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- Nilsson, Anna, et al.
(författare)
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Neuropeptidomics of mouse hypothalamus after imipramine treatment reveal somatostatin as a potential mediator of antidepressant effects
- 2012
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Ingår i: Neuropharmacology. - : Elsevier BV. - 0028-3908 .- 1873-7064. ; 62:1, s. 347-357
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Tidskriftsartikel (refereegranskat)abstract
- Excessive activation of the hypothalamic pituitary adrenal (HPA) axis has been associated with numerous diseases, including depression, and the tricyclic antidepressant imipramine has been shown to suppress activity of the HPA axis. Central hypothalamic control of the HPA axis is complex and involves a number of neuropeptides released from multiple hypothalamic subnuclei. The present study was therefore designed to determine the effects of imipramine administration on the mouse hypothalamus using a peptidomics approach. Among the factors found to be downregulated after acute (one day) or chronic (21 days) imipramine administration were peptides derived from secretogranin 1 (chromogranin B) as well as peptides derived from cerebellin precursors. In contrast, peptides SRIF-14 and SRIF-28 (1-11) derived from somatostatin (SRIF, somatotropin release inhibiting factor) were significantly upregulated by imipramine in the hypothalamus. Because diminished SRIF levels have long been known to occur in depression, a second part of the study investigated the roles of individual SRIF receptors in mediating potential antidepressant effects. SRA880, an antagonist of the somatostatin-1 autoreceptor (sst1) which positively modulates release of endogenous SRIF, was found to synergize with imipramine in causing antidepressant-like effects in the tail suspension test. Furthermore, chronic co-administration of SRA880 and imipramine synergistically increased BDNF mRNA expression in the cerebral cortex. Application of SRIF or L054264, an sst2 receptor agonist, but not 1,803807, an sst4 receptor agonist, increased phosphorylation of CaMKII and GluR1 in cerebrocortical slices. Our present experiments thus provide evidence for antidepressant-induced upregulation of SRIF in the brain, and strengthen the notion that augmented SRIF expression and signaling may counter depressive-like symptoms.
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- Palhagen, Sven, et al.
(författare)
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Monoamines, BDNF, IL-6 and corticosterone in CSF in patients with Parkinsons disease and major depression
- 2010
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Ingår i: JOURNAL OF NEUROLOGY. - : Springer Science Business Media. - 0340-5354 .- 1432-1459. ; 257:4, s. 524-532
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Tidskriftsartikel (refereegranskat)abstract
- The biochemical basis of major depression (MD) in Parkinsons disease (PD) is largely unknown. To increase our understanding of MD in PD patients, the levels of monoamine metabolites (HVA, 5-HIAA and MHPG), BDNF, orexin-A, IL-6 and corticosterone were examined in cerebrospinal fluid. The analyses were performed in MD patients with (n = 11) and without (n = 12) PD at baseline and after 12 weeks of treatment with the antidepressant citalopram, and in patients with solely PD (n = 14) at baseline and after 12 weeks. The major findings were that PD patients with MD had significantly lower baseline levels of MHPG, corticosterone and IL-6 when compared to patients with solely MD. In response to citalopram treatment, patients with solely MD exhibited an expected decrease in 5-HIAA and MHPG levels which was not found in PD patients with MD. Moreover, the levels of BDNF and IL-6 were lower in PD patients with MD compared with patients with solely MD after treatment with citalopram. Thus, the biochemical basis and the response to citalopram differ between PD patients with MD and patients with solely MD.
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- Qi, Hongshi
(författare)
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Studies on antidepressant-mediated regulation of signal transduction
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Depression affects around 16% of the population at some point in their lives and major depressive disorder is a leading cause of disability worldwide. Depression is caused by an interaction of genetic and environmental factors, but the molecular and cellular mechanisms underlying its pathogenesis are not entirely clear. The monoamine hypothesis of depression, which involves imbalances in serotonergic, noradrenergic and possibly dopaminergic functions, has dominated notions and explanations of the pathophysiology of depression. Most clinically used antidepressants act by increasing the synaptic levels of these monoamines. While these treatments are beneficial in many cases, a large population of depressed patients do not respond, or respond suboptimal, to these current antidepressant treatments. There is accumulating evidence that depression is associated with impairments of synaptic plasticity, dendritic arborization and cell proliferation/survival in hippocampus and frontal cortex and normalization of these processes could lead to antidepressant responses. The neurochemical mechanisms underlying these functional and structural impairments are poorly understood, but appear to involve changes in glutamate neurotransmission, neuropeptides, neurotrophins and intracellular signaling cascades. The present studies used biochemical and behavioural techniques and found that the atypical antidepressant, tianeptine, which is a serotonin reuptake enhancer, increased phosphorylation of the GluA1 subunits of AMPA glutamate receptors both in brain slices and in intact animals. Antidepressant and stimulatory behavioral responses to tianeptine were attenuated in mice bearing point mutations at Ser831-/Ser845-GluA1. Acute elevated platform stress, known to inhibit synaptic plasticity in hippocampal→frontal cortex neurotransmission, was found to downregulate a putative BDNF/MEK/MAPK signaling cascade in frontal cortex which could be counteracted by tianeptine, imipramine and the glucocorticoid receptor antagonist mifepristone. The serotonin receptors mediating the antidepressant effects of serotonin reuptake inhibitors, the currently most prescribed class of antidepressants, are not fully understood. Here, it is reported blockade of 5-HT6 receptors with the antagonist SB271046 counteracts the potentiating actions of fluoxetine on cortical phospho-Ser845-GluA1 and reduces its antidepressant-like behavioral action. Moreover, the 5-HT6 receptor agonist EMDT mimics antidepressant-like biochemical and behavioral effects of fluoxetine. In conclusion, these studies have shown that the atypical antidepressant tianeptine can potentiate signaling cascades associated with synaptic plasticity and add further evidence that tianeptine acts as an enhancer of AMPA glutamate transmission. These studies also suggest, for the first time, a role for 5-HT6 receptors in mediating antidepressant responses.
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