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Biomedical subjects

J R Kaplan

Publications and source records attributed to J R Kaplan.

At least 19 recordsLinked to original sources
PubMed2002

Premenopausal social status and hormone exposure predict postmenopausal atherosclerosis in female monkeys.

OBJECTIVE: To determine whether premenopausal social subordination in female monkeys predicts postmenopausal atherosclerosis, and whether any such effect is altered by chronic exposure to contraceptive steroids or postmenopausal hormone replacement. METHODS: One hundred seventy-seven (177) premenopausal cynomolgus monkeys (Macaca fascicularis) housed in social groups of five or six were fed an atherogenic diet that, for half of the animals, also contained an oral contraceptive (OC). Individuals were judged socially dominant or subordinate based on behavioral observations. After 26 months animals were oophorectomized, biopsied for iliac atherosclerosis, and for the next 36 months were fed one of three atherogenic diets containing soy protein: 1) phytoestrogen-free; 2) phytoestrogens intact; and 3) phytoestrogen-free plus conjugated equine estrogens. Plasma lipids and menstrual cyclicity were also assessed. Finally, all animals were necropsied and the extent of atherosclerosis measured in the coronary and iliac arteries. RESULTS: The interaction of premenopausal social status and OC exposure predicted postmenopausal coronary artery atherosclerosis (P =.02). Subordinate animals not receiving OCs developed twice the coronary atherosclerosis of similarly untreated dominants (P <.01), an outcome mitigated by premenopausal OC exposure (P <.01). These effects occurred across postmenopausal treatment groups and independent of variation in plasma lipids. The same associations were observed in the iliac arteries, and, to a similar extent, both pre- and post-menopausally. Hormone data suggest that untreated premenopausal subordinates may have been estrogen deficient. CONCLUSION: Premenopausal social subordination exacerbates postmenopausal atherosclerosis, an effect possibly mediated by estrogen deficiency and shown here to be prevented by premenopausal OC exposure. These results occur irrespective of postmenopausal treatment.

Animals↗
PubMed2001

Cholesterol reduction and non-illness mortality: meta-analysis of randomised clinical trials.

OBJECTIVE: To investigate the association between cholesterol lowering interventions and risk of death from suicide, accident, or trauma (non-illness mortality). DESIGN: Meta-analysis of the non-illness mortality outcomes of large, randomised clinical trials of cholesterol lowering treatments. STUDIES REVIEWED: 19 out of 21 eligible trials that had data available on non-illness mortality. INTERVENTIONS REVIEWED: Dietary modification, drug treatment, or partial ileal bypass surgery for 1-10 years. MAIN OUTCOME MEASURE: Deaths from suicides, accidents, and violence in treatment groups compared with control groups. RESULTS: Across all trials, the odds ratio of non-illness mortality in the treated groups, relative to control groups, was 1.18 (95% confidence interval 0.91 to 1.52; P=0.20). The odds ratios were 1.28 (0.94 to 1.74; P=0.12) for primary prevention trials and 1.00 (0.65 to 1.55; P=0.98) for secondary prevention trials. Randomised clinical trials using statins did not show a treatment related rise in non-illness mortality (0.84, 0.50 to 1.41; P=0.50), whereas a trend toward increased deaths from suicide and violence was observed in trials of dietary interventions and non-statin drugs (1.32, 0.98 to 1.77; P=0.06). No relation was found between the magnitude of cholesterol reduction and non-illness mortality (P=0.23). CONCLUSION: Currently available evidence does not indicate that non-illness mortality is increased significantly by cholesterol lowering treatments. A modest increase may occur with dietary interventions and non-statin drugs.

Accidents↗
PubMed2001

Lake pigments facilitate analysis of fecal cortisol and behavior in group-housed macaques.

Fecal steroid analyses are becoming more popular among both field and laboratory scientists. The benefits associated with sampling procedures that do not require restraint, anesthesia, and blood collection include less risk to both subject and investigator, as well as the potential to obtain endocrine profiles that do not reflect the influence of stress. However, the utility of the fecal steroid method has been limited in field conditions because of problems associated with sample identification. Here, we present evidence that Lake pigments are a valuable tool for the identification of individual fecal samples from group-housed female cynomolgus macaques. Further, we present data that suggest that excreted cortisol can be assayed from such samples, leading to the finding that time of day of sample collection influences cortisol concentrations, with morning samples producing higher values (t = 2.769, P = 0.024). Finally, the collection of physiological data from group-housed animals permits the evaluation of the relationship between endocrine status and behavior. This study demonstrated that morning fecal cortisol was significantly correlated with competitive and proximity behaviors, although not with rank in two stable social groups. In conclusion, the utility and validity of fecal steroid analyses continue to expand with further investigations.

Animals↗
PubMed2001

Dominance, cortisol, and behavior in small groups of female cynomolgus monkeys (Macaca fascicularis).

The relationships among social rank, basal cortisol concentrations, and social behavior were assessed in adult female cynomolgus monkeys (Macaca fascicularis). Subjects were 157 unrelated, reproductively intact animals housed in 30 small groups. Rank determinations were made monthly. Blood samples were collected on two occasions, 4.5 and 7.5 months following initial group formation. Regular behavioral observations were conducted on a subset of animals over a period of 4 weeks, 9 months following group formation. Analyses revealed that serum cortisol values were significantly correlated across the two sampling periods, with no significant change in absolute values. While social rank was positively correlated across both samples, there was no relationship between rank and cortisol. However, dominant and subordinate animals did differ in the rates of performance of aggressive and submissive behaviors. These data suggest that social rank does not influence baseline serum cortisol in adult female cynomolgus monkeys, despite stability in measures of rank and cortisol and the presence of the usual behavioral differences between dominants and subordinates.

Animals↗
PubMed2001

Social impulsivity inversely associated with CSF 5-HIAA and fluoxetine exposure in vervet monkeys.

Animal and human research suggests that the central serotonin system is involved in the inhibition of impulsive behavior. Two studies were designed to assess this relationship in male vervet monkeys (Cercopithecus aethiops sabaeus) using a standardized test of impulsivity in a social context: the Intruder Challenge. In the first study, an index of impulsivity in response to an unfamiliar adult male intruder (including latency to approach and aggressive and assertive interactions) was inversely correlated with levels of the serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA) in cisternal cerebrospinal fluid (r = -0.33, p <.01, n = 138). The approach, but not aggressive, component of the Impulsivity Index was the primary contributor to this relationship (partial r = -0.27, p <.01). The second experiment compared responses to the Intruder Challenge after 9 weeks of daily treatment with fluoxetine (2 mg/kg, i.m.) or vehicle. Fluoxetine-treated subjects (n = 6) had significantly lower Impulsivity Index scores than controls (n = 12). The results from these two investigations provide evidence for serotonergic influences on social impulsivity.

Age Factors↗
PubMed2000

Predictors of social status in cynomolgus monkeys (Macaca fascicularis) after group formation.

The purpose of the present study was to determine whether various behavioral and hormonal markers obtained in individually housed monkeys would be predictive of social rank following group housing. Body weight, serum cortisol and testosterone levels, and locomotor activity in an open-field apparatus were examined in 20 experimentally naive male cynomolgus monkeys (Macaca fascicularis) while they were individually housed. It was hypothesized that eventual subordinate monkeys would have higher cortisol levels and increased locomotor activity scores. These monkeys were then placed in social groups of four (five pens of four monkeys), and social rank was determined based on outcomes of dyadic agonistic encounters. Body weight correlated significantly with eventual social rank. In general, the heavier the monkey the higher the social rank. Locomotor activity in an open-field apparatus following administration of a low dose of cocaine (0.01 mg/kg, i.v.), which has been shown to increase CNS dopamine, correlated with eventual social rank such that individually housed monkeys with high levels of locomotion were more likely to become subordinate. Serum cortisol and testosterone levels failed to correlate with eventual social rank. Hypothalamic-pituitary feedback sensitivity and adrenal responsiveness were examined by measuring cortisol levels after administration of dexamethasone and following ACTH challenge. Cortisol responses in these tests were not associated with eventual social rank. These results suggest that, in addition to body weight, the level of reactivity in a novel environment after administration of a low dose of cocaine is a potential trait marker for social rank. This trait is apparently not associated with hormone levels, but may involve other CNS mechanisms.

Animals↗
PubMed1999

Behavioral responses to ovariectomy and chronic anabolic steroid treatment in female cynomolgus macaques.

A pilot study was conducted to investigate the effects of ovariectomy on rates of aggressive and affiliative behavior, as well as body size, in 38 young adult female cynomolgus monkeys (Macaca fascicularis) living in isosexual social groups of four to five animals. In addition, we assessed the effects of nandrolone decanoate (an anabolic steroid used for postmenopausal hormone replacement therapy) on indices of aggression, submission, and body size. Animals were randomized into three experimental conditions: 1) sham ovariectomized, untreated (SHAM); 2) ovariectomized, untreated (OVX); and, 3) ovariectomized, treated with nandrolone decanoate for 24 months (NAN). Each individual was observed for 10 min, one to two times per month, and all instances of agonistic and affiliative behavior were recorded by means of focal animal sampling. Ovariectomized, untreated animals exhibited a two- to threefold increase in aggression compared to SHAM or NAN animals; F(2, 32) = 4.09, p = 0.026; however, the expression of prosocial or affiliative behaviors as measured by rates of grooming and initiating friendly behavior was unaffected. At an i.m. dose of 25 mg every 2 weeks, nandrolone decanoate caused a 60% increase in body weight of the animals compared to untreated intact and ovariectomized animals, F(2, 31) = 161.57, p < 0.0001.

Aggression↗
PubMed1999

Cerebrospinal fluid monoaminergic metabolites differ in wild anubis and hybrid (Anubis hamadryas) baboons: possible relationships to life history and behavior.

The article reports monoaminergic metabolite [homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylglycol (MHPG)], values from the cerebrospinal fluid (CSF) of 27 wild baboons (Papio hamadryas) aged 40 to 140 months. Animals were either anubis, or anubis with hamadryas admixture; males of the latter subspecies generally have a reduced tendency to disperse from their natal groups. Overall, the values and interrelationships among the CSF monoamine metabolites resembled data reported from closely related, captive-housed animals. For example, age was significantly correlated with HVA concentrations (r = -60, p < .05), but not with the other metabolites. Notably, males characterized by hamadryas admixture had significantly higher concentrations of HVA, 5-HIAA, and MHPG (p < .05, respectively), a result possibly driven by differences in serotonergic activity. These data provide initial evidence that variation in central monoaminergic activity, as indicated by CSF monoamine metabolite concentrations, may reflect differences in behavior and life history that have taxonomic and, perhaps, evolutionary significance.

Age Factors↗
PubMed1999

PET imaging of dopamine D2 receptors with [18F]fluoroclebopride in monkeys: effects of isoflurane- and ketamine-induced anesthesia.

The purpose of the present study was to determine whether positron emission tomography (PET) studies in monkeys with the dopamine (DA) D2 receptor ligand [18F]fluoroclebopride (FCP) would be significantly influenced by anesthetic induction with isoflurane (approximately 5.0%) compared to induction with 10 mg/kg ketamine. Five experimentally-naive adult male cynomolgus monkeys (Macaca fascicularis) were trained to sit calmly in a primate restraint chair. Before the first PET scan, each monkey was anesthetized, by mask, with isoflurane. After complete sedation, the monkey was intubated and anesthesia was maintained throughout the PET study by isoflurane (approximately 1.5%). At least 1 month later, a second PET study was conducted in which anesthesia was induced with ketamine and maintained by isoflurane (approximately 1.5%). Irrespective of induction anesthetic, there was a high uptake of [18F]FCP and a linear rate of washout from the basal ganglia for all monkeys. There were also no differences in time to peak uptake (approximately 25 min), in clearance half-life (t1/2 = 140-164 min) or in D2 binding (distribution volume ratios of 2.48 vs. 2.50). These results indicate that induction anesthetic did not differentially affect D2 binding of [18F]FCP in monkeys. Furthermore, the low variability between studies indicates that [18F]FCP is an excellent ligand for longitudinal studies of D2 receptors in nonhuman primates.

Anesthetics↗
PubMed1999

Status, stress, and atherosclerosis: the role of environment and individual behavior.

Atherosclerosis induced by moderate hyperlipoproteinemia in group-housed cynomolgus monkeys differs significantly between animals of dominant and subordinate social status. The nature of this association also varies by sex, and in males, by stability of the social environment. Dominant males develop more extensive atherosclerosis than subordinates when housed in unstable, but not stable, social groups; in contrast, subordinate females develop greater atherosclerosis than dominants, and do so irrespective of the conditions of social housing. Experimental investigations reveal that the first of these associations (males) is mediated by concomitant sympathoadrenal activation and the second (females) by ovarian impairment associated with the stress of social subordination. We believe our findings offer clues to the neuroendocrine mediation of behavioral influences on coronary artery disease in humans. This is particularly true where these influences reflect asymmetries in the power or status relationships among individuals within similar social environments, or when dimensions of temperament or disposition give rise to such relationships. We propose that these data also may be informative regarding the pathophysiological sequelae of social stratification (in which disease incidence varies by class membership within populations), but only where social environments engendered by class inequalities exacerbate status-dependent behavioral differences among individuals within communities of associates.

Animals↗
PubMed1998

Effects of chronic social separation on cardiovascular disease risk factors in female cynomolgus monkeys.

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 < 0.001). Increased heart rates could not be explained by activity levels, which were lower during social separation than in social groupings (P < 0.001). Ovarian function (i.e. luteal-phase progesterone concentrations) was not influenced by housing condition. Single caging reduced the extent of social signaling, even though animals were in visual and auditory contact. Rates of affiliative behaviors increased and time spent alone decreased in post-reunion social groups compared to pre-separation social groups (P's < 0.01). The results indicate that chronic social separation in this group-living species may exacerbate atherosclerosis via altered autonomic activity, as evidenced by higher heart rates during social separation.

Animals↗
PubMed1997

Assessing the observed relationship between low cholesterol and violence-related mortality. Implications for suicide risk.

Health advocacy groups advise all Americans to restrict their dietary intake of saturated fat and cholesterol as an efficacious and safe way to lower plasma cholesterol concentrations and thus reduce the risk of coronary heart disease and other atherosclerotic disorders. However, accumulating evidence suggests that naturally low or clinically reduced cholesterol is associated with increased nonillness mortality (principally suicide and accidents). Other evidence suggests that such increases in suicide and traumatic death may be mediated by the adverse changes in behavior and mood that sometimes accompany low or reduced cholesterol. These observations provided the rationale for an ongoing series of studies in monkeys designed to explore the hypothesis that alterations in dietary or plasma cholesterol influence behavior and that such effects are potentiated by lipid-induced changes in brain chemistry. In fact, the investigations in monkeys reveal that reductions in plasma cholesterol increase the tendency to engage in impulsive or violent behavior through a mechanism involving central serotonergic activity. It is speculated that the cholesterol-serotonin-behavior association represents a mechanism evolved to increase hunting or competitive foraging behavior in the face of nutritional threats signaled by a decline in total serum cholesterol (TC). The epidemiological and experimental data could be interpreted as having two implications for public health: (1) low-cholesterol may be a marker for risk of suicide or traumatic death and (2) cholesterol lowering may have adverse effects for some individuals under some circumstances.

Animals↗
PubMed1997

Behaviorally elicited heart rate reactivity and atherosclerosis in ovariectomized cynomolgus monkeys (Macaca fascicularis).

It has been hypothesized that atherogenesis is accelerated among individuals who exhibit heightened cardiovascular reactions to psychologic stress. We have reported previously that the coronary atherosclerosis of cholesterol-fed, male and reproductively intact (premenopausal) female cynomolgus monkeys was exacerbated in animals that experienced the largest heart rate (HR) reactions to a fear-eliciting laboratory stressor. In this article, we report a similar relationship among 20 female monkeys that were rendered estrogen-deficient (by ovariectomy) and subsequently treated with replacement of both estrogen and progesterone. At the beginning of a 30-month study period, animals were fitted with ECG telemetry devices, and their HRs were recorded under baseline and stressed conditions. Stress HR measurements were obtained during a standard challenge involving threatened capture and physical handling of the animals. As part of a related experiment, monkeys were then ovariectomized and, for the remainder of the study, administered 17 beta-estradiol (continuously) and progesterone (cyclically) by subcutaneous Silastic implant (Dow Corning). Animals consumed a cholesterol-containing diet throughout, and HR measurements were repeated in the 24th month. At necropsy, the magnitude of animals' HR responses to stress correlated significantly with intimal area measurements in the left anterior descending and circumflex coronary arteries (r = .59 and r = .57, respectively; P < .009). This association was due to a marked exacerbation of coronary atherosclerosis in animals comprising the upper third of the reactivity distribution. Although total and HDL cholesterol concentrations also covaried with HR reactivity, the greater atherosclerosis of "high" HR reactors persisted after statistical adjustment for concomitant variability in plasma lipids. HR reactivity was unrelated to blood pressure, body weight, or social behavior.

Animals↗
PubMed1997

Using ethological principles to study psychosocial influences on coronary atherosclerosis in monkeys.

Studies with male cynomolgus monkeys suggest that atherosclerosis is potentiated among individuals that are habitually successful in their aggressive encounters with social strangers, thereby retaining dominant social status in an unstable environment. Further, the increased risk of atherosclerosis experienced by such animals is related, in part, to the autonomic (sympathetic) adjustments they make while responding to the demands of retaining dominant status. These data provide clear support for the hypothesis that psychosocial factors influence disease pathogenesis via neuroendocrine mediation. Additionally, they provide initial evidence in favor of Jim Henry's suggestion that the pattern of neuroendocrine response to environmental challenge depends on the type and degree of control an animal can exert in such circumstances (Henry & Stephens 1977).

Animals↗
PubMed1995

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↗
PubMed1995

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↗