Corticosterone mediates some but not other behavioural changes induced by prenatal stress in rats.

The effect of daily varied stress from days 13-21 of gestation in Wistar rats was investigated by tests of learning and memory and anxiogenic behaviour in the 60-day-old offspring of both sexes. Prenatal stress decreased the anogenital distance in males at 1 day of age. Anxiogenic behaviour in the elevated plus maze was seen in prenatally-stressed rats of both genders. There was no significant gender difference in the rate of spatial learning in the Morris water maze but prenatal stress only slowed that of males. In the object recognition test with an inter-trial interval of 40 min, females but not males, discriminated between a familiar and novel object. Prenatal stress did not affect object discrimination in females but feminised that in males. Maternal adrenalectomy with replacement of basal corticosterone levels in the drinking fluid prevented all of the above effects of prenatal stress in the offspring. To mimic the peak corticosterone levels and time course of elevation in response to stress, corticosterone (3 mg/kg) was injected twice (0 and 30 min) on days 13-16 and once on days 17-20 of gestation to adrenalectomised mothers. This treatment re-instated anxiogenic behaviour similar to that induced by prenatal stress, indicating that it is mediated by exposure of the foetal brain to raised levels of corticosterone. However, steroid administration to adrenalectomised dams did not decrease anogenital distance, feminise object recognition memory or slow spatial learning in their male offspring. The findings indicate that other adrenal hormones are necessary to induce these effects of prenatal stress.

Testosterone mediates sex difference in hypothermia and cholinesterase inhibition by rivastigmine.

The fall in body temperature and inhibition of hypothalamic cholinesterase induced by rivastigmine (a pseudo-reversible carbamate inhibitor) were compared in male and female rats. In males, 1.5 mg/kg lowered body temperature by 1 degrees C and in females by 3.2 degrees C (P<0.001) and inhibited cholinesterase by 65% and 74%, respectively (P<0.05). Pilocarpine (20 mg/kg) decreased body temperature by 1.1 degrees C in males and 1.9 degrees C in females (P<0.05). Orchidectomy, but not ovariectomy, abolished the sex difference in the hypothermic effect of pilocarpine and the enzyme inhibition induced by rivastigmine, but not in its effect on body temperature. Testosterone (10 mg/rat) decreased the cholinesterase inhibition and the temperature reduction induced by rivastigmine in gonadectomised males and females, but that induced by pilocarpine in males only. In conclusion, rivastigmine causes less inhibition of cholinesterase because testosterone may interfere with its entry into the brain. Testosterone may further decrease the temperature-lowering effect of rivastigmine and acetylcholine receptor agonists in males by an action at a receptor level.

Effect of prenatal stress on plasma corticosterone and catecholamines in response to footshock in rats.

The effect of prenatal stress was investigated on the sympathoadrenal response to novelty and footshock by measuring the time course of the changes in circulating corticosterone (COR) catecholamines and their metabolites. Pregnant rats were subjected to noise and light stress, three times weekly on an unpredictable basis throughout gestation. When the male offspring of stressed rats (PS) and those of unstressed mothers (C) were 4.5-5 months of age, they were prepared with indwelling catheters in the tail artery 24 h before the experiment. Resting levels of plasma COR, noradrenaline (NA), adrenaline (AD), dihydroxyphenylglycol (DHPG), dihydroxyphenylacetic acid (DOPAC), and dihydroxyphenylalanine (DOPA) were measured. Further blood samples were taken within 3 min of their transfer to the shock box, 1-2, 5, 15, and 45 min after footshock. Plasma COR was significantly higher in PS than in C rats at rest, but those of adrenaline, NA, and their metabolites did not differ in the two groups. Transfer of the rats to the shock box increased plasma COR, NA, adrenaline, and dihydroxyphenylglycol in both groups, and dihydroxyphenylalanine and dihydroxyphenylacetic acid only in PS rats. All the catechols increased further 2-3 min after footshock, except dihydroxyphenylalanine in PS rats. Plasma NA and dihydroxyphenylglycol levels were significantly higher in PS than in C rats immediately after footshock, indicating a greater activation of the sympathetic nervous system in PS rats. The findings demonstrate for the first time that prenatal stress can induce long term changes in the sensitivity of the sympathoadrenal system to stress.

Gender differences in sympathoadrenal activity in rats at rest and in response to footshock stress.

A comparison was made of the dynamics of sympathoadrenal activity in 11 age-matched male and female rats, under basal conditions and after exposure to footshock. Rats were prepared with indwelling catheters in the tail artery 24 h before the experiment. Measurements were made of plasma corticosterone (COR), norepinephrine (NE), epinephrine (EPI), dihydroxyphenylalanine (DOPA), dihydroxyphenylglycol (DHPG) and dihydroxyphenylacetic acid (DOPAC) under resting conditions, after transfer to the shock box (novelty) and at various times after footshock. Under basal conditions, males have significantly higher blood pressure and plasma DHPG/NE ratios but lower plasma levels of COR, NE and DOPAC than females. Three min after exposure to the shock chamber (novelty stress) there were significant increases in COR, EPI, NE and DHPG in both sexes, while DOPA increased only in females and DOPAC remained unchanged in both sexes. Footshock produced a further increase in EPI, NE and DOPAC within 2 min, which lasted about 15 min. There were significant sex differences in the extent and duration of the response of COR, EPI and DHPG. The data show that the female sympathoadrenal system is more reactive than that of the male to the stresses of a novel environment and footshock. The smaller DHPG/NE ratios in females at rest and after stress suggest that neuronal uptake of NE is lower in females than in males. The finding that stress produces larger increments of plasma DOPA and DOPAC in female rats indicates that tyrosine hydroxylase in the sympathetic nerve terminals and adrenal medulla may also be higher than in males.

Impaired baroreflex sensitivity in the aetiology of salt hypertension in the rabbit.

This study was designed to see whether normotensive rabbits with an impairment in baroreflex control of heart rate due to genetic factors are more susceptible to high salt or deoxycorticosterone acetate (DOCA)-salt hypertension. The baroreflex sensitivity of 27 conscious rabbits was assessed by both the 'steady-state' and 'ramp' methods in response to injections of phenylephrine (2.5-30 micrograms/kg). Animals with differing baroreflex sensitivities were then given 4 weeks treatment with 8% NaCl and 1.3% KCl in food (treatment A), or DOCA (25 mg pellet, subcutaneously) with 0.5% NaCl and 0.13% KCl in drinking water (treatment B). A third group were maintained on a regular diet of food and water (controls). A highly significant negative correlation (r = 0.91, P less than 0.01) was found between the increase in mean arterial pressure (MAP) produced either by treatment A or treatment B and the baroreflex sensitivity before treatment. There was no significant correlation between the increase in MAP and initial MAP; increase in body weight; serum K+ after treatment; baroreflex sensitivity before treatment, when assessed by the 'ramp' method. It is concluded that animals with low baroreflex sensitivity due to a reduced ability to suppress cardiac sympathetic activity in response to a pressor stimulus, are more likely to develop hypertension as a result of salt loading. It remains to be determined whether the susceptibility to salt of rabbits with lower baroreflex sensitivity is also associated with a difference in the renal excretion of Na+ ions.

Endogenous opiates mediate cardiac sympathetic inhibition in response to a pressor stimulus in rabbits.

Two different patterns of response to a pressor stimulus occurred in conscious rabbits. This difference was not apparent when a depressor stimulus was applied. At levels of mean arterial pressure exceeding 120 mmHg one group of animals exhibited a marked bradycardia which was due to sympathetic inhibition in addition to vagal activation while this sympathetic component appeared to be lacking in the second group of animals. Naloxone (0.1 mg/kg i.v.) markedly reduced the sympathetic inhibition elicited by phenylephrine but had no significant effect on the reflex vagal stimulation. Naloxone thereby abolished the difference in sensitivity of baroreflex control of heart rate in response to a pressor stimulus between the two groups of rabbits. Naloxone did not influence the sensitivity of the reflex response to nitroprusside. Morphine (2 mg/kg) increased the vagal component of the baroreceptor reflex in response to a pressor stimulus and the sensitivity of the reflex response to nitroprusside in all the rabbits, and this was antagonized by naloxone (0.1 mg/kg). Morphine also potentiated and naloxone antagonized the bradycardic response at levels of MAP exceeding 120 mmHg, in those rabbits which appeared to lack the cardiac sympathetic inhibitory component of the reflex. The results show that endogenous and exogenous opiates can increase the reflex bradycardia in response to a pressor stimulus in the conscious rabbit. The difference in baroreflex sensitivity in different animals may result from their varying ability to activate endogenous opioid systems which depress cardiac sympathetic activity.

Sympathetic component of baroreflex control of heart rate is impaired in hypertension-prone (SBH) Sabra rats.

Baroreflex control of heart rate in response to phenylephrine was studied in conscious Sabra hypertension-prone (SBH) rats, at a prehypertensive stage, and hypertension-resistant (SBN) rats. Baroreflex sensitivity as determined from the slope of the relationship of mean arterial blood pressure and heart period was significantly lower in SBH rats (0.58 +/- 0.06 versus 1.71 +/- 0.11 ms/mmHg in SBN rats, P less than 0.01) before the development of hypertension. Sympathetic nerve blockade with guanethidine (15 mg/kg) significantly reduced the slope of the mean arterial blood pressure-heart period relationship in SBN rats to 0.45 +/- 0.05 ms/mmHg (P less than 0.01) and increased the pressor response to phenylephrine, without having any effect on these parameters in SBH rats. Atropine methyl nitrate (1 mg/kg) abolished reflex vagal bradycardia in response to phenylephrine in both groups of rats. This suggests that SBH rats are unable to withdraw the sympathetic cardiac component of the baroreflex in response to a pressor stimulus and appear to rely only on increased vagal activity to effect bradycardia.

Baroreflex sensitivity and susceptibility to systolic hypertension induced by DOCA-salt in the Sabra rat.

Rats of the salt-resistant Sabra strain (SBN) have a more sensitive baroreflex control of heart rate than do normotensive hypertension-prone salt-sensitive (SBH) rats. To test the hypothesis that increased baroreflex sensitivity confers resistance to hypertension, aortic baroreceptor deafferentation (ABD) was performed in 7- to 10-wk-old SBN rats. This treatment reduced the slope of the mean arterial pressure-heart period (MAP-HP) relationship in response to infusions of increasing doses of phenylephrine in conscious rats, from 1.92 +/- 0.21 to 0.66 +/- 0.11 ms X mmHg-1 (P less than 0.01). The latter value did not differ significantly from that of untreated SBH rats (0.56 +/- 0.07 ms X mmHg-1). Treatment of uniphrectomized SBH, SBN-ABD, and sham-operated SBN rats for 3 wk with deoxycorticosterone acetate (DOCA; 25-mg pellet) and 0.9% NaCl + 0.4% KCl (to maintain normal serum K+ values) as drinking fluid caused increases in systolic blood pressure from 126 +/- 3 to 147 +/- 5 mmHg and 104 +/- 6 to 130 +/- 8 mmHg in the former two groups, respectively, but no significant change (105 +/- 3 to 110 +/- 4 mmHg) in SBN rats when measured by an indwelling arterial catheter in the tail artery. The slopes of the MAP-HP relationships of each of the above three groups of rats were not significantly altered by DOCA-salt treatment. It is concluded that a decrease in baroreflex control of the heart by ABD can render SBN rats sensitive to DOCA-salt-induced systolic hypertension.