Neuropeptidomics of mouse hypothalamus after imipramine treatment reveal somatostatin as a potential mediator of antidepressant effects (original) (raw)
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Chronic antidepressant treatment modulates the release of somatostatin in the rat nucleus accumbens
Neuroscience Letters, 2006
This study investigated the in vivo neuronal release of somatostatin in the rat nucleus accumbens (NAc), and the effect of chronic administration of antidepressants. Microdialysis studies were performed on male Sprague-Dawley rats, in accordance with the EU guidelines (EEC Council 86/609). Somatostatin levels were quantified by radioimmunoassay (RIA) or enzyme linked immuno sorbent assay (ELISA). A high concentration of potassium ions (K + , 100 mM) was used to ascertain the neuronal release of somatostatin. Antidepressant treatments involved the administration of citalopram (20 mg/2 ml/kg, i.p., once daily) or desipramine (DMI, 5 mg/2 ml/kg, i.p., twice daily) for 21 days. Control groups received saline (2 ml/kg for 21 days, i.p.) once or twice daily respective of the antidepressant treatment. Basal levels of somatostatin released were found to be 20.01 ± 0.52 fmol/sample. K + (100 mM) increased somatostatin levels at 205% of basal. Chronic citalopram and desipramine treatments also increased the somatostatin levels by 83 ± 32% and 40 ± 6% of basal, respectively. These findings indicate that somatostatin is released neuronally in the NAc. Antidepressants influence its release in a positive manner, suggesting the necessity of further studies for the elucidation of the involvement of somatostatin in the putative therapeutic effects of these agents.
Somatostatin content and receptors in the cerebral cortex of depressed and control subjects
Journal of Neurology, Neurosurgery & Psychiatry, 1988
Somatostatin-like immunoreactivity is reduced in the cerebrospinal fluid in depression and this is presumed to reflect alterations in cerebral somatostatinergic systems. We have examined this hypothesis by measuring this immunoreactivity and somatostatin receptors in post-mortem cortical tissue from depressed patients and control subjects. There was no significant difference in the temporal and occipital cortex in somatostatin-like immunoreactivity or in somatostatin receptor affinity and binding capacity between depressed and control groups. It is concluded that there may not be an alteration of cortical somatostatin function in depression.
Pharmacological Reports, 2013
Neuropeptides have been implicated in the physiology and pathophysiology of stress responses and therefore may play an important role in the pathogenesis of affective disorders such as Major Depression Disorder (MDD). The data presented in this mini-review demonstrate the role of prolactin (PRL) and somatostatin (STT) in the pathology and pharmacotherapy of MDD, focusing particularly on the response to antidepressant treatment, and compare the available data with the results obtained in our laboratory using the well-validated chronic mild stress (CMS) animal model of MDD. Despite the availability of many pharmacological therapies for depression, ca. 35% patients remain treatment resistant. This clinical situation is also true for rats subjected to CMS; some animals do not respond to antidepressant therapy and are considered treatment resistant. The most interesting results presented in this mini-review concern the changes in PRL and SST receptors in the brains of rats subjected to the full CMS procedure and IMI treatment and demonstrate the role of these receptors in the mechanisms of antidepressant action. The possible interaction between SST and PRL, the involvement of the D 2 dopamine receptor, and their direct protein-protein interactions are also discussed, with the conclusion that these two neurohormones play an important role in the mechanism of resilience after stress as well as in the mechanism of action of antidepressant drugs.
Life Sciences, 1999
Expression of the mRNA for somatostatin (SRIF) in the periventricular nucleus (PeN), the level of SRIF in the stalk-median eminence (SME) and the concentration of growth hormone (GH) in the plasma were examined in depressionmodel rats in an attempt to confirm the hypothesis that SRIF neurons in the hypothalamus are hypofunctional in this model. We exposed male Wistar rats to intermittent walking stress for two weeks and then we measured their spontaneous running activity for 12 days. We divided the rats into a depression-model group and a partial-recovery group according to the spontaneous running activity of each rat after the termination of exposure to stress. Expression of SRIF mRNA in the PeN of the hypothalaimus was monitored by in situ hybridization and relative levels were determined with an image analysis system. The relative level of expression of SRIF mRNA in the PeN was lower in rats in the depression-model group than in the control group and the partial-recovery group. The level of SRIF in the SME was lower and the plasma concentration of GH was higher in the depression-model group than in the other groups. Our findings suggest that reduced expression of mRNA for SRIF in the PeN might be associated with the pathophysiology of rats with this particular model of depressia'n.
Low levels of somatostatin in human CSF mark depressive episodes
Psychoneuroendocrinology, 1984
Somatostatin-like immunoreactivity was measured in the cerebrospinal fluid (CSF) of 85 inpatients with current or recent episodes of major depressive disorders, diagnosed according to Research Diagnostic Criteria (RDC) as assessed with the Schedule for Affective Disorders and Schizophrenia (SADS). Several biopsychiatric tests were run during the same week of investigation. Results indicate low levels of CSF somatostatin to be a state marker for episodes of depression characterized by sad appearance, feelings of tiredness, insomnia, and subjective inability to acknowledge any external precipitants for the depression. CSF somatostatin was negatively related to platelet monoamine oxidase (MAO) activity; MAO activity appeared to account better for the degree of melancholic features than did somatostatin. The ratio between 3-methoxy-4-hydroxyphenylglycol (MHPG) and homovanillic acid (HVA) in CSF also correlated negatively with somatostatin. A positive relationship was noted between CSF xanthine and somatostatin. There was a highly significant curvilinear correlation between CSF somatostatin and serum TSH concentrations, but no correlations between CSF somatostatin and serum GH or prolactin, or with plasma cortisol before or after dexamethasone. SOMATOSTATIN is a cyclic tetradecapeptide (MW 1640 daltons) that inhibits the release of growth hormone (GH) from the pituitary (Vale et al., 1975). The name "panhibin" has been suggested to emphasize its powerful inhibitory function in a number of systems, including TSH release (McCann, 1982). Somatostatin-like immunoreactivity is widely distributed in rat brain (Brownstein et al., 1975; Kobayashi et al., 1977). In a post-mortem study on humans, Eckernas et al. (1978) found rather high concentrations of somatostatin in the neostriatum, while the highest levels were localized in the hypothalamus and in the medial part of the amygdaloid complex. S¢rensen (1982) studied human brain material obtained during neurosurgical operations of twelve patients and found somatostatinpositive cell bodies to be widely distributed and present in all cortical layers and in all areas studied (frontal, parietal and temporal). Cell bodies were numerous in the cortex, especially in layer I, where somatostatin fibers were in close contact with other cells. Very large somatostatin cells with long fibers were found throughout the subcortical white matter. Somatostatin-and avian pancreatic polypeptide (APP)-like immunoreactivities were reported by Vincent et al. (1982) to coexist in the rat forebrain (neocortex, hippocampus, and other areas) and, at least in the peripheral nervous system, somatostatin has been shown to occur in some sympathetic noradrenergic neurons (HOkfelt et al., 1977). The importance of the somatostatin system is demonstrated by the finding of this peptide in all regions of the fetal rat brain as early as 14 days post-mating (McGregor et al., 1982).
European Journal of Pharmacology, 2013
To gain insight into the possible immune targets of antidepressant, we evaluated the expression of several inflammatory mediators in the hypothalamus of rats chronically (28 days) treated with the serotonin selective reuptake inhibitor fluoxetine (5 mg/kg, i.p.) or the tricyclic compound imipramine (15 mg/kg, i.p.). We focused our attention on the hypothalamus as it plays a key role in determining many of the somatic symptoms experienced by depressed patients. This brain region, critical also for expression of motivated behaviours, participates in the control of the hypothalamic-pituitary-adrenal axis activity and in stress response as well as coordinates physiological functions such as sleep and food intake that have been found altered in a high percentage of depressed patients. Notably, hypothalamus is a key structure for brain cytokine expression and function as it integrates signals from the neuro, immune, endocrine systems. By means of quantitative Real Time PCR experiments we demonstrated that a chronic treatment with either fluoxetine or imipramine resulted in a reduction of IL-6 and IFN-γ mRNAs and increased IL-4 mRNA expression in the rat hypothalamus. Moreover, we demonstrated that hypothalamic expression of members of IL-18 system was differentially affected by chronic antidepressant treatments. Chronically administered fluoxetine decreased IL-8 and CX3CL1 hypothalamic expression, while a chronic treatment with imipramine decreased p11 mRNA. Our data suggest that a shift in the balance of the inflammation toward an anti-inflammatory state in the hypothalamus may represent a common mechanism of action of both the chronic treatments with fluoxetine and imipramine.
Brain Research, 2008
Although glucocorticoid feedback sensitivity of the hypothalamic-pituitary-adrenal (HPA) axis is frequently impaired in depression, atypical depression may exhibit increased feedback sensitivity. Because monoamine oxidase inhibitors (MAOI) are often more effective than tricyclic antidepressants (TCA) for atypical depression, we hypothesized that to normalize HPA function in atypical depression, MAOI would differ from TCA in decreasing rather than increasing feedback sensitivity. Consistent with this hypothesis and prior evidence for opposing effects on HPA feedback in mice, we report contrasting effects of chronic MAOI (phenelzine) and TCA (imipramine) treatment on neural corticosteroid receptor gene expression in adrenalectomized male C57BL/6 mice with fixed glucocorticoid levels. Our findings corroborate prior reports of antidepressant-induced increases in hippocampal mineralocorticoid (MR) and glucocorticoid receptor (GR) expression.
Journal of Clinical Investigation, 1991
Imipramine is the prototypic tricyclic antidepressant utilized in the treatment of major depression and exerts its therapeutic efficacy only after prolonged administration. We report a study of the effects of short-term (2 wk) and long-term (8 wk) administration of imipramine on the expression of central nervous system genes among those thought to be dysregulated in imipramine-responsive major depression. As assessed by in situ hybridization, 8 wk of daily imipramine treatment (5 mg/kg, i.p.) in rats decreased corticotropin-releasing hormone (CRH) mRNA levels by 37% in the paraventricular nucleus (PVN) of the hypothalamus and decreased tyrosine hydroxylase (TH) mRNA levels by 40% in the locus coeruleus (LC). These changes were associated with a 70% increase in mRNA levels of the hippocampal mineralocorticoid receptor (MR, type I) that is thought to play an important role in mediating the negative feedback effects of low levels of steroids on the hypothalamicpituitary-adrenal (HPA) axis. Imipramine also decreased proopiomelanocortin (POMC) mRNA levels by 38% and glucocorticoid receptor (GR, type II) mRNA levels by 51% in the anterior pituitary. With the exception of a 20% decrease in TH mRNA in the LC after 2 wk of imipramine administration, none of these changes in gene expression were evident as a consequence of short-term administration of the drug. In the light of data that major depression is associated with an activation of brain CRH and LC-NE systems, the time-dependent effect of long-term imipramine administration on decreasing the gene expression of CRH in the hypothalamus and TH in the LC may be relevant to the therapeutic efficacy of this agent in depression. (J. Clin. Invest. 1991. 87:831-837).
Antidepressants and their neuroendocrine mechanisms in depression
Previously, we have shown that in vitro antidepressants modulate glucocorticoid receptor (GR) function and expression, and have suggested that these effects could be relevant for the mechanism of action of antidepressants. To further clarify the interaction between antidepressants and glucocorticoids, we evaluated the in vitro effect of the tricyclic antidepressant, clomipramine (CMI), on the GR function in 15 treatment-resistant depressed inpatients and 28 healthy controls. Diluted whole-blood cells were incubated for 24 h in the presence or absence of CMI (10 mM). Glucocorticoid function was measured by glucocorticoid inhibition of lypopolysaccharide (LPS)stimulated interleukin-6 (IL-6) levels. The results show that glucocorticoids (dexamethasone, prednisolone, cortisol and corticosterone) caused a concentration-dependent inhibition of LPS-stimulated IL-6 levels. In healthy controls, CMI decreased glucocorticoid inhibition of LPS-stimulated IL-6 levels, while this effect was not present in depressed patients. Therefore, depressed patients, who were clinically treatment resistant, also showed a lack of effect of the antidepressant in vitro. Upcoming studies shall test whether assessing the effects of antidepressants in vitro on GR function could predict future treatment response in a clinical setting.