treatment of mood disorders and dementia. The antidepressant drug amitriptyline exerts its main effects on the serotonergic and noradrenergic systems and the antidementia drug rivastigmine acts mainly on the cholinergic system. However, given the close relationship between different neurotransmitter systems we have investigated the influence of amitriptyline and rivastigmine on the mRNA expression of the neuronal transporter, EAAC1, in rats. The results showed for the first time an involvement of EAAC1 in amitriptyline and rivastigmine treatment. Amitriptyline induced an acute increase in EAAC1 mRNA expression, which 24 hour after administration returned to baseline levels. Chronic treatment, on the other hand, induces a significant decrease in cortical areas, which we suggest results in enhanced neuronal transmission. Rivastigmine treatment, acute as well as chronic, induced increases in the mRNA expression in hippocampus. We hypothesize that this counteracts the excitotoxic glutamate levels seen in Alzheimer's disease.

Further, environmental enrichment has been shown to have beneficial effects on capillary supply, the number of glial cells and dendritic spines, the thickness and weight of cortex, the concentration of cholinesterase, LTP and synaptic strength in animals. It has also been reported that humans that lead an active life have a reduced risk of developing Alzheimer's disease. This suggests that an active and stimulated life may have a protective effect against dementia in man, by creating a cognitive reserve which provides a buffer against brain pathology or age-related changes. We investigated the influence of environmental enrichment on the mRNA expression of NMDA and AMPA receptors and on EAACl and showed for the first time that EAAC1 mRNA is decreased after environmental enrichment. This is probably followed by an increase of glutamate in the synapse, which in turn leads to enhanced neuronal transmission including enhanced memory formation and learning. Furthermore, we confirmed in greater detail previous findings on the upregulation of NMDA mRNA and show that the regulation is regionally and hemisphere specific. We also confirm that AMPA mRNA is not per se changed by environmental enrichment in adult animals.

This work provides further evidence about the involvement of the glutamatergic system in affective and cognitive disorders. Improved knowledge of the glutamatergic system will contribute to the development of strategies aimed at limiting pathological changes associated with glutamatergic dysfunctions.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet , 2006. , 66 p.
Series
Linköping Studies in Health Sciences. Thesis, ISSN 1100-6013 ; 78
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-35978Local ID: 29247ISBN: 91-85643-29-7 (print)OAI: oai:DiVA.org:liu-35978DiVA: diva2:256826
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2013-09-18
List of papers
1. Modulation of neuronal glutamate transporter rEAAC1 mRNA expression in rat brain by amitriptyline
Open this publication in new window or tab >>Modulation of neuronal glutamate transporter rEAAC1 mRNA expression in rat brain by amitriptyline
2004 (English)In: Brain Research. Molecular Brain Research, ISSN 0169-328X, E-ISSN 1872-6941, Vol. 126, no 1, 74-77 p.Article in journal (Refereed) Published
Abstract [en]

Glutamate transporters regulate the glutamate concentration in the synaptic cleft within the CNS, a regulation required for normal brain function. In several neurological conditions, the amount of glutamate is altered. One reason for the changes in glutamate concentration might be impaired glutamate transporter function. In this study, an in situ hybridisation technique has been used to elucidate changes in mRNA expression of the glutamate transporter, excitatory amino acid carrier 1 (EAAC1), after treatment with the tricyclic antidepressant (TCA) amitriptyline. The results lead to the suggestion that treatment with tricyclic antidepressants leads to changes in the EAAC1 mRNA expression in rat brain suggesting involvement of the glutamate system in the tricyclic treatment of depression.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-24088 (URN)10.1016/j.molbrainres.2004.03.023 (DOI)000222569100009 ()3654 (Local ID)3654 (Archive number)3654 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2013-09-18
2. Rivastigmine as a Modulator of the Neuronal Glutamate Transporter rEAAC1 mRNA Expression
Open this publication in new window or tab >>Rivastigmine as a Modulator of the Neuronal Glutamate Transporter rEAAC1 mRNA Expression
2005 (English)In: Dementia and Geriatric Cognitive Disorders, ISSN 1420-8008, E-ISSN 1421-9824, Vol. 19, no 1, 18-23 p.Article in journal (Refereed) Published
Abstract [en]

Alzheimer’s disease is a neurodegenerative disorder that affects the cholinergic, glutamatergic and monoaminergic systems in the neocortex and hippocampus. Today, the major pharmacological treatment involves the use of acetylcholinesterase inhibitors (AChEIs). In this study, an in situ hybridisation technique (using digoxigenin-labelled cRNA probes) was used to elucidate changes in mRNA expression of the neuronal glutamate transporter, rat excitatory amino carrier 1 (rEAAC1), after treatment with the AChEI rivastigmine. Compared with saline-treated rats, the rats subchronically (3 days) and chronically (21 days), but not acutely, treated with rivastigmine showed a significant increase in rEAAC1 mRNA expression in the hippocampal areas cornu anterior 1 (CA1), CA2, CA3 and dentate gyrus (p < 0.01), but not in the cortical areas. These results provide the first evidence that the glutamatergic system is modulated following acetylcholinesterase inhibition by rivastigmine, a finding, which is likely to be of importance for the clinical effects.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-42255 (URN)10.1159/000080966 (DOI)000226012200004 ()62059 (Local ID)62059 (Archive number)62059 (OAI)
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2013-09-18
3. Environmental enrichment induces changes in the mRNA expression of rat EAAC1 and NMDA but not in AMPA
Open this publication in new window or tab >>Environmental enrichment induces changes in the mRNA expression of rat EAAC1 and NMDA but not in AMPA
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Interaction with the environment has a key role in refining the neuronal circuitry required for normal brain function throughout life. Profound effects of enriched environment has been shown on neuronal strucrure and chemistry in experimental animals. Epidemiological studies imply that this is true also in man, thus cognitive stimulation has a protective effect on neurodegeneration, e.g. Alzheimer's disease. Glutamatergic corticocortical pathways are imperative for cognitive functions, such as memory and learning, and long term porenriation relies on the AMPA and NMDAglutamate rcceptors. The glutamate signalling is also dependent on a fine-runed transport system, in the hippocampus primarily by theglutamate transporter EAACl. In this study we show how environmental enrichment modulates these parts of the glutamarergic system using in siru hybridization. This work demonstrates for the first time that environmental enrichment modulates the mRNA expression of EAAC1 which is significantly decreased in hippocampal and cortical areas. We also provide further evidence about the upregulation of NMDA mRNA after environmental enrichement, and show it to have a regionally and hemisphere specific regulation. The current work also confirms that AMPA mRNA is nor per se changed by environmental enrichment in adult animals. Taken together, our results extend the knowledge of the glutamatergic system and its modulation by environmental enrichment and could contribute to the development of strategies aimed at limiting pathological changes associated with glutamatergic dysfunctions.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-97633 (URN)
Available from: 2013-09-18 Created: 2013-09-18 Last updated: 2013-09-18

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