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Captodiamine, a putative antidepressant, enhances hypothalamic BDNF expression in vivo by synergistic 5-HT2c receptor antagonism and sigma-1 receptor agonism
Author(s)
Date Issued
2013-10
Date Available
2013-06-26T14:09:40Z
Abstract
The putative antidepressant captodiamine is a 5-HT2c receptor antagonist and agonist at sigma-1 and D3 dopamine receptors, exerts an anti-immobility action in the forced swim paradigm, and enhances dopamine turnover in the frontal cortex. Captodiamine has also been found to ameliorate stress-induced anhedonia, reduce the associated elevations of hypothalamic corticotrophin releasing factor (CRF) and restore the reductions in hypothalamic BDNF expression. Here we demonstrate chronic administration of captodiamine to have no significant effect on hypothalamic CRF expression through sigma-1 receptor agonism however both sigma-1 receptor agonism or 5-HT2c receptor antagonism were necessary to enhance BDNF expression. Regulation of BDNF expression by captodiamine was associated with increased phosphorylation of transcription factor CREB and mediated through sigma-1 receptor agonism but blocked by 5-HT2c receptor antagonism. The existence of two separate signalling pathways was confirmed by immunolocalisation of each receptor to distinct cell populations in the paraventricular nucleus of the hypothalamus. Increased BDNF induced by captodiamine was also associated with enhanced expression of synapsin, but not PSD-95, suggesting induction of long-term structural plasticity between hypothalamic synapses. These unique features of captodiamine may contribute to its ability to ameliorate stress-induced anhedonia as the hypothalamus plays a prominent role in regulating HPA axis activity.
Sponsorship
Higher Education Authority
Other Sponsorship
Enterprise Ireland Commercialisation Fund (ATRP/2003/BRI/117 and CFTD/2008/115);Postgraduate Scholarship (RR) from the Higher Education Authority Programme for Research in Third-Level Institutions (cycle 4) (Bio)Pharmaceutical and Pharmacological Sciences National Graduate Enhancement Programme.
Type of Material
Journal Article
Publisher
Sage
Journal
Journal of Psychopharmacology
Volume
27
Issue
10
Start Page
930
End Page
939
Language
English
Status of Item
Not peer reviewed
This item is made available under a Creative Commons License
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