K.D. Cairncross

Time course for plasma 11-hydroxycorticosteroid elevation in rats during stress.

The time course of plasma 11-hydroxysteroid elevation was studied in two stress situations: regular unsignalled foot shock which produces an intermediate steroid elevation and irregular signalled foot shock with the possibility of escape, which produces an extreme steroid elevation. The initial time course for steroid elevation followed a similar pattern for both treatment groups with the exception that in the irregular signalled group the plasma steroid elevation was more pronounced and there was an indication of biphasic response. The results are discussed in terms of possible inhibitory feedback pathways.

Endogenous brain norepinephrine levels following bilateral olfactory bulb ablation

Changes in endogenous norepinephrine (NE) levels after bilateral olfactory bulb section have been found to occur in the rat brain. Since olfactory tract projections are confined to the ventral adrenergic pathway, and this pathway projects to the pyriform cortex, it was decided to examine the distribution of endogenous NE between the pyriform cortex and the remaining neocortex. It was demonstrated that significant reductions in NE content occurred in both brain regions, although the greater reduction occurred in the pyriform cortex. there were no significant changes in hypothalamic NE. It is concluded that sensory deprivation plus olfactory system damage induce specific changes in central function, which relate to noradrenergic pathways.

The effect of psychoactive drugs on plasma corticosterone levels and behaviour in the bulbectomised rat

Abstract Bilateral olfactory bulbectomy (OB) in the rat produces a rise in circulating 11-hydroxycorticosterone (11-OHCS) to intermediate levels (40–50 μg/100 ml plasma). Following footshock extreme corticosterone elevation occurs (65–80 μg/100 ml plasma). Bulbectomy also produces behavioural changes which include hyper-reactivity and an acquisition deficit in a step-down passive avoidance test. Treatment of the bulbectomised rat with amitriptyline (5 and 10 mg/kg), mianserin (5 and 10 mg/kg) and viloxazine (2 and 5 mg/kg) administered IP for at least 7 days corrected the acquisition deficit, reduced the hyper-reactivity and the elevated corticosterone levels in a reproducible manner. This reduction in 11-OHCS concentrations occurred in bulbectomised rats with and without footshock. In contrast, the antidepressant drugs did not produce these changes in sham-operated controls (SO). The central stimulant, amphetamine (1 and 3 mg/kg/day for 7 days, IP), increased 11-OHCS concentrations in unstressed OB and SO rats. There was no further elevation in the 11-OHCS concentrations of stressed rats of both OB and SO groups. This drug further impaired the acquisition of both OB and SO rats and increased the reactivity scoring of both groups. The major tranquillizer, chlorpromazine (1 and 3 mg/kg IP for 7 days), reduced plasma 11-OHCS levels and the hyperreactivity of both OB and SO groups. It did not reduce the acquisition deficit exhibited by the OB rats. Chlordiazepoxide (5 and 15 mg/kg IP for 7 days), had a profile similar to that of chlorpromazine except that it impaired acquisition in the SO group. Thus using the techniques described above it is possible to separate the antidepressants from other major classes of psychotropic drugs.

Morphological changes induced in rats following prolonged exposure to stress

Prolonged exposure of male C. S. F. rats to irregular signalled footshick from which they could escape for up to 71 days produced profound morphological changes. Retardation in growth, adrenal hypertrophy associated with an increase in the zona fasiculata a-nd zona reticularis, and changes in the microcirculation of the heart were observed. There was a significant degree of congestion and dilatation of the microcirculation which was most marked in large venules, collecting venules and veins. An increase in PAS +ve material marginated in the venous endothelium was observed also, together with a suggested increase in mast cells and presence of vacuoles in the intima-media of the coronary arterioles. No pathological changes were observed in the renal cortex and medulla or the gastric lining. The changes in the microcirculation of the heart are discussed in terms of an oedematous reaction and a histamine type leakage of the endothelial lining.

Effect of stress on the uptake of 3H-norepinephrine into rat myocardium ☆

Spontaneously beating atria from rats previously exposed to irregular, signalled footshock were incubated with 3H-norepinephrine. A significant reduction in the uptake and retention of radioactivity was found in the atria from stressed animals compared with unstressed controls. A kinetic study of the uptake process in both the stressed and control groups showed a similar Km value but a significantly different Vmax. It was concluded that the enhanced myocardial sensitivity to catecholamines previously reported can be explained in part, on the basis of an inhibition of neuronal uptake.

Effect of amitriptyline on avoidance learning in rats following olfactory bulb ablation

It has been established that following bilateral olfactory bulb ablation there occurs a performance deficit in rats exposed to aversive learning procedures. Associated with the behavioral deficit, there occurs a reduction in total cortical norepinephrine (NE). If the behavioural deficit observed is a sequitur or correlate of the NE reduction, then drug therapy aimed at increasing NE availability in the cortex should overcome the reduction in performance. Amitriptyline increases NE availability by inhibiting uptake mechanisms and increases the rate of synthesis of NE. Rats, previously bulb ablated, were treated with amitriptyline over a 10 to 14 day period and tested in aversive situations. It was demonstrated that the drug treated rats showed improved performance early in acquisition, and that the performance improvement was maintained when the treatment period was extended to 14 days. These results indicate that amitriptyline was inducing a true pharmacological effect, and that the improved performance could be correlated with increased NE availability in the cerebral cortex.

Myocardial sensitivity to catecholamines following exposure of rats to irregular, signalled footshock

Emotional stress is associated with an increased activity of both the pituitary-adrenal cortical system and the sympathetic-adrenal medullary systems resulting in raised plasma levels of glucocorticoids and catecholamines. There is evidence to suggest that prolonged stress induced adrenergic hyperactivity initiated myocardial pathogenesis and that this may relate to a corticosteroid catecholamine interaction. In the present study driven atrial strips removed from stressed male CSF rats were found to exhibit an enhanced sensitivity to both norepinephrine and epinephrine. These animals had previously been subjected to irregular foot shock associated with a warning signal; a situation producing a high plasma steroid level. The enhanced myocardial sensitivity to both catecholamines was observed in naive animals subjected to a single period, and persisted unchanged in animals stressed daily over a 28 day period. The hypersensitivity of the myocardium observed immediately after stress was maintained for at least 24 hr, whereas the circulating steroid level had returned to control values within 3 hr. In animals subjected to regular stress without a warning signal, a situation producing a much lower steroid level, no enhanced myocardial sensitivity was observed. While the aetiology of the phenomenon of enhanced myocardial sensitivity to catecholamines is not entirely understood, the evidence presented suggests that it may be related to the extreme elevation of circulating glucocorticoids. The sensitivity of the vas deferens however, was unaltered even though the animals were subjected to the stressor producing a high plasma steroid level. This apparent specifcity of the stress induced sensitivity change is discussed on the basis of receptor differences.

Changes in Myocardial Function as a Consequence of Prolonged Emotional Stress

Publisher Summary This chapter demonstrates that it is possible to induce an increased sensitivity of the heart to catecholamines in an experimental model utilizing endogenously released corticosterone. Two questions that could be asked of such a model presented themselves. Firstly, how does corticosterone induce increased myocardial sensitivity, and secondly what physiological changes would be observed following long term stress associated with increased emotionality? In answer to the first question two experiments were undertaken. One experiment related to the endogenous levels of adrenaline and NA in the rat myocardium following exposure to irregular-signalled escape stress. The results indicate that the depletion of NA is more pronounced in the atria, and such a conclusion implicates neuronal rather than extraneuronal uptake mechanisms. To examine this question more closely, a second experiment was undertaken in which the effect of the stress procedure on the uptake of [ 3 H] NA into the rat myocardium was examined. Such an experiment was feasible because the uptake characteristics of tritiated noradrenaline (NA) into neuronal and extraneuronal stores have been well documented. Thus, it may be concluded that prolonged unpredictable stress can induce pathological changes in the myocardium, and this may be associated with extreme glucocorticoid elevation.

Endogenous levels of catecholamines in the rat myocardium following exposure to stress.

Following exposure of male rats to irregular signalled footshock from which they could escape, the endogenous level of norepinephrine in the myocardium was significantly reduced. In atria the depletion of endogenous norepinephrine was significant following 1 day of stress. This significant depletion was maintained following 4 days of stress but began to return towards control levels by Day 10. A similar, but less pronounced pattern was seen with the ventricles. Little if any epinephrine was detected in both control and stress atria and ventricles. From the results presented it is postulated that irregular signalled footshock results in an inhibition of neuronal uptake.

The effect of sulfinpyrazone on morphological changes in the coronary vasculature induced by prolonged unpredictable stress in the rat

It was confirmed that prolonged unpredictable stress in the rat induces morphological change in the coronary microcirculation. These changes include dilation in venules, deposits staining positive with PAS in the venules due to platelet aggregation and a breakdown of the endothelial lining in arterioles. Sulfinpyrazone is reported to prevent platelet agglutination, and shows effectiveness in the clinic in preventing re-infarction following infarction. Accordingly rats were exposed to the stress regimen for 50 days, and groups were treated with sulfinpyrazone, either prophylactically (receive drug for 50 days) or therapeutically (receive drug Day 30 to Day 50). The morphology of the hearts of treated animals were compared with those of placebo treated controls. It was demonstrated that therapeutic sulfinpyrazone did not prevent (p less than 0.01), but reduced the incidence of morphological change in the coronary microcirculation. Prophylactic sulfinpyrazone had a distinct protective effect (p less than 0.001). It was demonstrated that the plasma corticosterone levels in both drug groups did not fall to the level found in control groups. The results are discussed in terms of a glucocorticoid-sulfinpyrazone interaction preventing prostaglandin release which will prevent platelet aggregation. It is possible that the interaction relates to maintaining the integrity of the microcirculatory endothelial cells, thus preventing the local release of inflammatory substances.