Patricia M. Stephens

The use of psychosocial stimuli to induce prolonged systolic hypertension in mice.

&NA; The increase in systolic pressure with age, which is observed in some but not all human populations, is believed to be a response to repeated symbolic stimuli arising from the social environment. An attempt was made to simulate these conditions in experimental animals by playing on their inborn drives for territory, survival, and reproduction. Meaningful stimuli were presented to CBA mice in a series of long‐term experiments. The methods involved (1) mixing of animals previously maintained in different boxes, (2) aggregation in small boxes, (3) subjecting groups to threat from a predator, and (4) inducing conflict for territory by placing equal numbers of males and females in an interconnected box system. In the experimental situations involving the most severe psychosocial stimulation, the mean arterial blood pressure rose from 126 mm. Hg to the range 150–160; it was sustained at these higher levels for 6–9 months. Those aggregated from birth showed less pressure elevation (to the range 140–150). Blood pressures in females were in the same range as those of males that had been aggregated from birth, but castrates showed minimal effects. Ether anesthesia did not abolish a sustained pressure rise, but the persistently elevated pressure of threatened animals returned to the normal range when reserpine was given. The study demonstrated that social groupings of nonprimates can be used in the experimental approach to the role of psychosocial stimuli and the early environment in the etiology of human hypertension.

A model of psychosocial hypertension showing reversibility and progression of cardiovascular complications.

The sequence of pathophysiological changes that can result from the stimulating effects of a sustained disturbance of the social environment was studied in ten colonies of socially deprived mice. Sixteen formerly isolated males were placed with 16 normal females in population cages consisting of seven intercommunicating boxes. Six of these socially disturbed 32-member colonies were terminated after periods of interaction ranging from 2 days to 9 months. The remaining four were terminated a month or more after the males had been returned to individual isolation. Indirect blood pressure measurements, body and heart weights, and sections of hearts and aortas were studied in the males. Following the shorter exposures, blood pressure reverted to normal in a few days. Exposures of 6 months or more were associated with unchanged body weights and sustained increases in heart weight and blood pressure readings. In addition, there was a significant development of aortic arteriosclerosis and myocardial fibrosis. These changes persisted despite prolonged return to isolation.

Effect of Psychosocial Stimulation on the Enzymes Involved in the Biosynthesis and Metabolism of Noradrenaline and Adrenaline

&NA; Various groups of CBA mice were exposed to differing levels of psychosocial stimulation by mutual confrontation for 6 months after reaching maturity. Their experiences ranged from individual isolation, through standard boxing, to a colony life in an intercommunicating box system containing males and females. The blood pressures of the socially stimulated groups increased to 170 ± 20 mmHg; those of the boxed and isolated animals remained a normal 126 ± 12 mmHg. Adrenal weights, adrenal noradrenaline and adrenaline, monoamine oxidase, tyrosine hydroxylase (the rate‐limiting enzyme in catecholamine synthesis) and phenylethanolamine‐N‐methyltransferase (PNMT, the enzyme that converts noradrenaline to adrenaline) were all increased in the stimulated groups. A significant decrease in the two latter enzymes was observed in the isolated animals. It is suggested that the increase in catecholamine‐forming enzymes resulting from psychosocial stimulation may be neuronally mediated, and that it is not an immediate response as in the case of a sudden discharge of noradrenaline and adrenaline in states of anger, fear or aggression.

The role of psychosocial factors in the development of arteriosclerosis in CBA mice: Observations on the heart, kidney and aorta☆

Abstract Approximately 300 mixed male and female CBA mice were exposed to 6 months of social confrontation in intercommunicating population cages. Histological sections were scored for severity of the ensuing acute and chronic interstitial nephritis, of glomerular mesangial changes, of myocardial fibrosis, and of arteriosclerotic degeneration of the intramural coronary vessels and of the aorta. The severity of the changes was contrasted with those found in a control group of the same or greater age in which sexes were separated and the living conditions were arranged to avoid confrontation. The accuracy of the scoring technique was shown to be sufficient to differentiate the severity of the various lesions; and in all of the conditions studied, significantly higher scores were obtained in the socially stimulated group.

Caffeine as an intensifier of stress-induced hormonal and pathophysiologic changes in mice

Psychosocially stressed male mice competing in a Henry-Stephens complex population cage develop hypertension, cardiovascular damage, and chronic interstitial nephritis. Their plasma renin, noradrenaline, corticosterone, and adrenal-catecholamine synthetic enzymes are increased and they die prematurely. Adding 3.3 mg of caffeine a day per kilogram of mouse body weight (the equivalent of 20 micrograms/ml decaffeinated coffee) to their drinking water significantly intensifies most of these changes. A dose of 90 mg/kg of caffeine (the equivalent of 560 micrograms/ml, i.e., brewed tea or coffee) further increases the effects. The drug-induced enhancement of competitive social stimulation of the neuroendocrine system resulted in a further increase of plasma renin and corticosterone levels as well as blood pressure and adrenal weight. These effects together with accelerated mortality and increased pathology indicate that chronic consumption of caffeinated liquids adds to the risks of psychosocial stress.

The social environment and essential hypertension in mice: possible role of the innervation of the adrenal cortex.

Publisher Summary In this chapter, a distinction is drawn between social stimuli that lead to the arousal of the sympathoadrenal medullary as opposed to the hypothalamoadrenocortical system. The focus of this chapter is on the status of a continuing effort to disentangle the social stimuli and behavioral patterns that lead to the arousal of the sympathoadrenal–medullary system from those involving the hypothalamoadrenal–cortical system and to continue with the problem of relating these to low renin essential hypertension. The recently discovered evidence that autonomic innervation of the adrenal cortex plays a part in steroidogenesis may prove related to the abnormalities in adrenal morphology and in the peculiar biochemical correlates of low renin essential hypertension as a possible variant of primary aldosteronism. Studies of the model of psychosocial hypertension with CBA mice living in a population cage indicate that as the chronically conflicting colonies age, the individual members shift away from a state of high catecholamine sympathetic arousal. The older groups develop fixed hypertension and adrenal hypertrophy with increased corticosterone and phenylethanolamine N-methyltransferase levels. They fight far less and avoid confrontations. It is proposed that under the influence of depression plus arousal repeated stimulation of the autonomic innervation of the adrenal cortex in combination with sustained hormonal drives may lead to the peculiar pathophysiology of low renin essential hypertension.

Antibody response to bovine serum albumin in mice: the efffects of psychosocial environmental change.

Abstract The effects of psychosocial environmental change upon circulating antibody response to antigenic challenge was investigated in CBA/USC mice. Mice were reared in isolation and selected groups were subsequently exposed to psychosocial stimulation. Antibody titers of mice that remained in isolation were significantly higher than the titers of mice exposed to psychosocial stimulation. One group of mice exposed to psychosocial stimulation and then returned to isolation showed titers significantly below those of mice exposed to psychosocial stimulation only. These data indicate that psychosocial environmental changes can be productive of significant suppression of antibody formation in mice.

Plasma Renin Activity in Psychosocial Hypertension of CBA Mice

We studied plasma renin activity (PRA) in male full-color brown Agouti (CBA) mice subjected to varying degrees of psychosocial stress induced by manipulation of their housing patterns. Blood samples were obtained from unanesthetized mice by retro-orbital puncture; blood pressure (BP) was measured by tail plethysmography. At 4 months of age, PRA was lower in mice isolated since weaning (isolates) than in mice housed together in standard cages (boxed sibs). Isolation of boxed sibs for 7 days also decreased PRA. PRA did not change in isolates during a 10-month period. In contrast, PRA and BP changed markedly after 4-month-old isolates were placed in an interconnected box system [population cage (PC)] which increased social interaction and competition; values at all times were greater than those of isolated controls. PRA increased rapidly during the first 1-2 days, declined from these high values over the next 3 weeks to values similar to those of boxed sibs (but higher than control isolates), and then rose again progressively during the next 5-6 months. BP was elevated within 1 week (particularly in subordinate mice), then rose slowly throughout the experiment. During the first 2 months, PRA and BP were inversely correlated; no significant correlation existed after 2 months. Hematocrit tended to be lower in PC mice from 7 days on. Blood urea was increased in 10-month-old PC mice. Increased PRA and BP also occurred in boxed sibs placed in PC for 3-10 weeks. The pattern of PRA changes in these mice is analogous to that observed in certain forms of human essential hypertension and is further evidence that psychosocial hypertension in CBA mice may be an appropriate model for the study of essential hypertension.

Force breeding, social disorder and mammary tumor formation in CBA/USC mouse colonies: a pilot study.

&NA; If the newborn of a socially organized CBA/USC mouse colony are regularly removed (force breeding), the social order breaks dowm. There is fighting among the males and the young are lost due to neglect and injury by the females (cronism). A high incidence of mammary tumor formation is observed during the disorder of such formerly socialized groups. In the pilot study being reported, force breeding initiated at the sixth month of colony life eventually at the ninth month led to fighting and the loss of young by cronism. All 12 female colony members developed tumors during the subsequent 5 months. Meanwhile, tumors developed in only 8% of the same age Study Siblings and in 46% of Study Breeders maintained under rapid breeding conditions. Force breeding is a knowm moderately effective tumorigenic technique. Since tumors did not occur in the population cage until its social system broke down, this suggests that the combination of force breeding and social disorder‐induced neuroendocrine changes is peculiarly favorable to tumor development.

Psychosocial stress induces high blood pressure in a population of mammals on a low-salt diet

The relative importance of salt intake and psychosocial stimulation in the development of high blood pressure has been studied in colonies of CBA/USC mice. Approximately 50 males were observed for 3-4 months in five population cages which successfully induced chronic psychosocial interaction, resulting in chronic hypertension. Under these conditions, progressive arteriosclerosis develops together with myocardial hypertrophy, increased catecholamine synthesis and increased angiotensin sensitivity. Previous work indicates that this condition shows the characteristics of renin dependent human hypertension. A special grain based diet was used which included 0.014% sodium. This resulted in the ingestion of the equivalent of 40 mmol/l sodium or 3.0 g NaCl in a 70-kg man. This, and an even more stringent synthetic diet containing less than 0.01% NaCl, i.e. less than 2 g NaCl per day in man, were contrasted with the standard chow which contains 0.4% sodium. Over 4 months of social interaction the psychosocial stimulation proved to be the critical factor and, despite the low-salt intake, blood pressure rose to the same levels as those of control groups on a normal diet containing 1% salt. Hypertension occurs in the absence of kidney failure as assessed by blood urea. Plasma renin levels on the low-salt grain based diet were double those on standard chow, showing that the diet was sufficiently low in salt to activate the renin-angiotensin system.