Cholesterol, serotonin, and behavior in young monkeys.
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Aggression↗
Biomedical subjects
J R Kaplan
Publications and source records attributed to J R Kaplan.
Benefits of exogenous oestrogen in inhibiting stress-related coronary artery atherosclerosis.
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Animals↗
Long-term effects of chronic social stress on serotonergic indices in the prefrontal cortex of adult male cynomolgus macaques.
We examined the effects of chronic social stress and social rank on monamine concentrations in the prefrontal cortex (PFC) in adult male cynomolgus macaques (Macaca fascicularis). Seventy-five animals were housed in five-member social groups for 28 months and were exposed to three experimental conditions. A 'no-stress' condition was comprised of animals housed in groups of stable membership throughout the study. Animals assigned to a 'past-stress' condition had their group memberships reorganized at monthly intervals during the first (but not last) 14 months of the study, and a third 'recent-stress' condition consisted of social groups reorganized only during the last 14 months. At necropsy, the brains were collected and frozen at -70 degrees C until analyzed. Prefrontal orbital cortex was assayed for monoamines (serotonin (5-HT), dopamine (DA), norepinephrine (NE)), metabolites (5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), 3-methoxy-4-hydroxyphenethyleneglycol (MHPG)), and tryptophan using high-performance liquid chromatography with electrochemical detection. Animals in the past-stress condition had significantly lower PFC 5-HIAA concentrations compared to those in the no-stress condition (P < 0.05). PFC 5-HT concentrations of animals in the past-stress condition were significantly lower than those in the no-stress and recent-stress conditions (P < 0.01). The concentrations of DA, HVA, NE and MHPG were not altered. These data suggest that exposure to chronic social stress is associated with long-term selective reductions in serotonergic activity in the PFC. This effect may underlie the association in human beings between reduced serotonergic function and conditions such as pathological grief and posttraumatic stress disorder.
Animals↗
Aggression and brain serotonergic responsivity: response to slides in male macaques.
The association between central serotonergic responsivity (measured by prolactin response to acute administration of fenfluramine hydrochloride) and aggressivity was examined in 40 adult male cynomolgus monkeys (Macaca fascicularis). Prolactin response to fenfluramine was distributed bimodally with 24 monkeys displaying a "low" prolactin response and 15 showing a "high" prolactin response to the fenfluramine challenge. Behavioral responsivity was assessed by placing the monkeys individually in an open-field enclosure and presenting a series of photographic slides depicting both threatening and nonthreatening images. Monkeys that were low prolactin responders displayed significantly more aggressive gestures in response to a threatening slide of a human being than did the high responders (p < 0.05). Insofar as fenfluramine-stimulated prolactin release assesses serotonergic responsivity, these data support related findings in people and nonhuman primates linking reduced serotonergic activity and aggression.
Aggression↗
Dominant social status and contraceptive hormone treatment inhibit atherogenesis in premenopausal monkeys.
The stress of social subordination is associated with exacerbation of coronary artery atherosclerosis in premenopausal cynomolgus monkeys, possibly as a result of the ovarian dysfunction that reliably accompanies subordinate social status. The primary objective of the current study was to determine whether treatment with an oral contraceptive (OC) provides relative protection from development of atherosclerotic plaques, especially among animals made vulnerable to atherosclerosis by social subordination. In the present study, 193 adult female monkeys (Macaca fascicularis) were placed in social groups of 5 or 6 animals each. Half of the animals were then fed an atherogenic diet to which had been added a triphasic OC, while the remainder received only the atherogenic diet. At the end of 26 months, atherosclerosis was measured in an iliac artery biopsy taken from each monkey. The results demonstrated that among untreated animals subordinate individuals developed significantly more atherosclerosis than did their dominant counterparts (P < .01); however, OC treatment inhibited atherosclerosis in subordinate animals (P < .05) and eliminated the difference between dominant and subordinate animals that was observed in the untreated condition. Subordinate social status and OC treatment were both associated with reduced plasma concentrations of HDL cholesterol (P < .01 for both), and subordinate monkeys also had elevations in LDL cholesterol plus VLDL cholesterol (P < .01). Nonetheless, the interaction between social status and OC treatment remained significant even after covariance adjustment for variation in plasma lipids. Taken together, these results suggest that social subordination worsens, whereas OC treatment inhibits, atherosclerosis, and that these effects are independent of concomitant variability in plasma lipids.
Animals↗
Effects of androgens on coronary artery atherosclerosis and atherosclerosis-related impairment of vascular responsiveness.
The factors responsible for the marked gender differences in risk of coronary heart disease and atherosclerosis severity remain largely undetermined. While some clinical and experimental evidence supports a protective effect of endogenous estrogen on the initiation and progression of atherosclerosis and incidence of coronary heart disease, much of the epidemiological data do not support this conclusion. The possibility that endogenous androgens may have adverse effects on atherosclerosis progression and coronary risk has received little attention. We investigated the effects of experimentally induced hyperandrogenism in female cynomolgus monkeys with diet-induced atherosclerosis. Animals were assigned randomly to one of four treatment groups: (1) untreated controls, (2) ovariectomized (sex hormone-deficient) controls, (3) treated with androstenedione and estrone (mild hyperandrogenism), or (4) treated with testosterone (male plasma androgen pattern). At necropsy, coronary atherosclerosis was approximately twice as extensive (P < .05) in testosterone-treated animals relative to untreated controls, while treatment with androstenedione and estrone had no effect on atherosclerosis extent. Coronary plaque size was positively correlated with lumen size in intact and ovariectomized controls; however, there was no evidence of a similar relation between animals in either androgen treatment group. The atherogenic effects of testosterone were independent of variations in plasma lipoprotein and nonlipoprotein risk variables. Although chronic hyperandrogenism had adverse effects on atherosclerosis progression, it reversed (P < .03) atherosclerosis-related impairment of endothelium-dependent vasodilator responses. We conclude that an experimentally induced male plasma androgen pattern results in exacerbation of diet-induced atherosclerosis-related arterial remodeling in female monkeys.(ABSTRACT TRUNCATED AT 250 WORDS)
Androgens↗
Characterization of mineralocorticoid and glucocorticoid receptors in primate brain.
Characteristics of neural corticosteroid receptors were studied in 51 adrenally-intact macaque monkeys using a modification of a corticosteroid receptor assay developed in this laboratory for rodent studies. Using cortisol as a ligand, two receptor subtypes could be distinguished and with similar Kd's to those observed in rodents, as measured with corticosterone. The time course showed maximum binding for mineralocorticoid receptors at 24 h and for glucocorticoid at 4 h. There were regional differences in the number of available binding sites for each receptor type, as well as an inverse correlation between the concentration of cortisol in the blood at the time of death and the number of available binding sites. In general this paper emphasizes the similarities between such receptors in primate and those in other species, similarities that could be detected despite the technical constraints of studying tissue taken from non-adrenalectomized animals.
Animals↗
Antiatherogenic effects of beta-adrenergic blocking agents: theoretical, experimental, and epidemiologic considerations.
Theoretical considerations and results from experimental studies in animal models suggest that long-term beta-adrenergic blockade should be antiatherogenic. Some of these experimental results indicate that beta-blockers could inhibit atherogenesis and thus prevent clinical events independently of any effects on blood pressure through concomitant reductions in heart rate, blood velocity and energy, endothelial permeability to lipoproteins, and the likelihood of plaque rupture. Any such independent inhibition of atherogenesis implies, in turn, that beta-blockers might be more desirable than alternative antihypertensive therapies in persons at high risk for atherosclerotic diseases. Results of the three major trials directly comparing beta-blockers to diuretics in the primary prevention of coronary heart disease among patients with hypertension were largely inconclusive. However, ancillary data from these and other trials are consistent in demonstrating that beta-adrenergic blockade is associated with anti-coronary heart disease effects and, thus, is perhaps antiatherogenic. A definitive evaluation of the antiatherogenic effects of beta-blockers is not forthcoming because no large clinical trials directly assessing the effect of these drugs on atherosclerosis have been done or are planned.
Adrenergic beta-Antagonists↗
Dexamethasone resistance among nonhuman primates associated with a selective decrease of glucocorticoid receptors in the hippocampus and a history of social instability.
We have studied some of the neuroendocrine and social correlates of dexamethasone resistance in a nonhuman primate population. Subjects were 51 male Macaca fascicularis monkeys with known behavioral histories and who had been given dexamethasone (DEX) suppression tests a week prior to killing. We compared the subset of monkeys who were most DEX responsive (post-DEX cortisol values of 3.1 +/- 0.5 micrograms/dl) versus a DEX-resistant subset (cortisol values of 9.2 +/- 2.0 micrograms/dl); we found two features that distinguished these groups: (a) DEX-resistant monkeys had significantly fewer available glucocorticoid receptor (GR) binding sites in the hippocampus; they did not differ in numbers of mineralocorticoid receptor (MR) sites in the hippocampus, nor in numbers for either receptor in the cortex or hypothalamus as a whole. (b) Animals had resided for a number of years in social groups that were either stable or were repeatedly destabilized by changing of group membership; the latter has been shown to constitute a sustained stressor. DEX-resistant animals were more than twice as likely to have come from an unstable group as were DEX-responsive monkeys. Rodent studies have shown that sustained stress can cause a selective downregulatory decrease in the numbers of hippocampal corticosteroid receptors, and that such a loss is associated with DEX resistance. The present data suggest similar associations in the primate, and may be of relevance to the DEX resistance observed in a subset of human depressives.
Animals↗
Relationship of cardiovascular reactivity and anger expression to serum lipid concentrations in healthy young men.
The relationship between behaviorally evoked cardiovascular reactivity, preferred mode of anger expression, and serum lipid concentrations was examined in 63 healthy, young adult males. Subjects derived from three studies, each evaluating cardiovascular response to laboratory stressors. All participants completed the Spielberger Anger Expression Scale and provided fasting blood samples for lipid determinations. A significant negative correlation, calculated by meta-analytic procedures, was noted between a baseline-free measure of heart rate reactivity and high density lipoprotein-cholesterol (HDL-C) concentrations (r = -0.26, p = 0.05). However, the previously reported relationship between cardiovascular reactivity and elevated total serum cholesterol (TSC) was not found. Additionally, men scoring high on a self-report measure of the tendency to express anger outwardly had significantly higher HDL-C concentrations than men scoring low on this measure (r = 0.30, p = 0.02); when subjects were stratified by level of cardiovascular reactivity, this relationship was apparent only among those showing the greatest magnitude of heart rate and blood pressure responses to acute mental stress.
Adolescent↗
Low or lowered cholesterol and risk of death from suicide and trauma.
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Anticholesteremic Agents↗
Low versus high prolactin responders to fenfluramine challenge: marker of behavioral differences in adult male cynomolgus macaques.
Prolactin response to acute administration of fenfluramine hydrochloride is considered an indirect assessment of "net" central serotonergic activity. This study compared behavioral characteristics of adult, male cynomolgus macaques (Macaca fascicularis) having "low" or "high" prolactin responses to fenfluramine challenge. The subjects were 75 animals housed in five-member social groups for 28 months. In month 23, prolactin responses to fenfluramine challenge were evaluated. Observations of specific behaviors (aggressive, submissive, affiliative, and nonsocial) were made three times per week on animals in each social group. The dominance status of each animal within a social group was assessed at weekly intervals. Low prolactin responders had a significantly higher index of "overt" aggression (ratio of fights involving physical contact and chasing or lunging/all forms of aggressive behavior) compared to high prolactin responders (p < .03). There were no differences in the dominance status of low and high responders (p = .34). Furthermore, low responders were more socially withdrawn than high responders, as they spent significantly more time alone (passive or neutral state; p < .03) and less time in passive body contact with other animals than high responders (p < .05). These data support the hypothesis that reduced central serotonergic activity in nonhuman primates is associated with a high level of overt aggression and a low level of positive social interaction.
Aggression↗
Plaque changes and arterial enlargement in atherosclerotic monkeys after manipulation of diet and social environment.
To study the effects of dietary and social manipulations on lesion progression in male monkeys with established atherosclerosis, 83 animals fed a diet containing 1 mg cholesterol per kcal for 14 months were either necropsied (baseline group, n = 21) or assigned to one of three experimental conditions: 1) a diet containing a high amount of fat and cholesterol and a stressful social situation (HiFC-stress, n = 18); 2) a diet lower in fat and cholesterol and a stressful social situation (LoFC-stress, n = 21); or 3) the low-fat, low-cholesterol diet and a nonstressful social situation (LoFC-no stress, n = 23). After 28 months, all animals were necropsied. Coronary atherogenesis was arrested among monkeys in the LoFC-stress and LoFC-no stress conditions compared with that of animals in the baseline condition (plaque areas of 0.35 mm2, 0.30 mm2, and 0.38 mm2, respectively). Lesions in animals fed the LoFC diet (both stress and no-stress groups) were significantly smaller than those in monkeys in the HiFC-stress condition (0.96 mm2). Furthermore, aortic cholesterol content was significantly decreased and luminal areas were relatively larger among monkeys in both LoFC conditions compared with animals in the baseline and HiFC-stress conditions (p < 0.05 for all). The results demonstrate that a low-fat, low-cholesterol diet can halt plaque development, reduce arterial cholesterol content, and permit compensatory arterial enlargement, processes that were unaffected by social stress in this investigation.
Animals↗
Effects of psychosocial stress on endothelium-mediated dilation of atherosclerotic arteries in cynomolgus monkeys.
The objectives of this study were to determine if psychosocial stress impairs dilation through endothelium-derived relaxing factor (EDRF)-mediated mechanisms and if this effect is long lasting. Monkeys were fed an atherogenic diet for 36 mo while in one of three experimental conditions: (a) stable social groups ("unstressed," n = 6); (b) unstable social groups for the first half of the experiment and stable groups for the second half ("early stress," n = 8); and (c) stable groups for the first half of the experiment and unstable groups for the second half ("late stress," n = 6). Iliac arteries were studied in organ chambers containing Krebs' buffer and 10(-6) M indomethacin. Arteries from the late stress group had impaired dilation (shift of the dose-response curve down and to the right) to acetylcholine and the calcium ionophore A23187 (for both, P < 0.05), but not to nitroprusside (P > 0.05), compared with unstressed or early stress monkeys. NG-methyl-L-arginine reduced the dose-response curve to both acetylcholine and A23187 in the unstressed group and resulted in similar vascular responses among all three groups (P > 0.05). We conclude that current, but not previous, exposure to chronic stress impairs endothelium-mediated dilation of atherosclerotic iliac arteries of cynomolgus monkeys through an EDRF-mediated mechanism.
Acetylcholine↗
Effects of exercise and stress on body fat distribution in male cynomolgus monkeys.
The effects of exercise and stress on regional and whole body adiposity were examined in an established animal model of diet-induced coronary artery atherosclerosis, the cynomolgus monkey (Macaca fascicularis). A total of 79 adult male monkeys were assigned to four experimental groups after baseline stabilization and training: (i) exercise, stress, (n = 20); (ii) exercise, no stress (n = 20); (iii) sedentary, stress (n = 20); and (iv) sedentary, no stress (n = 19). The monkeys consumed an ad libitum diet containing 188 mg cholesterol per day with 43% of calories as saturated fat. Anthropometric measurements of regional and whole body adiposity were collected throughout the study. A subset (n = 40) of animals representing all four groups underwent computerized tomography (CT) scans at the end of the study to determine amounts of total abdominal, intra-abdominal and subcutaneous abdominal adipose tissue. Results indicate that, in general, stress interacted with exercise to affect anthropometric measurements of regional adiposity. In contrast, stress had independent and significant effects on the amount and distribution of abdominal fat as measured using CT. Stressed monkeys in both the exercise and sedentary groups had more intra-abdominal fat (and thus greater intra-abdominal-:subcutaneous abdominal fat ratios) than their nonstressed counterparts. There were no significant interactions between exercise and stress or exercise effects on abdominal fat distribution as measured by CT. These results support the belief that an arousal syndrome caused by chronic stress, and resulting in increased activity along the hypothalamo-adrenal axis, may play a role in the preferential deposition of fat in the abdomen.(ABSTRACT TRUNCATED AT 250 WORDS)
Adipose Tissue↗
Effects of a low-fat diet on brain serotonergic responsivity in cynomolgus monkeys.
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Aggression↗
Alterations in specific antibody production due to rank and social instability.
Separate studies examined the influence of the social environment of male cynomolgus macaques on primary and secondary antibody responses to immunization with tetanus toxoid. All animals showed evidence of both primary and secondary anti-tetanus antibody response. In the first study, subordinate animals had a greater primary antibody response to tetanus toxoid, while a single social reorganization (acute stressor) did not influence the response. In the second study, social rank was not associated with the secondary antibody response but repeated social reorganizations (chronic stressor) resulted in a greater level of specific antibody production in comparison to nonreorganized controls. These effects could not be accounted for on the basis of nonspecific differences in total serum IgG or serum albumin.
Animals↗
Psychosocial factors impair vascular responses of coronary arteries.
BACKGROUND: Four sets of monkeys were used to examine the effect of chronic psychosocial disruption and diet on dilator responses of coronary arteries. METHODS AND RESULTS: One set consisted of monkeys consuming monkey chow and living in a stable social setting (nonatherosclerotic controls, n = 6). Three sets consumed an atherogenic diet for 14 months followed by one of three treatments for the next 16 months: 1) a high-cholesterol diet and housed in unstable social groups (n = 9); 2) a low-cholesterol diet and housed in unstable (n = 8); or 3) stable groups (n = 10). Quantitative coronary angiography revealed that intracoronary infusion of acetylcholine resulted in a change of diameter (versus infusion of 5% dextrose in water) of +4 +/- 1% in control monkeys and -11 +/- 4% in unstable monkeys consuming a high-cholesterol diet (p less than 0.05). In monkeys consuming the cholesterol-lowering diet, the change in artery diameter was +2 +/- 4% in stable and -10 +/- 4% in unstable social conditions (p less than 0.05) despite a similar plaque size (0.4 +/- 0.2 and 0.5 +/- 0.1 mm2) and total plasma cholesterol concentrations (179 +/- 9 and 172 +/- 6 mg/dl), respectively. The arterial response to nitroglycerin was similar among all groups of monkeys. CONCLUSIONS: We conclude that chronic social disruption is associated with relative arterial constriction in response to acetylcholine in atherosclerotic monkeys consuming a cholesterol-lowering diet.
Animals↗