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Selective effects on NGFI-A, MR, GR and NGFI-B hippocampal mRNA expression after chronic treatment with different subclasses of antidepressants in the rat
Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Geriatrics.
Department of Public Health and Clinical Medicine, Medicine, Umeå University Hospital, Umeå, Sweden.
Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Geriatrics. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Geriatric Medicine.
Astra Arcus AB, Södertälje, Sweden.
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2000 (English)In: Psychopharmacology, ISSN 0033-3158, Vol. 151, no 1, 7-12 p.Article in journal (Refereed) Published
Abstract [en]

There is a latency period of several weeks before the onset of clinical effect of antidepressant drugs. The detailed mechanisms underlying drug-induced adaptive neuronal changes are not known. To elucidate the involvement of changes in gene expression of candidate transcription factors, we treated rats for 21 days with buspirone, fluoxetine, 8-OH-DPAT and moclobemide. In situ hybridization was used to study mRNAs encoding NGFI-A, NGFI-B and the glucocorticoid receptors, MR and GR. NGFI-A mRNA expression increased profoundly in the hippocampal formation and the cerebral cortex after all drug treatments, especially after moclobemide treatment (77-122% increase), with the exception of buspirone. MR mRNA expression was induced in hippocampal CA1/CA2 subregions (27-37%) by all antidepressants, while moclobemide and 8-OH-DPAT significantly increased GR gene expression mainly in the CA1 region (31-44%). NGFI-B mRNA was significantly decreased in the hippocampal CA3 subfield (23%) and restrosplenial granular cortex (38%) by moclobemide treatment. There are selective effects of antidepressant drugs on specific transcription factors. These may be important for adaptive neuronal and neuroendocrine changes after antidepressant treatment including HPA axis negative feedback regulation.

Place, publisher, year, edition, pages
2000. Vol. 151, no 1, 7-12 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-27674DOI: 10.1007/s002130000468Local ID: 12412OAI: diva2:248226
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2009-11-02Bibliographically approved
In thesis
1. Pharmacological and Developmental Aspects on Neuronal Plasticity
Open this publication in new window or tab >>Pharmacological and Developmental Aspects on Neuronal Plasticity
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Neuronal plasticity means the ability of the brain, its cells and networks to adapt and adjust to new challenges, a process which is ongoing throughout life. The goal of this thesis was to gain better understanding of the molecular events that follow different types of stimulations of brain structures such as the hippocampus, a key region for cognitive functions with overriding control on the corticosteroid system. A better knowledge of the mechanisms involved in neuronal plasticity is fundamental in the development of strategies for improving health in patients suffering from major depression or cognitive disorders such as Alzheimer’s disease.

Antidepressant drugs induce the expression of several genes involved in neuronal plasticity, a mechanism which may explain the several weeks time lag between treatment initiation and clinical effect commonly observed in patients. Besides, there are indications that disturbances in the corticosteroid system are involved in the pathogenesis of major depression. Therefore, the mRNA expression of the glucocorticoid receptors (GR) and mineralocorticoid receptors (MR) as well as of the immediate-early genes NGFI-A and NGFI-B was analyzed using in situ hybridization in the hippocampus and cortex after 21 days treatment with various antidepressant drugs having different monoaminergic profiles. The mRNA expression of the transcription factors was selectively increased depending on region and also on the monoaminergic profile of the drug given. Generally, drugs with less specificity for monoamines had an overall more anatomically wide-spread inducible effect.

In a follow-up study the message expression of the synaptic protein NP2 was investigated in a similar setting where long-term (21 days) was compared with short-term (3 days) antidepressant treatment. In addition to the hippocampus, the medial habenula, a relay station within the limbic system was analyzed. Overall there was an upregulation of NP2 mRNA expression following long-term treatment irrespective of the monoaminergic profile of the drug. Simultaneously, NP2 mRNA was analyzed in rats exposed to enriched, normal or deprived environments respectively, an experimental setting known to affect neuronal plasticity. However, in contrast to the pharmacological treatment, this environmental stimulation did not lead to alterations in NP2 mRNA expression in any of the regions studied.

Finally, the function of NP2 as well as the closely related proteins NP1 and NPR was investigated. The “knock-out mouse” technique was used to eliminate these neuronal pentraxins (NPs), both individually and in various combinations. Since previous data had suggested that the NPs are involved in synaptic development, axonal refinement in the visual system during development was analyzed in these animals. In the NP1/NP2 knock-out mice, synaptic formation, axonal development and refinement occurred at a significantly slower rate than in wild-type mice, indicating that the NPs may be necessary for activity-dependent synaptogenesis.

In conclusion, the results of the studies constituting this thesis demonstrate that long-term treatment with antidepressant drugs, possessing different monoaminergic profiles, has selective effects on the expression of NGFI-A, NGFI-B, GR and MR in the mammalian brain. In general, the least selective drugs exhibit the most profound effect suggesting that induction of neuronal plasticity is more effective with multiple neuronal inputs. The results also show that NP2 expression is induced by antidepressant drugs, in contrast to environmental stimulation, supporting the presence of different pathways for inducing neuronal plasticity depending on type of stimuli. Finally, this thesis indicates that the neuronal pentraxins play an important part in synaptic development.


Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2009. 62 p.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1151
National Category
Medical and Health Sciences
urn:nbn:se:liu:diva-51450 (URN)978-91-7393-519-7 (ISBN)
Public defence
2009-12-18, Berzeliussalen, Hälsouniversitetet, Campus US, Linköpings Universitet, Linköping, 00:00 (Swedish)
Available from: 2009-11-02 Created: 2009-11-02 Last updated: 2009-11-02Bibliographically approved

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