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Mitochondrial dysfunction is evident in diseases affecting cognition and metabolism such as Alzheimer’s disease and type 2 diabetes. Human studies of brain mitochondrial function are limited to postmortem tissue, preventing the assessment of bioenergetics by respirometry. Here, we investigated the effect of two diets on mitochondrial bioenergetics in three brain regions: the prefrontal cortex (PFC), the entorhinal cortex (ERC), and the cerebellum (CB), using middle-aged nonhuman primates. Eighteen female cynomolgus macaques aged 12.3 ± 0.7 yr were fed either a Mediterranean diet that is associated with healthy outcomes or a Western diet that is associated with poor cognitive and metabolic outcomes. Average bioenergetic capacity within each brain region did not differ between diets. Distinct brain regions have different metabolic requirements related to their function and disease susceptibility. Therefore, we also examined differences in bioenergetic capacity between brain regions. Mitochondria isolated from animals fed a Mediterranean diet maintained distinct differences in mitochondrial bioenergetics between brain regions, whereas animals fed the Western diet had diminished distinction in bioenergetics between brain regions. Notably, fatty acid β-oxidation was not affected between regions in animals fed a Western diet. In addition, bioenergetics in animals fed a Western diet had positive associations with fasting blood glucose and insulin levels in PFC and ERC mitochondria but not in CB mitochondria. Altogether, these data indicate that a Western diet disrupts bioenergetic patterns across brain regions and that circulating blood glucose and insulin levels in Western-diet fed animals influence bioenergetics in brain regions susceptible to Alzheimer’s disease and type 2 diabetes. NEW & NOTEWORTHY We show that compared with cynomolgus macaques fed a Mediterranean diet, a Western diet resulted in diminished bioenergetic pattern between brain regions related to blood glucose and insulin levels, specifically in brain regions susceptible to neurodegeneration and diabetes. In addition, fatty acid metabolism not directly linked to the TCA cycle and glucose metabolism did not show differences in bioenergetics due to diet.

Persistent psychological stress increases the risk of many chronic diseases of aging. Little progress has been made to effectively reduce stress responses or mitigate stress effects suggesting a need for better understanding of factors that influence stress responses. Limited evidence suggests that diet may be a factor in modifying the effects of stress. However, long-term studies of diet effects on stress reactive systems are not available, and controlled randomized clinical trials are difficult and costly. Here we report the outcomes of a controlled, randomized preclinical trial of the effects of long-term consumption (31 months, ~ equivalent to 9 human years) of Western versus Mediterranean - like diets on behavioral and physiological responses to acute (brief social separation) and chronic (social subordination) psychosocial stress in 38 adult, socially-housed, female cynomolgus macaques. Compared to animals fed a Western diet, those fed the Mediterranean diet exhibited enhanced stress resilience as indicated by lower sympathetic activity, brisker and more overt heart rate responses to acute stress, more rapid recovery, and lower cortisol responses to acute psychological stress and adrenocorticotropin (ACTH) challenge. Furthermore, age-related increases in sympathetic activity and cortisol responses to stress were delayed by the Mediterranean diet. Population level diet modification in humans has been shown to be feasible. Our findings suggest that population-wide adoption of a Mediterranean-like diet pattern may provide a cost-effective intervention on psychological stress and promote healthy aging with the potential for widespread efficacy., Highlights • There is no population level treatment to reduce stress and associated disease. • Mediterranean diet reduced sympathetic activity. • Mediterranean diet reduced cortisol response to acute stress and to ACTH challenge. • Mediterranean diet delayed age-related increases in sympathetic activity and cortisol responses to stress. • These results suggest a dietary strategy to increase stress resilience.

Chronic psychosocial stress is associated with increased risk of many chronic diseases including type 2 diabetes mellitus. However, it is difficult to establish a causal relationship between stress and diabetes in human studies because stressors often are self-reported and may be distant in time from metabolic consequences. Macaques are useful models of the effects of chronic psychosocial stress on health and may develop obesity and diabetes similar to human beings. Thus, we studied the relationships between social subordination stress – a well-validated psychological stressor in macaques – and body composition and carbohydrate metabolism in socially housed, middle-aged female cynomolgus monkeys (Macaca fascicularis; n=42). Following an 8-week baseline phase, the monkeys were fed a Western diet for 36 months (about equivalent to 10 human years). Social status was determined based on the outcomes of agonistic interactions ([Formula: see text] observation hours/monkey). Phenotypes collected included plasma cortisol, body composition, circulating markers of glucose metabolism, activity levels, and heart rate variability measured as RMSSD (root of mean square of successive differences) and SDDN (standard deviation of beat to beat interval) after 1.5- and 3-years on diet. Mixed model analyses of variance revealed that aggression received, submissions sent, and cortisol were higher, and RMSSD and SDNN were lower in subordinates than dominants (social status: p 100 mg/dl) incidence was significantly higher in subordinates (23%) than dominants (0%) (Fisher’s exact test, p

AMP-activated protein kinase (AMPK) is a molecular sensor that is critical for the maintenance of cellular energy homeostasis, disruption of which has been indicated in multiple neurodegenerative diseases including Alzheimer's disease (AD). Mammalian AMPK is a heterotrimeric complex and its enzymatic α subunit exists in two isoforms: AMPKα1 and AMPKα2. Here we took advantage of a recently characterized non-human primate (NHP) model with sporadic AD-like neuropathology to explore potential relationships between AMPK signaling and AD-like neuropathology. Subjects were nine female vervet monkeys aged 19.5 to 23.4 years old. Subjects were classified into three groups, control lacking AD pathology (n = 3), moderate AD pathology (n = 3), and more severe AD Pathology (n = 3). We found increased activity (assessed by phosphorylation) of AMPKα2 in hippocampi of NHP with AD-like neuropathology, compared to the subjects without AD pathology, with no alterations of AMPKα1 activity. Across all subjects, CSF Abeta42 was inversely associated with cerebral amyloid plaque density. Further, Aβ plaque burden is correlated with levels of either soluble or insoluble brain Aβ measurement. Unbiased mass spectrometry based proteomics studies combined with bioinformatics analysis revealed that many of the dysregulated proteins characteristic of AD neuropathology are associated with AMPK signaling. Our findings on the AMPK molecular signaling cascades provide further support for use of the NHP model to investigate new therapeutic strategies and development of novel biomarkers for Alzheimer's disease.

Selective serotonin reuptake inhibitor (SSRI) antidepressants are widely prescribed for depression and other disorders. SSRIs have become one of the most commonly used drugs in the United States, particularly by women. Acute effects on body composition and carbohydrate metabolism have been reported, but little is known regarding the effects of chronic SSRI use. We evaluated the effects of chronic administration of a commonly prescribed SSRI, sertraline HCl, on body weight and composition, fat distribution, carbohydrate metabolism, as well as activity, in adult female depressed and nondepressed cynomolgus monkeys (Macaca fascicularis; n = 42) using a placebo-controlled, longitudinal, randomized study design. Phenotypes were evaluated prior to and after 18 months of oral sertraline (20 mg/kg) or placebo. Over the 18 month treatment period, the placebo group experienced increases in body weight, body fat (visceral and subcutaneous) fasting insulin concentrations, and homeostasis model assessment of insulin resistance scores (HOMA-IR). Sertraline treatment prevented increases in body weight, fat, insulin, and HOMA-IR (all p < 0.05), without significantly altering activity levels. Sertraline treatment altered adiponectin in an unusual way — reducing circulating adiponectin in depressed monkeys without affecting fat mass or body weight. Deleterious effects on adiponectin, a potentially insulin-sensitizing and atheroprotective protein, may result in adverse effects on cardiovascular health despite otherwise beneficial effects on body composition and carbohydrate metabolism.

Background Left ventricular ( LV ) diastolic dysfunction often precedes heart failure with preserved ejection fraction, the dominant form of heart failure in postmenopausal women. The objective of this study was to determine the effect of oral estradiol treatment initiated early after ovariectomy on LV function and myocardial gene expression in female cynomolgus macaques. Methods and Results Monkeys were ovariectomized and randomized to receive placebo (control) or oral estradiol at a human‐equivalent dose of 1 mg/day for 8 months. Monkeys then underwent conventional and tissue Doppler imaging to assess cardiac function, followed by transcriptomic and histomorphometric analyses of LV myocardium. Age, body weight, blood pressure, and heart rate were similar between groups. Echocardiographic mitral early and late inflow velocities, mitral annular velocities, and mitral E deceleration slope were higher in estradiol monkeys (all P LV filling pressure. MCP1 (monocyte chemoattractant protein 1) and LV collagen staining were lower in estradiol animals ( P 1.2‐fold change; false discovery rate, P P Conclusions Estradiol treatment initiated soon after ovariectomy resulted in enhanced LV diastolic function, and altered myocardial gene expression towards decreased extracellular matrix deposition, improved myocardial contraction, and calcium homeostasis, suggesting that estradiol directly or indirectly modulates the myocardial transcriptome to preserve cardiovascular function.

Major depressive disorder and coronary heart disease often co-occur in the same individuals. Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed for depression and other disorders, but their effects on coronary heart disease risk remain unclear. We determined the effects of an SSRI on coronary artery atherosclerosis (CAA) in an established nonhuman primate model used to clarify the association between depression and CAA.Forty-two adult female cynomolgus macaques consuming a Western diet were characterized during an 18-month pretreatment phase and assigned to SSRI (sertraline hydrochloride 20 mg/kg, per os, once a day) or placebo balanced on pretreatment depression, body weight (BW), and iliac artery atherosclerosis extent measured via biopsy. After 18 months, CAA extent was measured using histomorphometry.Before and during treatment, depressed monkeys had lower BW, body mass index, and plasma high-density lipoprotein cholesterol, and higher heart rates during the pretreatment (p.01) but not the treatment phase (p = .17). There were no pretreatment differences between the sertraline and placebo groups. Sertraline reduced anxious behavior but had no effect on BW, body mass index, heart rate, plasma lipids, or depression. CAA, analyzed by a 2 (depressed, nondepressed) × 2 (placebo, sertraline) × 3 (coronary arteries) analysis of covariance adjusted for pretreatment iliac atherosclerosis, was greater in depressed than in nondepressed monkeys (p.036), and in sertraline than in placebo-treated monkeys (p = .040). The observed CAA extent in depressed monkeys treated with sertraline was 4.9 times higher than that in untreated depressed monkeys, and 6.5 times higher than that in nondepressed monkeys, on average.Depressed animals developed more CAA, and long-term treatment with sertraline resulted in more extensive CAA.

Overall health has been linked to socioeconomic status, with the gap between social strata increasing each year. Studying the impact of social position on health and biological functioning in nonhuman primates has allowed researchers to model the human condition while avoiding ethical complexities or other difficulties characteristic of human studies. Using female cynomolgus macaques (Macaca fascicularis), our lab has examined the link between social status and stress for 30 years. Female nonhuman primates are especially sensitive to social stressors which can deleteriously affect reproductive health, leading to harmful consequences to their overall health. Subordinates have lower progesterone concentrations during the luteal phase of menstrual cycle, which is indicative of absence or impairment of ovulation. Subordinate animals receive more aggression, less affiliative attention, and are more likely to exhibit depressive behaviors. They also express higher stress-related biomarkers such as increased heart rates and lower mean cortisol. While no differences in body weight between dominant and subordinate animals are observed, subordinates have lower bone density and more visceral fat than their dominant counterparts. The latter increases risk for developing inflammatory diseases. Differences are also observed in neurological and autonomic function. A growing body of data suggests that diet composition may amplify or diminish physiological stress responses which have deleterious effects on health. More experimental investigation of the health effects of diet pattern is needed to further elucidate these differences in an ongoing search to find realistic and long-term solutions to the declining health of individuals living across the ever widening socioeconomic spectrum.

The cynomolgus monkey (Macaca fascicularis) has been increasingly used in biomedical research. Although living conditions affect behavioral and physiological characteristics in macaques, little data is available on how living conditions influence blood-based parameters in the cynomolgus monkey. We hypothesize that there are significant differences in serum biochemical and hematological parameters in single-caged versus socially housed cynomolgus monkeys, and that age and sex influence the effect of living conditions on these parameters. Sixty single-caged and 60 socially housed cynomolgus monkeys were segregated by age group (juvenile, adult) and sex. The effects of living condition, age, sex, and the interactions between these factors on commonly reported serum biochemical and hematological parameters were analyzed by a three-way analysis of variance (ANOVA). Then, the differences between single-caged and socially housed subjects were tested in each parameter by Student's t-test. Creatinine, glucose, triglyceride, alanine aminotransferase, red blood cell volume distribution width (SD, CV), median fluorescence reticulocyte percentage, white blood cell and basophil counts, and monocyte (count, %) were lower in single-caged subjects. Blood urea nitrogen and globulin were lower in single-caged juveniles and adults, respectively. Red blood cell count, hemoglobin, hematocrit, and neutrophil (count, %) were higher, and reticulocyte and lymphocyte (counts, %) were lower, in single-caged juveniles. Mean corpuscular hemoglobin concentration was higher in single-caged subjects (but more pronounced in adults). Total protein was higher in single-caged juvenile males and lower in single-caged adult females. Alkaline phosphatase was lower in single-caged juvenile females. Mean corpuscular hemoglobin was higher, and high fluorescence reticulocyte percentage was lower, in single-caged adult males. In conclusion, living conditions significantly affect several serum biochemical and hematological parameters in the cynomolgus monkey, and these effects vary by age and sex. As this macaque is commonly housed under different living conditions, these findings should aid researchers in avoiding inaccurate conclusions concerning this species. Am. J. Primatol. 76:1011–1024, 2014. © 2014 Wiley Periodicals, Inc.

2 Sticht Center on Aging, Section on Comparative Medicine Pathology, Radiology, 3 Section on Comparative Medicine (Pathology), 4 Section on Radiologic Sciences, and 5 Background. Knowledge of adipose composition in relation to mortality may help delineate inconsistent relationships between obesity and morality in old age. We evaluated relationships between abdominal visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) density, mortality, biomarkers, and characteristics. Methods. VAT and SAT density were determined from computed tomography scans in persons aged 65 and older, Health ABC (n = 2,735) and AGES-Reykjavik (n = 5,131), and 24 nonhuman primates (NHPs). Associations between adipose density and mortality (4-13 years follow-up) were assessed with Cox proportional hazards models. In NHPs, adipose density was related to serum markers and tissue characteristics. Results. Higher density adipose tissue was associated with mortality in both studies with adjustment for risk factors including adipose area, total fat, and body mass index. In women, hazard ratio and 95% CI for the densest quintile (Q5) versus least dense (Q1) for VAT density were 1.95 (1.36-2.80; Health ABC) and 1.88 (1.31-2.69; AGES-Reykjavik) and for SAT density, 1.76 (1.35-2.28; Health ABC) and 1.56 (1.15-2.11; AGES-Reykjavik). In men, VAT density was associated with mortality in Health ABC, 1.52 (1.12-2.08), whereas SAT density was associated with mortality in both Health ABC, 1.58 (1.21-2.07), and AGES-Reykjavik, 1.43 (1.07-1.91). Higher density adipose tissue was associated with smaller adipocytes in NHPs. There were no consistent associations with inflammation in any group. Higher density adipose tissue was associated with lower serum leptin in Health ABC and NHPs, lower leptin mRNA expression in NHPs, and higher serum adiponectin in Health ABC and NHPs.

Depression and altered serum lipids in cynomolgus monkeys on a Western diet. Research over the past 15 years has suggested a high comorbidity of depression and coronary heart disease (CHD). However the mechanisms responsible for this relationship are poorly understood. This study was designed to examine the relationships between depressive behaviors and concentrations of circulating lipids and lipid signaling molecules that may be common to both CHD and depression in a cohort of cynomolgus monkeys (Macaca fascicularis) consuming a ‘Western’ diet, enriched with saturated fat and cholesterol. Socially-housed adult female cynomolgus monkeys (n=36) were fed the Western diet for 27 months and depressive behavior was recorded weekly. Body weight, body mass index and circulating cholesterol profiles were measured in all animals, and fatty acids (FA) and FA-based signaling molecules were measured in the 6 least and 6 most depressed monkeys. Monkeys consuming the Western diet exhibited a broad range of percent time spent in depressive behavior. The percent time spent depressed was positively correlated with total plasma and LDL cholesterol and negatively correlated with HDL cholesterol. Despite being leaner, depressed monkeys had higher concentrations of monounsaturated fats (C16:1 and C17:1), a higher ω6/ω3 polyunsaturated fatty acid (PUFA) ratio and higher concentrations of omega-6 (ω6) PUFAs, particularly C18:2ω6 and C20:3ω6. FA ratios suggest that stearoyl CoA desaturase 1 activity was increased in depressed monkeys. Depressed female cynomolgus monkeys had elevated concentrations of serum lipids and lipid signaling molecules that are typically associated with obesity, insulin resistance and cardiovascular disease, which may account in part for the comorbidity of depression and CHD.

Objectives—Magnetic resonance imaging (MRI) studies report hippocampal (HC) volume reductions in depression. Despite observations in the HC of functional heterogeneity and ovarian steroid influence, few studies report regional volume alterations or control for menstrual cycle phase. Using in vitro methods, we recently observed reduced anterior HC volume in antidepressant-naive, ovarian-intact, behaviorally depressed adult female monkeys. The purpose of this study was to confirm these findings in vivo and examine whether lack of ovarian steroids affects the relationship between depression and HC volume. Methods—MRI was used to measure whole, anterior, and posterior HC volumes in a matched sample of antidepressant-naive, surgically-postmenopausal, adult female cynomolgus macaques characterized for behavioral depression (n=6 depressed, 6 nondepressed). High resolution structural MRIs were acquired, and HC regions of interest were manually segmented. HC volumes were normalized to whole brain volumes prior to analysis. Results—Similar to the previous in vitro study, HC volume measured in vivo was associated with depression. In contrast to the previous study of ovarian-intact females, whole, anterior and posterior volumes of both left and right HC were significantly smaller in depressed compared to nondepressed surgically postmenopausal females. Conclusions—These findings confirm and extend previous observations of smaller HC volumes in behaviorally depressed female monkeys, and suggest a possible role for ovarian steroids in HC protection in depression. Further studies of the potential modulating effects of ovarian function on the relationship between depression and HC volume are warranted.

Abdominal obesity is prevalent and often accompanied by an array of metabolic perturbations including elevated blood pressure, dyslipidemia, impaired glucose tolerance or insulin resistance, a prothrombotic state, and a proinflammatory state, together referred to as the metabolic syndrome. The metabolic syndrome greatly increases coronary heart disease (CHD) risk. Social stress also increases CHD although the mechanisms through which this occurs are not completely understood. Chronic stress may result in sustained glucocorticoid production, which is thought to promote visceral obesity. Thus, one hypothesis is that social stress may cause visceral fat deposition and the metabolic syndrome, which, in turn increases CHD. CHD is caused by coronary artery atherosclerosis (CAA) and its sequelae. Cynomolgus monkeys (Macaca fascicularis) are a well-established models of CAA. Social subordination may be stressful to cynomolgus monkeys and result in hypercortisolemia and exacerbated CAA in females. Herein is reviewed a body of literature which suggests that social stress increases visceral fat deposition in cynomolgus monkeys, that subordinate females are more likely than dominants to have visceral obesity, that females with visceral obesity have behavioral and physiological characteristics consistent with a stressed state, and that females with high ratios of visceral to subcutaneous abdominal fat develop more CAA. While these relationships have been most extensively studied in cynomolgus macaques, obesity-related metabolic disturbances are also observed in other primate species. Taken together, these observations support the view that the current obesity epidemic is the result of a primate adaptation involving the coevolution with encephalization of elaborate physiological systems to protect against starvation and defend stored body fat in order to feed a large and metabolically demanding brain. Social stress may be engaging these same physiological systems, increasing the visceral deposition of fat and its sequelae, which increase CHD risk.

Our previous work in cynomolgus monkeys demonstrated significant relationships between (i) social reorganization stress and visceral fat deposition, and (ii) central fat deposition and coronary artery atherosclerosis (CAA). Nevertheless, direct relationships between CAA and visceral fat have not been demonstrated in people or animals, nor have relationships among stress, visceral obesity, and CAA been observed within a single study. Here, we examine the hypothesis that visceral obesity provides a link between social stress and CAA. Subjects were 41 socially housed females that consumed an atherogenic diet for 32 months. Social behavior and ovarian function were continuously recorded; dexamethasone suppression tests, telemetered overnight heart rate, BMI, visceral (VAT) and subcutaneous abdominal (SAT) adipose tissue were measured before necropsy. Females with high VAT:SAT were relatively subordinate, socially isolated, received more aggression and less grooming, desensitized to circulating glucocorticoids, had impaired ovarian function, higher heart rates late in the day, and more CAA than low VAT:SAT females. High-BMI females had higher heart rates than low-BMI females. Poor ovarian function in high VAT:SAT females is a novel observation suggesting the need for studies of fat distribution and ovarian function in women. The results of this study are the first to demonstrate a relationship between CAA and visceral obesity, and suggest that social stress may exacerbate CAA in part by increasing the ratio of visceral:subcutaneous fat mass in selected individuals susceptible to diet-induced CAA. Further studies are needed to understand the complex and multifactorial temporal relationship among relative visceral obesity, physiological stress responses, and CAA.

Depression and coronary heart disease (CHD) are leading contributors to disease burden in women. CHD and depression are comorbid; whether they have common etiology or depression casues CHD is unclear. The underlying pathology of CHD, coronary artery atherosclerosis (CAA), is present decades before CHD, and the temporal relationship between depression and CAA is unclear. The evidence of involvement of depression in early CAA in cynomolgus monkeys, an established model of CAA and depression, is summarized. Like people, monkeys may respond to the stress of low social status with depressive behavior accompanied by perturbations in hypothalamic-pituitary-adrenal (HPA), autonomic nervous system, lipid metabolism, ovarian, and neural serotonergic system function, all of which are associated with exacerbated CAA. The primate data are consistent with the hypothesis that depression may cause CAA, and also with the hypothesis that CAA and depression may be the result of social stress. More study is needed to discriminate between these two possibilities. The primate data paint a compelling picture of depression as a whole-body disease.

A 13-year-old, obese, female cynomolgus monkey ( Macaca fascicularis) was observed in a 5-year neurobehavioral study and was humanely euthanatized for experimental purposes. During this observational study, the monkey was noted to ovulate only rarely (0–3 times a year), with a prolonged menstrual cycle length (up to 161 days), hyperandrogenism (androstenedione area under the curve in response to adrenocorticotropic hormone up to 27.64 ng/ml), and hyperinsulinemia (fasting insulin up to 65.85 μIU/ml). This animal's body mass index was 65.46 kg/m2, with central obesity. On postmortem examination, the uterus was moderately enlarged, with an eccentric lumen and a broad-based endometrial polyp that consisted of complex glandular hyperplasia with atypia. Both ovaries contained many 2- to 3-mm follicles, without any corpora lutea. A diagnosis of polycystic ovary syndrome was made based on the clinical history, endocrinology, and gross and histopathologic findings.

Selective serotonin reuptake inhibitor (SSRI) use is ubiquitous because they are widely prescribed for a number of disorders in addition to depression. Depression increases the risk of coronary heart disease (CHD). Hence, treating depression with SSRIs could reduce CHD risk. However, the effects of long term antidepressant treatment on CHD risk, as well as other aspects of health, remain poorly understood. Thus, we undertook an investigation of multisystem effects of SSRI treatment with a physiologically relevant dose in middle-aged adult female cynomolgus monkeys, a primate species shown to be a useful model of both depression and coronary and carotid artery atherosclerosis. Sertraline had no effect on depressive behavior, reduced anxious behavior, increased affiliation, reduced aggression, changed serotonin neurotransmission and volumes of neural areas critical to mood disorders, and exacerbated coronary and carotid atherosclerosis. These data suggest that a conservative approach to prescribing SSRIs for cardiovascular or other disorders for long periods may be warranted, and that further study is critical given the widespread use of these medications.

The scientific community has been working feverishly on the problem of obesity, particularly since the Surgeon’s General’s 2001 call to action to prevent and decrease obesity.

To evaluate the effects of social subordination stress and chronic moderate alcohol consumption on indices of breast and endometrial cancer risk.Forty-six adult, ovariectomized, cynomolgus monkeys (Macaca fascicularis) were trained to voluntarily drink a placebo or a two-drink/day equivalent of ethanol (0.5 g/kg), 5 days a week for 26 months, the latter resulting in average blood alcohol levels of 42 mg/100 mL. Indices of cell proliferation and sex steroid receptor abundance were measured.Compared with dominants, socially subordinate females had increased cell proliferation and proportions of glandular (P0.02) and epithelial tissue (P = 0.009) and less stroma (P0.02) in endometrium, and increased tissue thickness in breast (P0.05). There was no evidence of increased risk of breast or endometrial cancer with chronic moderate alcohol consumption, as indicated by markers of cell proliferation and sex steroid receptor abundance. Chronic moderate alcohol consumption did not effect circulating sex steroid concentrations (all P0.10). The adipocyte hormones leptin and adiponectin were correlated with indices of cell proliferation and sex steroid receptor abundance.These observations suggest that social status was more important than chronic moderate alcohol consumption in endometrial and breast biology of surgically postmenopausal females. Endogenous sex steroid metabolism was not significantly affected by chronic moderate alcohol exposure consistent with the lack of estrogen-like effects on breast and endometrium. Social subordination stress was associated with initial cellular changes that may increase endometrial cancer risk. Ovariectomized cynomolgus monkeys may be a useful model for the study of effects of social factors and obesity on breast and endometrial cancer risk.

Oral contraceptives (OCs) are the most widely prescribed and effective of the reversible contraceptive methods. In addition to inhibiting ovulation, OCs alter central nervous system function in women; however, methodological problems have prevented clear human studies. Thus, in this experiment we investigated the effects of OC treatment on behavior, hypothalamic- pituitary-adrenal axis function and the central nervous system in 75 adult female cynomolgus monkeys (Macaca fascicularis) housed in social groups of four to five monkeys per pen. Monkey social groups were randomly divided into either a control or an OC treatment group which was administered a clinically prescribed OC (Triphasil(R), levonorgestrel and ethinyl estradiol tablets) for 2 years. OC treatment increased the frequency of contact aggression received, time spent in locomotion, and sitting close to another animal, and decreased time spent fearfully scanning. OC treatment decreased heart rate, increased activity levels, and increased baseline cortisol concentrations and the cortisol response to adrenocorticotropin compared to control animals. OC treatment decreased the prolactin response to fenfluramine suggesting decreased serotonergic activity. These results suggest that this triphasic OC disrupts social behavior, hypothalamic-pituitary-adrenal axis regulation and the underlying central nervous system function.

OBJECTIVE: To investigate the effects of hormone replacement therapy (HRT) and social stress on body fat distribution in an animal model of women’s health, the female cynomolgus macaque (Macaca fascicularis). DESIGN/SUBJECTS: Adult female cynomolgus monkeys were ovariectomized and fed an atherogenic diet for two years while housed in social groups of 3–8 monkeys each. Animals were then fed a lipid-lowering diet and randomized into four experimental groups: a baseline group which was necropsied immediately and not included in the study reported here, 26 females fed diet only (CONTROL), 22 females fed diet plus conjugated equine estrogens (CEE), and 21 females fed the diet plus CEE and medroxyprogesterone acetate (CEE+MPA). Treatment lasted 30 months. MEASUREMENTS: During the last nine months of treatment, social status was determined three times at three month intervals. At the end of the study, whole body obesity and fat distribution patterns were determined using anthropometry and computerized tomography (CT). RESULTS: The addition of a progestin to the estrogen replacement regimen administered to surgically postmenopausal monkeys, increased all anthropometric and CT measures of obesity except intra-abdominal fat. HRT had no effect on patterns of fat distribution. Socially-dominant, ovariectomized females were more obese than subordinates using both anthropometric and CT measurements of whole body obesity. Dominant females were more likely to have their fat deposited centrally as measured anthropometrically. However, CT measures revealed a trend for dominants to preferentially deposit fat in the subcutaneous abdominal depot in contrast to subordinates who deposited fat in the intra-abdominal depot. CONCLUSIONS: The results of this study suggest that progestins, when administered in combination with estrogens, may increase fat deposition, particularly in subcutaneous depots. In addition, the social stress experienced by subordinate monkeys, may have mild effects on fat deposition patterns, even after removal of ovarian function as a factor. These observations may have implications for treatment recommendations in postmenopausal women. Lastly, CT may measure different characteristics of fat distribution than skinfolds and circumferences.

The effects of contraceptive steroids and estrogen replacement therapy on behavior and neuroendocrine function were evaluated in adult female cynomolgus monkeys. During the 'premenopausal' phase of the experiment, the animals were assigned to either treatment with a triphasic oral contraceptive (OC) for 24 months or the untreated control group. The monkeys were then ovariectomized and half of each of the premenopausal groups were randomly assigned to either treatment with conjugated equine estrogens (ERT) or the untreated control group for 12 months (the 'postmenopausal' phase). All evaluations were completed during the postmenopausal phase of the experiment. Both types of exogenous steroid treatments appeared to increase cardiovascular and hypothalamic-pituitary-adrenal responses to stress in socially dominant but not socially subordinate females. A history of triphasic OC administration increased contact aggression received, and reduced the prolactin response to fenfluramine, suggesting reduced serotonergic activity, for at least a year following the cessation of triphasic OC treatment.

Depression is a proposed risk factor for heart failure based largely on epidemiological data; few experimental data addressing this hypothesis are available.Depression was evaluated in relation to cardiac structural and functional phenotypes assessed by transthoracic echocardiography in 42 adult female cynomolgus monkeys that consumed a Western-like diet for 3 years. Half of the monkeys were treated with sertraline HCl for 18 months, and depressive behavior was assessed for 12 months before echocardiography.Depressed monkeys (the 19/42 with depressive behavior rates above the mean rate) had higher heart rates (HRs; 171 [4.1[ versus 152 [6.1]) and smaller body surface area (0.13 [0.003] versus 0.15 [0.004]), left ventricular (LV) end-systolic dimension (0.75 [0.05] versus 0.89 [0.04]), LV systolic (0.76 [0.08] versus 1.2 [0.11]) and diastolic (2.4 [0.23] versus 3.4 [0.26]) volumes, and left atrial volumes (1.15 [0.14] versus 1.75 [0.12]; p values.05). Doppler profiles of depressed monkeys indicated greater myocardial relaxation (higher e' and higher e'/a' ratio) and lower filling pressures (lower E/e') compared to nondepressed monkeys (p values.05). Although sertraline treatment reduced HR (150 [5.8] versus 171 [4.8]) and modestly increased chamber dimensions (LV end-systolic dimension: 0.91 [0.05] versus 0.74 [0.03]; LV end-diastolic dimension, body surface area adjusted 1.69 [0.05] versus 1.47 [0.06]; p values.05), it did not overtly affect systolic or diastolic function (p values.10).These data suggest that behavioral depression in female primates is accompanied by differences in cardiac function, although not in ways classically associated with subclinical heart failure. Selective serotonin reuptakes show promise in supporting heart function by reducing HR and perhaps improving LV filling; however, further investigation is needed.

The anterior hippocampus is associated with emotional functioning and hippocampal volume is reduced in depression. We reported reduced neuropil volume and number of glia in the dentate gyrus (DG) and cornu ammonis (CA)1 of the anterior hippocampus in behaviorally depressed adult female cynomolgus macaques. To determine the biochemical correlates of morphometric and behavioral differences between behaviorally depressed and nondepressed adult female monkeys, glial and synaptic transcripts and protein levels were assessed in the DG, CA3 and CA1 of the anterior hippocampus. Glial fibrillary acidic protein (GFAP) was increased whereas spinophilin and postsynaptic density (PSD)-95 protein were decreased in the CA1 of depressed monkeys. GFAP was reciprocally related to spinophilin and PSD-95 protein in the CA1. Gene expression of GFAP paralleled the protein changes observed in the CA1 and was inversely related to serum estradiol levels in depressed monkeys. These results suggest that behavioral depression in female primates is accompanied by astrocytic and synaptic protein alterations in the CA1. Moreover, these findings indicate a potential role for estrogen in modulating astrocyte-mediated impairments in synaptic plasticity.

The effects of estradiol and 17alpha-dihydroequilenin on the apical dendrite spine density of pyramidal cells of the CA1 region of rat hippocampus were compared. 17alpha-Dihydroequilenin was as effective as estradiol in increasing spine densities relative to controls. 17alpha-Dihydroequilenin is not uterotrophic like estradiol but does have beneficial effects on the cardiovascular system, suggesting that it may be an effective single-agent hormone replacement therapy to treat menopausal symptoms and reduce chronic disease risk in menopausal women.

The present study was designed to characterize the discriminative stimulus effects of ethanol and the neurosteroid 3 alpha-hydroxy-5 alpha-pregnan-20-one (allopregnanolone) in nonhuman primates as a function of menstrual cycle phase. Female cynomolgus monkeys (Macaca fascicularis) were trained in a two-lever procedure to discriminate 1.0 g/kg ethanol (IG, 30 min pretreatment) from water using food reinforcement. A cumulative dosing procedure was used to assess changes in the potency of ethanol and an endogenous anxiolytic steroid in the follicular versus the luteal phase of the menstrual cycle. Plasma progesterone and allopregnanolone levels were determined within 24 h of testing to verify phase of menstrual cycle. The monkeys were more sensitive to the discriminative stimulus effects of ethanol and the ethanol-like effects of the endogenous neuroactive steroid allopregnanolone during the luteal phase of the menstrual cycle. These findings suggest that changes in the endogenous levels of ovarian-derived progesterone and allopregnanolone alter sensitivity to the discriminative stimulus effects of ethanol.

Socially subordinate adult female cynomolgus monkeys are hypercortisolemic, the targets of aggression, fearful, vigilant, receive little positive affiliative contact, exhibit pathological behaviors indicating anxiety, and are disengaged in the social events around them. Subordinates also have altered dopaminergic activity that may be due to decreased D2 receptor binding. Dopaminergic activity indices were more closely associated with affiliative than agonistic behaviors.

Although widely prescribed, little is known about the effects of selective serotonin reuptake inhibitors (SSRIs) on social behavior and cerebrospinal fluid (CSF) monoamines in female primates. The objective of this study was to determine the effects of sertraline on agonistic and affiliative behavior. Twenty-one adult female cynomolgus monkeys were housed in small, stable social groups, trained to participate in oral dosing, and began a 5-week cumulative dose–response study. Serial doses of 0, 5, 10, 15, and 20 mg/kg of sertraline were administered orally for 1 week each. Behavior was recorded daily during 10-min observations before and 4 h after dosing. On the seventh day of dosing, circulating sertraline/desmethylsertraline and CSF monoamines/metabolites were determined 4 h after the last dose. At 20 mg/kg, circulating sertraline/desmethylsertraline was in the therapeutic range. CSF 5-hydroxyindole acetic acid decreased by 33 % (p

The prevalence of obesity has rapidly escalated and now represents a major public health concern. Although genetic associations with obesity and related metabolic disorders such as diabetes and cardiovascular disease have been identified, together they account for a small proportion of the incidence of disease. Environmental influences such as chronic stress, behavioral and metabolic disturbances, dietary deficiency, and infection have now emerged as contributors to the development of metabolic disease. Although epidemiological data suggest strong associations between chronic stress exposure and metabolic disease, the etiological mechanisms responsible remain unclear. Mechanistic studies of the influence of chronic social stress are now being conducted in both rodent and nonhuman primate models, and phenotypic results are consistent with those in humans. The advantage of these models is that potential neural mechanisms may be examined and interventions to treat or prevent disease may be developed and tested. Further, circadian disruption and metabolic conditions such as diabetes mellitus could increase susceptibility to other stressors or serve as a stressor itself. Here, we review data from leading investigators discussing the interrelationship between chronic stress and development of metabolic disorders.

Young rhesus monkeys exposed to conditions of social restriction are subject to stress. The physiological indicator, plasma cortisol, can be used to measure this stress. A technique using dexamethasone suppression-adrenocorticotropic hormone (ACTH) challenge was used to determine whether inanimate enrichment and social housing condition affected plasma cortisol levels in juvenile rhesus monkeys. Cortisol levels in two cohorts of monkeys (N = 64) were determined first while monkeys were caged singly and then while caged in pairs. Both control and enriched subjects received the dexamethasone suppression-ACTH challenge procedure and, for each cohort, cortisol samples were obtained after 10 and 12 months of single-caging and subsequently after 2 and 4 months of pair-housing. Compared with controls, experimental subjects receiving inanimate environmental enrichment did not show lower levels of plasma cortisol. Although environmental enrichment may lead to behavioural improvements, it did not affect adrenal function in this study. Social housing condition (single vs. pair) also did not affect cortisol. Monkeys in most conditions responded appropriately to the dexamethasone suppression-ACTH challenge, indicating that levels of stress were not extreme. There were a number of significant interaction effects that were due to an atypical set of results for one of the control groups in one of the singly housed test sessions. Monkeys that spent their year of single-caging in indoor rooms showed higher activations of the hypothalamic-pituitary-adrenal system than did monkeys that spent their year of single-caging in outdoor buildings. This suggests that aspects of the environment outside of the cage (conspecific activity, environmental variation, etc.) may influence plasma cortisol. This is surprising, considering that inanimate and social enhancements within the cage had little effect.

Hippocampal (HC) function and morphology have been implicated in the pathophysiology of depression. Reduced HC volume has been observed in depressed humans, although the effect is not always significant. Studies of functional differentiation of the HC have revealed that the anterior portion is associated with emotional and anxiety-related functioning, and the posterior portion with memory processing. As such, measuring whole HC volume may mask differences seen only in the anterior or posterior HC. We used unbiased stereology to measure whole, anterior, and posterior HC volumes in 12 adult female cynomolgus macaques, half of which exhibited spontaneously occurring depressive behavior defined as a slumped/collapsed body posture with open eyes, and a relative lack of responsivity to environmental stimuli. The two groups were otherwise matched on circulating estradiol, progesterone, and cortisol levels, social status, estimated age, and body weight. Frozen postmortem HC tissue from depressed and nondepressed monkeys was serially sectioned and thionin-stained. According to established neuroanatomical guidelines and with the aid of Neurolucida software (MBF Bioscience), every tenth section throughout the extent of the HC was manually traced and used to reconstruct the 3-D models used to determine volumes. Anterior and posterior HC were delineated by the presence or absence of the uncus. No significant differences were found between depressed and nondepressed monkeys for whole or posterior HC volume, although the average HC volume was 4% smaller in depressed than nondepressed monkeys. Anterior HC volumes were significantly smaller (15.4%) in depressed compared to nondepressed monkeys. These results indicate that reduced volume in the anterior HC, an area previously implicated in emotional functioning, may be associated with a depressive phenotype in female cynomolgus macaques.

We report here on the social behavior of 30 adult male cynomolgus monkeys, maintained in social groups of five animals each and assigned for 22 months to one of two dietary conditions: a) "luxury"--relatively high fat, high cholesterol (43% calories from fat, 0.34 mg cholesterol/Calorie of diet); or b) "prudent"--relatively low fat, low cholesterol (30% calories from fat, 0.05 mg cholesterol/Calorie of diet). The dietary manipulation resulted in higher total serum cholesterol (TSC) and lower high density lipoprotein cholesterol (HDLC) concentrations in luxury diet animals than in their prudent diet counterparts (p's less than 0.05). Additionally, we monitored the occurrence of 21 behavioral acts frequently exhibited by this species in captivity. Of these behaviors, only contact aggression differed between dietary conditions (p less than 0.03), with prudent diet monkeys initiating more aggression than luxury diet animals. These results are consistent with studies linking relatively low serum cholesterol concentrations to violent or antisocial behavior in psychiatric and criminal populations and could be relevant to understanding the significant increase in violence-related mortality observed among people assigned to cholesterol-lowering treatment in clinical trials.

Understanding mechanisms of estrogen effects on cognition is critical for designing therapies for post-menopausal women and others with dementia. Hippocampus, an area important to cognitive function, responds robustly on estrogen. ERbeta and ERalpha transcripts were detected in the hippocampus and hypothalamus of an ovariectomized female monkey at a relatively high ERbeta/ERalpha ratio. These results suggest that ERbeta may play a role in mediating estrogen effects in the primate hippocampus and hypothalamus.

The effects of chronic moderate alcohol consumption on cardiac function are not understood. Acute stress may affect cardiac function by shifting autonomic cardiac regulation in favor of the sympathetic nervous system. Although alcohol consumption often increases at times of stress, the interactive effects of stress and chronic moderate alcohol consumption on cardiac regulation have not been studied. The objective was to assess the effects of long-term (1–2 years) moderate (a two-drink/day equivalent, 5 days/week) alcohol consumption on heart rate (HR) variability under normal and acutely stressful conditions in small stable groups of ovariectomized adult cynomolgus monkeys (Macaca fascicularis). Monkeys were trained to voluntarily drink their daily alcohol dose (

Context Current animal models of depression are inadequate to further our understanding of depression. New models that allow for analysis of cognitive function and sex differences are needed. Objective To characterize serotonin 1A (5-HT 1A ) receptor binding potential (BP) and its relationship with specific characteristics of behavioral depression in cynomolgus monkeys. Design A 23-month case-control study. Setting Small social groups in the laboratory. Subjects Seventeen adult female cynomolgus monkeys. Main Outcome Measures Serotonin 1A receptor BP was examined by positron emission tomography using the radioligand 4,2"-(methoxyphenyl)-1-[2"-( N -2"-pyridinyl)- p -fluorobenzamido]ethylpiperazine in the raphe, amygdala, hippocampus, and anterior cingulate cortex in monkeys characterized by behavioral observation as depressed or not depressed. Aggression, submission, affiliation, pathologic behaviors, and activity levels were determined by behavioral observation. Heart rate and hypothalamic-pituitary-adrenal function were also determined. Results Throughout the brain areas examined, there was a reduction in 5-HT 1A BP in depressed monkeys. The 5-HT 1A BP in the amygdala and hippocampus was associated with aggression and submission. Friendly interaction, grooming, and locomotion were associated with 5-HT 1A BP in the left cingulate cortex, whereas attention directed toward the environment was associated with 5-HT 1A BP in the right cingulate cortex. The 5-HT 1A receptor BP was inversely associated with heart rate in the raphe, left cingulate, and right amygdala. Conclusions This is the fourth in a series of studies that suggest that depressive behavior in adult female cynomolgus monkeys is similar to that observed in humans. It has been observed in 2 large groups of monkeys randomly selected from feral populations, suggesting that the capacity for depression is inherent in the species. This animal model holds promise to further our understanding of the basic mechanisms of affective behavior, the neuropathophysiologic characteristics of depression and the cognitive dysfunction that accompanies them, genetic and environmental factors that may affect depression risk, and the role of reproductive function in the excess depression risk in women.

Background: Although evidence has accumulated for the cardioprotective effects of moderate ethanol consumption, little is known about the effects on the liver of consuming the equivalent of two drinks per day. The objective of this study was to determine the effects of moderate ethanol administration on the hepatic content of enzymes involved in ethanol oxidation, on hepatic lipid accumulation, and on serum markers of liver function/damage in the monkey, Macaca fascicularis. Methods: Ovariectomized, adult monkeys were maintained for 34 months on an atherogenic diet containing cholesterol 1.21 mg/kJ. They were trained to drink ethanol plus vehicle at a dose of 0.5 g/kg body weight, which was administered 5 days a week for 2 years. Blood was collected for ethanol concentrations (1 hr after ethanol administration) and was also assayed for γ-glutamyltransferase, alanine aminotransferase (ALT), and alkaline phosphatase (ALP) activities. Liver obtained at necropsy was analyzed for triglyceride and cholesterol contents and for alcohol dehydrogenase, cytochrome P450 2E1, and cytochrome P450 3A4 by Western blots. Results: The blood ethanol concentrations measured 1 hr after ethanol administration were relatively constant over the 2-year dosing period. Hepatic levels of alcohol dehydrogenase and the cytochrome P450s were not significantly different between ethanol-consuming animals and control animals. Ethanol-associated increases in liver triglyceride were not significant due to high variability in hepatic lipid content in both the controls and ethanol consumers. However, covariance analyses using pretreatment concentrations of plasma cholesterol and apolipoprotein A-I suggested that the ethanol-related increase in hepatic free cholesterol was significant. Relative to controls, alcohol consumers had higher levels of serum ALT and a transient increase in ALP at 5 months. Conclusions: The observations made in this study on primates administered an atherogenic diet suggest that moderate ethanol ingestion has modest effects on the liver, including slightly increased ALT and ALP values. However, additional studies will be required to verify that this level of consumption is hepatotoxic when ingested over extended periods. This is still a concern because some human studies suggest that levels of ethanol considered to be cardioprotective cause liver injury when consumed over a lifetime.

Stress and sex steroidal milieu can each influence mood in women. The purpose of this study was to compare the effect of long-term conjugated equine estrogen (CEE), soy phytoestrogen (SPE), and social subordination stress on dorsal raphe serotonin neurotransmission of ovariectomized cynomolgus monkeys. Tryptophan hydroxylase (TPH) and serotonin reuptake transporter (SERT) protein content were determined, and the in vitro degradation of macaque SERT protein was examined in the presence and absence of protease inhibitors, serotonin (5-HT), and citalopram. Like CEE, SPE increased TPH protein levels. Social subordinates had markedly lower TPH protein levels than dominants regardless of hormone replacement. Therefore, these two variables had independent and additive effects. CEE and SPE increased SERT, and social status had no effect. Thus, the hormone-induced increase in SERT was accompanied by increased 5-HT synthesis and neuronal firing, which appears biologically reasonable as 5-HT prevented SERT degradation in vitro.

The relationship between the stress associated with low social status and disease susceptibility is apparent in human and non-human primates. In human beings, low socioeconomic status is associated with increased mortality from all causes, increased coronary heart disease (CHD) morbidity and mortality, increased rates of depression, the prevalence of themetabolic syndrome, and central obesity (1). We have studied these relationships in female cynomolgus monkeys for many years. Like human beings, low social status (subordinate) female monkeys are more susceptible than their dominant counterparts to a number of pathological processes that result in disease, including depression and coronary artery atherosclerosis. This chapter will focus on the relationship between social status, fat distribution patterns, and two disease endpoints in adult female cynomolgus monkeys, coronary heart disease risk and depression.

Among primate species there is pronounced variation in the relationship between social status and measures of stress physiology. An informal meta-analysis was designed to investigate the basis of this diversity across different primate societies. Species were included only if a substantial amount of published information was available regarding both social behavior and rank-related differences in stress physiology. Four Old World and three New World species met these criteria, including societies varying from small-group, singular cooperative breeders (common marmoset and cotton top tamarin) to large-troop, multi-male, multi-female polygynous mating systems (rhesus, cynomolgus, talapoin, squirrel monkeys, and olive baboon). A questionnaire was formulated to obtain information necessary to characterize the stress milieu for individuals in particular primate societies. We standardized cortisol values within each species by calculating the ratio of basal cortisol concentrations of subordinates to those of dominants in stable dominance hierarchies and expressing the ratio as a percentage (relative cortisol levels). The meta-analysis identified two variables that significantly predicted relative cortisol levels: subordinates exhibited higher relative cortisol levels when they (1). were subjected to higher rates of stressors, and (2). experienced decreased opportunities for social (including close kin) support. These findings have important implications for understanding the different physiological consequences of dominant and subordinate social status across primate societies and how social rank may differ in its behavioral and physiological manifestations among primate societies.

Previous studies on the intrinsic contractile properties of human myofibrils reported increase, decrease, or no change with aging, perhaps due to differences in physical activity, diet, and other factors. We examined myofilaments' contractile characteristics and physical performance, walking speed and climbing rate, in African green vervet monkeys, housed in social groups in large indoor-outdoor enclosures and fed the same diet. Physical performance and skinned vastus lateralis (VL) muscle fiber function were investigated in four young (11±1 yrs) and four old (23±1 yrs) monkeys. Fiber myosin heavy chain (MHC) isoform was determined by gel electrophoresis. The old monkeys walked slower (19%) and climbed less (63%) than young monkeys (p

The effect of estrogen and progesterone replacement therapy on the initiating events in atherogenesis was studied in surgically postmenopausal cynomolgus monkeys. Monkeys were ovariectomized and divided randomly into two groups, one receiving 17 beta-estradiol and cyclic progesterone treatment (n = 9) and ovariectomized controls receiving no hormone replacement therapy (n = 8). The monkeys were fed a moderately atherogenic diet for 18 wk to accelerate the early pathogenic processes but not to be of sufficient duration to produce grossly visible atherosclerotic lesions. Sex hormone replacement therapy decreased the accumulation of LDL and products of LDL degradation in the coronary arteries by greater than 70% while having no significant effect on plasma lipid, lipoprotein, or apoprotein concentrations. Arterial intimal lesions were small with no difference between groups. The reduction in arterial LDL metabolism occurred very early in the pathogenesis of atherosclerosis and was independent of indices of endothelial cell injury, such as enhanced endothelial cell turnover or leukocyte adhesion to the endothelium. Results of this study suggest that one mechanism by which sex hormone treatment inhibits the initiation of atherosclerosis is a direct effect at the level of the arterial wall by suppressing the uptake and/or degradation of LDL.

Background: Social subordination in female cynomolgus monkeys is stressful and activates the hypothalamic–pituitary–adrenal axis. In a previous experiment behavioral depression was observed in a subset of subordinates. Methods: In the experiment reported here behavioral and physiological indicators of stress were evaluated in dominant and subordinate female cynomolgus monkeys, and brain dopaminergic activity was assessed, as reflected in the prolactin response to haloperidol, a dopamine2 (D2) receptor antagonist. Results: Subordinates were aggressed more, spent more time in fearful scanning of the social environment, spent less time as the recipients of the active affiliative behavior of being groomed, had more variable heart rates in response to a novel environment, and were hypercortisolemic compared to dominants. Prolactin responses to haloperidol challenge were lower in subordinates than dominants, an observation consistent with the hypothesis that subordinate females have decreased D2 receptor function. Conclusions: These observations suggest that social subordination is stressful and may alter brain dopaminergic function in primates. The neurophysiological characteristics of social subordinates may contribute to their susceptibility to depression.

A lack of social support is associated with increased risk of coronary heart disease morbidity and mortality in human beings. Similarly, chronic social separation (single cage housing) potentiates atherosclerosis in female monkeys. Under the hypothesis that autonomic arousal and/or ovarian impairment may mediate this effect (as both are associated with increased atherosclerosis), heart rate and luteal phase plasma progesterone concentrations were measured in 12 female cynomolgus monkeys that were first socially housed, then individually housed, and finally returned to their original social groups. Afternoon heart rates increased during social separation compared to the social groupings (P