Effect of the antidepressant tianeptine on the activity of the hypothalamo-pituitary-adrenal axis (original) (raw)
Related papers
European Journal of Pharmacology, 1991
The possible cifect of tianeptine, a novel antidepressant agent, on the neuroendocrine response to stress was investigated in adult male rats. Tube restraint stress for 30 min induced a marked increase of plasma ACTH and corticosterone. A single i.p. injection of tianeptine (10 mg,/kg), 120 min before stress caused a significant decrease of ACTH and corticosterone levels. In order to investigate the kinetics of the effect of tianeptine, the drug was injected at various times (from 15 min to 12 h) before restraint stress. The inhibitory effect of tianeptine on stress-induced elevations of plasma ACTH and corticosterone occurred from 1 to 3 h after the injection. Administration of increasing doses of tianeptine revealed that only the highest doses (10 and 20 mg/kg) had a significant effect on stress-evoked stimulation of ACTH and corticosterone secretion. These results show that the antidepressant, tianeptine, reduces the activation of the hypothalamo-pituitary-adrenal (HPA) axis induced by restraint stress. Since depressed patients generally exhibit an elevated cortisol level, the present data suggest that part of the therapeutic properties of tianeptine could be accounted for by the effect of this antidepressant to modulate the activity of the HPA axis.
European Journal of Pharmacology, 1994
The effects of acute and chronic administration of tianeptine, a novel antidepressant agent, on the hypothalamo-pituitaryadrenal axis were studied in the adult male rat. A single injection of tianeptine did not alter the activity of the hypothalamopituitary-adrenal axis. In contrast, chronic administration of tianeptine (10 mg/kg twice a day for 15 days) induced a significant decrease in the concentration of corticotropin-releasing factor (CRF) in the hypothalamus and adrenocorticotropin (ACTH) in the anterior lobe of the pituitary. Chronic tianeptine treatment did not modify CRF levels in the cerebral cortex and hippocampus, and did not alter o~-melanocyte-stimulating hormone and/3-endorphin levels in the neurointermediate lobe of the pituitary. Using the in situ hybridization technique, we observed that chronic administration of tianeptine did not modify CRF mRNA levels in the paraventricular nucleus of the hypothalamus. The effect of chronic tianeptine treatment on the neuroendocrine response to stress was also investigated. Tube restraint stress for 30 min induced a significant depletion of hypothalamic CRF and a substantial increase of plasma ACTH and corticosterone. Tianeptine abolished the stress-induced reduction of hypothalamic CRF concentration and markedly reduced the stress-induced increase in plasma ACTH and corticosterone levels. Taken together, these results suggest that tianeptine acts primarily at the level of the hypothalamus: (1) in unstressed rats, tianeptine reduces hypothalamic CRF and pituitary ACTH contents; (2) in stressed animals, tianeptine attenuates the activation of the hypothalamo-pituitary-adrenal axis.
Biological Psychiatry, 1992
Tianeptine is a novel tricyclic agent that activates the neuronal uptake of serotonin (5hydroxytryptamine,. Taking into account the antidepressant effect of tianeptine in animals and humans, we have measured the influence of a pretreatment with tianeptine (10 mg/kg IP I hr beforehand) on some consequences of a single 2-hr restraint stress session in male rats. Thus, we have analyzed (1) 5-HT metabolism in various brain regions and plasma glucose (an index of sympathoadrenai activity) and corticosterone levels at the end of stress, and open field scores 18-19 hr after immobilization in saline-or tianeptine-pretreated rats. Tianeptine was found to leave unaltered stressinduced increases in cortical, hippocampal, hypothalamic, midbrain, and striatal serotonergic metabolism. Similarly, stress-elicited elevations in plasma glucose and corticosterone levels were not affected by tianeptine pretreatment. On the other hand, tianeptine pretreatment reversed stress-induced deficit in exploratory activity. To test whether the latter positive effect of tianeptine was associated with changes in plasma glucose and corticosterone levels during t~e early phase of stress, we have measured plasma glucose and corticosterone levels (at O, 5, 15, 30, and 60 rain) in resting and stressed (catheterized) rats. The results indicated that tianeptine pretreatment did not alter plasma glucose and corticosterone early responses to stress. Although this study confirmed the antidepressant effect of tianeptine, the neurochemical and neuroendocrinological mechanisms underlying this positive effect remain to be determined.
Hypothalamic–pituitary–adrenal axis, neuroendocrine factors and stress
Journal of Psychosomatic Research, 2002
The stress system coordinates the adaptive responses of the organism to stressors of any kind. The main components of the stress system are the corticotropin-releasing hormone (CRH) and locus ceruleus -norepinephrine (LC/NE)-autonomic systems and their peripheral effectors, the pituitary -adrenal axis, and the limbs of the autonomic system. Activation of the stress system leads to behavioral and peripheral changes that improve the ability of the organism to adjust homeostasis and increase its chances for survival. The CRH and LC/NE systems stimulate arousal and attention, as well as the mesocorticolimbic dopaminergic system, which is involved in anticipatory and reward phenomena, and the hypothalamic b-endorphin system, which suppresses pain sensation and, hence, increases analgesia. CRH inhibits appetite and activates thermogenesis via the catecholaminergic system. Also, reciprocal interactions exist between the amygdala and the hippocampus and the stress system, which stimulates these elements and is regulated by them. CRH plays an important role in inhibiting GnRH secretion during stress, while, via somatostatin, it also inhibits GH, TRH and TSH secretion, suppressing, thus, the reproductive, growth and thyroid functions. Interestingly, all three of these functions receive and depend on positive catecholaminergic input. The end-hormones of the hypothalamic -pituitary -adrenal (HPA) axis, glucocorticoids, on the other hand, have multiple roles. They simultaneously inhibit the CRH, LC/NE and b-endorphin systems and stimulate the mesocortico-limbic dopaminergic system and the CRH peptidergic central nucleus of the amygdala. In addition, they directly inhibit pituitary gonadotropin, GH and TSH secretion, render the target tissues of sex steroids and growth factors resistant to these substances and suppress the 5 0 deiodinase, which converts the relatively inactive tetraiodothyronine (T 4 ) to triiodothyronine (T 3 ), contributing further to the suppression of reproductive, growth and thyroid functions. They also have direct as well as insulin-mediated effects on adipose tissue, ultimately promoting visceral adiposity, insulin resistance, dyslipidemia and hypertension (metabolic syndrome X) and direct effects on the bone, causing ''low turnover'' osteoporosis. Central CRH, via glucocorticoids and catecholamines, inhibits the inflammatory reaction, while directly secreted by peripheral nerves CRH stimulates local inflammation (immune CRH). CRH antagonists may be useful in human pathologic states, such as melancholic depression and chronic anxiety, associated with chronic hyperactivity of the stress system, along with predictable behavioral, neuroendocrine, metabolic and immune changes, based on the interrelations outlined above. Conversely, potentiators of CRH secretion/action may be useful to treat atypical depression, postpartum depression and the fibromyalgia/chronic fatigue syndromes, all characterized by low HPA axis and LC/NE activity, fatigue, depressive symptomatology, hyperalgesia and increased immune/inflammatory responses to stimuli. D
Journal of Endocrinology
Corticotropin-releasing factor (CRF), a 41 amino acidcontaining peptide, appears to mediate not only the endocrine but also the autonomic and behavioral responses to stress. Stress, in particular early-life stress such as childhood abuse and neglect, has been associated with a higher prevalence rate of affective and anxiety disorders in adulthood. In the present review, we describe the evidence suggesting that CRF is hypersecreted from hypothalamic as well as from extrahypothalamic neurons in depression, resulting in hyperactivity of the hypothalamic-pituitaryadrenal (HPA) axis and elevations of cerebrospinal fluid (CSF) concentrations of CRF. This increase in CRF neuronal activity is also believed to mediate certain of the behavioral symptoms of depression involving sleep and appetite disturbances, reduced libido, and psychomotor changes. The hyperactivity of CRF neuronal systems appears to be a state marker for depression because HPA axis hyperactivity normalizes following successful antidepressant treatment. Similar biochemical and behavioral findings have been observed in adult rats and monkeys that have been subjected to early-life stress. In contrast, clinical studies have not revealed any consistent changes in CSF CRF concentrations in patients with anxiety disorders; however, preclinical findings strongly implicate a role for CRF in the pathophysiology of certain anxiety disorders, probably through its effects on central noradrenergic systems. The findings reviewed here support the hypothesis that CRF receptor antagonists may represent a novel class of antidepressants and/or anxiolytics.
Pharmacology & Therapeutics, 1990
Changes in hormones of the hypothalamic-pituitary-adrenal (HPA) axis in patients suffering from anxiety and depressive disorders are reviewed, and the changes that occur when animals are exposed to test situations used preclinically to model anxiety or depression. The effects of exogenous administration of HPA hormones both clinically and in animal tests is discussed and the effects of clinically used anxiolytics and antidepressants on hormones of the HPA axis. The final section discusses stress-induced changes in the CNS.
Journal of Pharmacology and Experimental Therapeutics, 2003
Corticotropin-releasing factor (CRF) is the major physiological regulator of the hypothalamic-pituitary-adrenal (HPA) axis and serves to coordinate the mammalian endocrine, autonomic, and behavioral responses to stress. Considerable literature from clinical and preclinical data suggests that hypersecretion of hypothalamic and/or extrahypothalamic CRF systems is a major factor in the pathogenesis of affective and anxiety disorders. Based on this premise, a CRF 1 receptor antagonist has been hypothesized to possess anxiolytic and/or antidepressant properties. In this study, an acute dose of the lipophilic CRF 1 receptor antagonist 3-[6-(dimethylamino)-4-methyl-pyrid-3-yl]-2,5-dimethyl-N,N-dipropyl-pyrazolo[2,3-a]pyrimidin-7-amine (R121919), administered i.v. to rats with surgically implanted jugular cannula 60 min before a 5-min restraint stress, dose dependently attenuated peak plasma adrenocorticopin hor-
European Psychiatry, 1993
The effects of the novel antidepressant tianeptine, after acute or chronic administration, were compared in normal and restraint-stressed (30 min or 2 h) Wistar rats. Tianeptine, at the dose of 10 mg/kg, did not exert any effect in non-stressed rats. However, in animals restrained for 30 min, tianeptine reduced the increase of circulating ACTH and /3-endorphin levels without modification of corticosterone. Moreover, it antagonized the deficit of vertical exploratory activity in an open field. In rats restrained for 2 hours, a single injection of tianeptine suppressed the stress-induced increase of TAT hepatic activity and moderately attenuated the deficit of activity in the open field. This effect was less marked and not statistically significant after chronic treatment.
Psychoneuroendocrinology, 1988
The effect of chronic administration of the clinically effective antidepressants, imipramine, clomipramine and desipramine, on corticosterone (CS) release in male rats was investigated. Chronic administration of imipramine, clomipramine and desipramine at a dose of 20 mg/kg b.w./day, but not at a dose of 2 mg/kg b.w./day, suppressed blood CS concentration at 2000h and abolished its circadian rhythm The normal circadian rhythm of CS release resumed seven days after the termination of imipramine injection. The acute administration of imipramine (20 mg/kg b.w./day) at 0800h but not at 2000h elevated CS concentrations. Chronic administration of imipramine (20 mg/kg b.w./day) tended to increase the inhibitory effect of dexamethasone on CS release. Adrenocortical sensitivity to exogenous adrenocorticotropic hormone tended to be decreased by chronic administration of imiprarnine (20 mg/kg b.w./day). These results indicate that antidepressants have effects on the hypothalamo-pituitary-adrenocortical axis which may confound psychoneuroendocrinological tests, such as the dexamethasone suppression test, for the diagnosis of affective disorders.
Development of CRF1 Receptor Antagonists as Antidepressants and Anxiolytics
CNS Drugs, 2006
that are considered to be stress-related disorders because some form of stressful life event often triggers their symptoms. Corticotropin-releasing factor (CRF) is a 41-amino-acid neuropeptide involved in mediating neuroendocrine, autonomic and behavioural responses to stress, and clinical studies provide evidence for the role of CRF in the development of depression and anxiety disorders. Two CRF receptor subtypes have been identified to date-the CRF1 receptor and the CRF2 receptor. Preclinical models provide evidence of a role for CRF1 receptors in the activation of the stress response. Data from these experiments suggest that antagonism of CRF1 receptor activity may provide an effective pharmacological treatment for stress-related psychiatric disorders. This review highlights progress to date with the development of CRF1 receptor antagonists as potential pharmacotherapies for depression and anxiety disorders. Although additional research is needed to fully investigate the efficacy and safety profiles of CRF1 receptor antagonists as candidate medications for these disorders, the results of preclinical experiments and clinical trials are encouraging. Further development of these compounds is warranted. Depression and anxiety disorders are highly Corticotropin-releasing factor (CRF) is a 41amino-acid neuropeptide involved in mediating prevalent forms of mental illness. Worldwide, deneuroendocrine, [5] autonomic [6,7] and behavioural repression will have a lifetime occurrence of 8-12% in sponses to stress. [8,9] CRF is the main regulator of all individuals. [1] In addition, in the US alone apthe hypothalamic-pituitary adrenal (HPA) axis proximately 30% of all adults will experience some stress response, which has been traditionally used by form of anxiety disorder at some point during their biologists as a method of quantifying stress. [5] lives. [2] These conditions place a considerable economic burden on society [1,3] and have a high preva-Results from clinical studies suggest a role for lence of comorbidity. [4] Often, stressful life events CRF in the development of depression and anxiety trigger or worsen the symptoms of these disorders, disorders. For example, CRF levels are elevated in and patients diagnosed with them have difficulty the CSF of patients diagnosed with post-traumatic coping with stress. stress disorder. [10] Clinically depressed individuals