Cristina García-Marquez

Chronic stress increases serotonin and noradrenaline in rat brain and sensitizes their responses to a further acute stress

Abstract: The effects of 1 h/day restraint in plastic tubes for 24 days on the levels of serotonin (5‐HT), 5‐hydroxyindole‐acetic acid (5‐HIAA), tryptophan (TP), and noradrenaline (NA) in six regions of rat brain 20 h after the last restraint period were investigated. The levels of 5‐HT, 5‐HIAA, and NA but not TP increased in several regions. The effects of 1 h of immobilization on both control and chronically restrained rats were also studied. Immobilization per se did not alter brain 5‐HT, 5‐HIAA, and TP levels, but decreased NA in the pons plus medulla oblongata and hypothalamus. However, immobilization after chronic restraint decreased 5‐HT, increased 5‐HIAA, and decreased NA in most brain regions in comparison with values for the chronically restrained rats. We suggest that chronic restraint leads to compensatory increases of brain 5‐HT and NA synthesis and sensitizes both monoaminergic systems to an additional acute stress. These changes may affect coping with stress demands.

Chronic stress depresses exploratory activity and behavioral performance in the forced swimming test without altering ACTH response to a novel acute stressor.

The present study investigated the effects of chronic stress on some behavioral and endocrine variables in adult male rats. The variables were always measured the day that followed the stress session to chronically stressed rats. Two stress models were used: chronic shock (CS), and a combination of various stressors randomly chosen each day (CV). Chronic but not acute exposure to the stressors resulted in decreased exploratory activity in the holeboard. Likewise, only chronic exposure to shock or variable stressors resulted in increased immobility in the Porsolts test. Taken together these results suggest that changes in exploratory and forced swimming activities might be affected by chronic stress. In contrast, neither CS nor CV rats showed altered basal or stress-induced levels of ACTH which suggests that the activity of the axis was unchanged. Although the present data indicate that chronic stress caused behavioral abnormalities closely related to that expected to take place in some type of depressive disorders, endocrine data are not in good agreement with those occurring in depression.

Interaction between chronic stress and clomipramine treatment in rats. Effects on exploratory activity, behavioral despair, and pituitary-adrenal function

The interaction between the effects of chronic electrical tail shock and clomipramine (CMI) on exploratory activity, behavioral despair and pituitary-adrenal function was studied in adult male rats. Both CMI and shock administered alone significantly reduced exploratory activity in a novel environment (holeboard). Neither interaction nor additive effects were observed when the two treatments were combined. In contrast, chronic shock increased the immobility in the forced swimming test (behavioral despair) and this effect was completely prevented by concomitant CMI administration. Pituitary-adrenal function was not significantly influenced by any of the treatments. The results indicate that: (a) chronic CMI treatment prevented some but not all behavioral changes caused by chronic shock, and (b) no interaction with basal and stress levels of pituitary-adrenal hormones was observed.

Chronic administration of clomipramine prevents the increase in serotonin and noradrenaline induced by chronic stress

The effects of chronic clomipramine administration (15 mg/kg daily for 23 days) on changes in serotonin (5-hydroxytryptamine, 5-HT), 5-hydroxyindoleacetic acid (5-HIAA) and noradrenaline (NA) induced by chronic stress have been studied in the rat brain. Chronic stress increased 5-HT in midbrain, pons and hippocampus, 5-HIAA in frontal cortex, midbrain, pons and hippocampus, and NA in midbrain and striatum. Chronic clomipramine significantly decreased the levels of 5-HT in most regions. In hypothalamus, hippocampus and perhaps in frontal cortex this effect possibly reflects decreased synthesis caused by an action on presynaptic 5-HT receptors. However, in midbrain, pons and striatum decreased 5-HT could not be attributed to a decrease in its synthesis since 5-HIAA also increased. This drug treatment also reduced NA in all regions except the striatum. Nevertheless, conclusions on NA synthesis or turnover cannot be drawn since only NA levels were measured. When administered concurrently, chronic clomipramine prevented the increases in 5-HT, 5-HIAA and NA produced by chronic stress. These results are in good accordance with previous findings showing that chronic antidepressant treatment also prevented behavioural disturbances induced by chronic stress.

Previous chronic ACTH administration does not protect against the effects of acute or chronic stress in male rats

The effect of previous chronic ACTH administration on the physiological response to acute and chronic immobilization stress was studied in adult male rats. Chronic ACTH administration slightly reduced food intake and drastically inhibited body weight gain. Serum corticosterone levels were similar in saline- and ACTH-treated rats twenty hours after the last administration. However, the corticosterone response to 1 hr immobilization was greatly reduced by previous ACTH administration. When the exposure to the stressor was prolonged up to 18 hours, the corticosterone response was similar in saline, and ACTH-treated rats. While body weight loss caused by starvation and acute stress was lower in ACTH-treated rats, stomach ulceration was greater in the latter animals. Although ACTH-treated rats showed higher body weight gain than saline-treated animals during chronic immobilization, this was probably due to catch-up growth as food intake inhibition caused by the stressor was similar in the two groups. Pituitary-adrenal adaptation to the repeated stressor was the same in saline- and ACTH-treated rats. Therefore, the effects of previous ACTH treated on the physiological response to either acute or chronic stress appear to be mixed, depending on the variable studied.

Tricyclic antidepressants activate the pituitary-adrenal axis in the rat. Tolerance to repeated drug administration

The effects of acute chronic administration of tricyclic antidepressants on the pituitary-adrenal axis were studied in adult male rats. Acute administration of desipramine, imipramine and chlorimipramine activated the pituitary-adrenal axis. The effect of imipramine was found to be of short duration with a significant increase at 30 and 60 min after the administration of the drug and a return to baseline levels at 180 min. The effect of imipramine was dose-dependent. Twenty hours after the last drug administration rats chronically injected with chlorimipramine showed normal basal and saline-induced levels of corticosterone. However the response of these rats to an acute dose of chlorimipramine was significantly lower than that of drug-naive rats, indicating tolerance to the drug. The mechanisms involved in the activation of the pituitary-adrenal axis caused by antidepressants and the tolerance to repeated drug administration are still unknown.

The effects of chronic intermittent stress on basal and acute stress levels of TSH and GH, and their response to hypothalamic regulatory factors in the rat.

The effect of chronic stress on basal and stress-induced alterations of TSH and GH was studied in adult male rats. Chronically stressed rats were subjected 6 days per week for 4 weeks to several acute stressors including saline injections, noise, ether and forced swimming. Each day, one stressor was chosen randomly. Twenty hr after the last stress session, basal levels of TSH were normal or increased, with no altered pituitary response to TRH. In contrast, the TSH rise induced by acute stress was blunted in chronically stressed rats. Chronic stress resulted in lower basal and acute stress levels of GH. These modifications were probably due to changes in the release of hypothalamic regulatory hormones, because no evidence for altered TSH response to TRH, and GH response either to GHRH or to somatostatin, was found. Some abnormal responses of GH to TRH and of TSH to GHRH were observed in chronically stressed rats. These data indicate that this type of chronic stress induced significant changes in basal and acute stress levels of GH and TSH in the rat.

Previous chronic chlorimipramine treatment did not modify some physiological responses to acute and chronic stress in rats

The effects of previous chronic administration of the tricyclic antidepressant drug chlorimipramine (CMI) on some physiological responses of adult male rats to stress has been studied. CMI significantly reduced food intake and body weight gain, but did not alter either adrenal weight or basal serum corticosterone levels. Corticosterone response to 1 h of immobilization stress was the same in saline and CMI-treated rats. When the rats previously treated with CMI were subjected to chronic immobilization stress, it was found that the drug did not alter the anorexic effects of the stressor, but reduced the rate of adaptation of adrenocorticotropin response to stress. These data indicate that previous chronic CMI administration does not prevent changes in the secretory activity of the pituitary-adrenal system or the reduction of food intake and body weight caused by strong stressors.

Long-lasting effects of chronic chlorimipramine treatment of rats on exploratory activity on a hole-board, and on immobility in the force swimming test

Abstract The study concerned the effects of acute and chronic clomipramine administration to male rats on exploratory activity in a novel environment (hole-board) and on immobility in the forced swimming test. Acute clomipramine administration did not alter either exploratory activity on a hole-board as measured 3 or 20 h after drug administration, or immobility in the forced swimming test as measured 20 h after drug administration. Approximately 20 h after the last injection of clomipramine, the rats chronically treated with the drug showed reduced exploratory activity on the hole-board. In contrast, chronic clomipramine treatment significantly increased the activity in the forced swimming test. The effects of the drug on exploratory and forced swimming activities persisted for 14 days after the cessation of clomipramine administration. These data indicate that chronic clomipramine administration exerted profound and long-lasting effects on central nervous system function. The long-lasting action of the drug on behaviour in the forced swimming test might explain the long-term beneficial effect of antidepressant drugs in counteractings behavioral depression.

The effects of chronic stress on corticosterone, GH and TSH response to morphine administration

The effects of a chronic stress model in which several acute stressors were applied on a random basis on corticosterone, growth hormone (GH) and thyroid stimulating hormone (TSH) responses to morphine administration were studied in adult male rats. Chronic stress resulted in lower corticosterone response to the drug. In contrast, GH response to morphine was enhanced in the former animals and TSH response remained unchanged. The physiological role of changes in hormone response to opiates remains to be established, but the present results suggest that central opioid pathways involved in the neuroendocrine control of the anterior pituitary did not respond homogeneously to chronic stress.