Adult Female Macaca Fascicularis Research Articles

Power spectrum analysis of EEG in a translational nonhuman primate model after chronic exposure to low levels of the common marine neurotoxin, domoic acid

Domoic acid (DA), the focus of this research, is a marine algal neurotoxin and epileptogen produced by species in the genus Pseudo-nitzschia. DA is found in finfish and shellfish across the globe. The current regulatory limit for DA consumption (20 ppm in shellfish) was set to protect humans from acute toxic effects, but there is a growing body of evidence suggesting that regular consumption of DA contaminated seafood at or below the regulatory limit may lead to subtle neurological effects in adults. The present research uses a translational nonhuman primate model to assess neurophysiological changes after chronic exposure to DA near the regulatory limit. Sedated electroencephalography (EEG) was used in 20 healthy adult female Macaca fascicularis, orally administered 0.075 and 0.15 mg DA/kg/day for at least 10 months. Paired video and EEG recordings were cleaned and a Fast Fourier Transformation was applied to EEG recordings to assess power differences in frequency bands from 1−20 Hz. When DA exposed animals were compared to controls, power was significantly decreased in the delta band (1−4 Hz, p < 0.005) and significantly increased in the alpha band (5−8 Hz, p < 0.005), theta band (9−12 Hz, p < 0.01), and beta band (13−20 Hz, p < 0.05). The power differences were not dose dependent or related to the duration of DA exposure, or subtle clinical symptoms of DA exposure (intentional tremors). Alterations of power in these bands have been associated with a host of clinical symptoms, such as deficits in memory and neurodegenerative diseases, and ultimately provide new insight into the subclinical toxicity of chronic, low-dose DA exposure on the adult primate brain.

Preclinical modeling of exposure to a global marine bio-contaminant: Effects of in utero Domoic acid exposure on neonatal behavior and infant memory

Domoic Acid (DA) is a naturally-occurring marine neurotoxin that is increasingly recognized as an important public health issue. Prenatal DA exposure occurs through the maternal consumption of contaminated shellfish/finfish. To better understand the fetal risks associated with DA, we initiated a longitudinal, preclinical study focused on the reproductive and developmental effects of chronic, low-dose oral DA exposure. To this end, 32 adult female Macaca fascicularis monkeys were orally dosed with 0, 0.075 or 0.15 mg/kg/day DA on a daily basis prior to breeding and throughout breeding and pregnancy. The doses included the proposed human Tolerable Daily Intake (TDI) (0.075 mg/kg/day) for DA. Adult females were bred to nonexposed males. To evaluate development during early infancy, offspring were administered a Neonatal Assessment modeled after the human Neonatal Behavior Assessment Scale and a series of Visual Recognition Memory problems using the novelty paradigm. Results indicated that prenatal DA exposure did not impact early survival reflexes or responsivity to the environment. Findings from the recognition memory assessment, given between 1 and 2 months of age, showed that exposed and control infants demonstrated robust novelty scores when test problems were relatively easy to solve. Performance was not diminished by the introduction of delay periods. However, when more difficult recognition problems were introduced, the looking behavior of the 0.15 mg/kg DA group was random and infants failed to show differential visual attention to novel test stimuli. This finding suggests subtle but significant impairment in recognition memory and demonstrates that chronic fetal exposure to DA may impact developing cognitive processes.

Effects of oral domoic acid exposure on maternal reproduction and infant birth characteristics in a preclinical nonhuman primate model

Domoic Acid (DA) is a naturally-occurring excitotoxin, produced by marine algae, which can bioaccumulate in shellfish and finfish. The consumption of seafood contaminated with DA is associated with gastrointestinal illness that, in the case of high DA exposure, can evolve into a spectrum of responses ranging from agitation to hallucinations, memory loss, seizures and coma. Because algal blooms that produce DA are becoming more widespread and very little is known about the dangers of chronic, low-dose exposure, we initiated a preclinical study focused on the reproductive and developmental effects of DA in a nonhuman primate model. To this end, 32 adult female Macaca fascicularis monkeys were orally exposed to 0, 0.075 or 0.15 mg/kg/day DA on a daily basis, prior to and during pregnancy. Females were bred to non-exposed males and infants were evaluated at birth. Results from this study provided no evidence of changes in DA plasma concentrations with chronic exposure. DA exposure was not associated with reproductive toxicity or adverse changes in the physical characteristics of newborns. However, in an unanticipated finding, our clinical observations revealed the presence of subtle neurological effects in the form of intentional tremors in the exposed adult females. While females in both dose groups displayed increased tremoring, the effect was dose-dependent and observed at a higher rate in females exposed to 0.15 mg/kg/day. These results demonstrate that chronic, low-level exposure to DA is associated with injury to the adult CNS and suggest that current regulatory guidelines designed to protect human health may not be adequate for high-frequency shellfish consumers.

The Mutual Influences between Depressed Macaca fascicularis Mothers and Their Infants

ObjectiveTo assess the influence of infant rearing on the behavior of depressed adult female Macaca fascicularis and the influence of depressed infant-rearing adult female Macaca fascicularis on their infants in a free enclosure environment.MethodsHere, 20 depressed subjects and then 20 healthy subjects were randomly selected from a total population of 1007 adult female Macaca fascicularis subjects. Four depressed subjects and eight healthy subjects were rearing infants. By focal observation, three trained observers video-recorded the selected subjects over a total observational period of 560 hours. The video footage was analyzed by qualified blinded analysts that coded the raw footage into quantitative behavioral data (i.e., durations of 53 pre-defined behavioral items across 12 behavioral categories) for statistical analysis.ResultsBetween infant-rearing and non-rearing healthy subjects, ten differential behaviors distributed across five behavioral categories were identified. Between infant-rearing and non-rearing depressed subjects, nine behaviors distributed across five behavioral categories were identified. Between infant-rearing healthy and infant-rearing depressed subjects, fifteen behaviors distributed across six behavioral categories were identified.ConclusionInfant-rearing depressed adult female Macaca fascicularis subjects may have a worse psychological status as compared to non-rearing depressed counterparts. Infant rearing may negatively influence depressed Macaca fascicularis mothers. Infant-rearing depressed subjects were less adequate at raising infants as compared to infant-rearing healthy subjects. Thus, maternal depression in this macaque species may negatively impact infatile development, which is consistent with previous findings in humans.

Depression-like behavioral phenotypes by social and social plus visual isolation in the adult female Macaca fascicularis.

Major depressive disorder (MDD) is a debilitating psychiatric mood disorder that affects millions of individuals globally. Our understanding of the biological basis of MDD is poor, and current treatments are ineffective in a significant proportion of cases. This current situation may relate to the dominant rodent animal models of depression, which possess translational limitations due to limited homologies with humans. Therefore, a more homologous primate model of depression is needed to advance investigation into the pathophysiological mechanisms underlying depression and to conduct pre-clinical therapeutic trials. Here, we report two convenient methods – social isolation and social plus visual isolation – which can be applied to construct a non-human primate model of depression in the adult female cynomolgus monkey (Macaca fascicularis). Both social and social plus visual isolation were shown to be effective in inducing depression-like behavior by significantly reducing socially dominant aggressive conflict behavior, communicative behavior, sexual behavior, and parental behavior. The addition of visual isolation produced more profound behavioral changes than social isolation alone by further reducing parental behavior and sexual behavior. Thus, the degree of behavioral pathology may be manipulated by the degree of isolation. These methods can be applied to construct a non-human primate model of depression in order to assess physiological, behavioral, and social phenomena in a controlled laboratory setting.

Comparing the relative benefits of grooming-contact and full-contact pairing for laboratory-housed adult female Macaca fascicularis

Tactile social contact is the most effective form of environmental enrichment for promoting normal behavior in captive primates. For laboratory macaques housed indoors, pair housing is the most common method for socialization. Pairs can be housed either in full contact (FC), or in protected contact (PC). At Washington National Primate Research Center, PC is provided by grooming-contact (GC) cages whereby two partners are housed individually in adjacent cages with access to each other through widely spaced vertical bars. Grooming-contact has been used to accommodate research protocol restrictions and improve the likelihood of compatibility for various pairings, in part by enabling male–female pairs. This study compares the benefits between the two housing types by video recording 14 pairs of adult female Macaca fascicularis in four sequential housing phases following an ABBA design: baseline grooming-contact, full contact shortly after introduction, 1-month-later full contact, and after reversion to grooming-contact. Prior to this study, pairs had been housed compatibly in GC. Twelve of the 14 long-term pairs transitioned successfully to full contact and data presented exclude the two failed pairs. Allogrooming increased significantly when pairs first switched from GC to FC (P=0.018), but the effect did not last through 1-month-later FC phase suggesting that the initial improvement in affiliative behavior was a transitory novelty response that did not persist. Self-grooming significantly decreased between the first GC and first FC phases (P=0.016), likely due to redirected allogrooming. Non-contact affiliative behavior towards partner or other conspecifics in the room did not differ, nor did agonism towards partner or others in the room. Occurrence of abnormal, tension, manipulation, miscellaneous active, and inactive behaviors did not differ significantly across housing phases. Proximity measurements indicated that pairs were significantly out of arm's reach more often in protected contact than when in full contact (P≤0.02). Proportion of time spent in physical contact significantly increased between the first GC and first FC phases (P=0.002), but subsequently declined. For both FC phases, partners chose to spend about 50% of their time in the same cage. Few behavioral improvements were seen after pairs switched to full contact and no negative effects came of reversion to grooming contact. This study suggests that tactile contact provided through widely spaced bars (grooming-contact) is a viable alternative to full contact housing for adult female longtailed macaques. It provides a degree of social housing while allowing both partners choice and control, key concepts in contemporary animal welfare guidelines.

Balicatib, a cathepsin K inhibitor, stimulates periosteal bone formation in monkeys

Balicatib, an inhibitor of the osteoclastic enzyme cathepsin K, was tested in ovariectomized monkeys, a model for osteoporosis. As expected, ovariectomy-induced bone mass changes were partially prevented by balicatib treatment. Bone turnover was significantly decreased at most sites, but unlike most bone resorption inhibitors, periosteal bone formation rates were increased. Selective inhibitors of the osteoclastic enzyme cathepsin K have potential in osteoporosis treatment. This study evaluated the efficacy of balicatib (AAE581), a novel inhibitor of human cathepsin K, on bone mass and dynamic histomorphometric endpoints in ovariectomized monkeys. Eighty adult female Macaca fascicularis underwent bilateral ovariectomies and were dosed twice daily by oral gavage with balicatib at 0, 3, 10, and 50 mg/kg for 18 months (groups O, L, M, H, respectively). Approximately 1 month after treatment initiation, the 50 mg/kg dose was decreased to 30 mg/kg. Twenty animals underwent sham-ovariectomies (group S). Bone mass was measured at 3-6 month intervals. At 18 months, vertebra and femur were collected for histomorphometry. In both spine and femur, group O animals lost BMD and all other groups gained BMD between 0 and 18 months. In balicatib-treated animals, BMD change in the spine was intermediate between group S and O, with groups L and M significantly different from group O. In femur, all three doses of balicatib significantly increased BMD gain relative to group O and group mean values were also higher than group S. Most histomorphometric indices of bone turnover in vertebra and femoral neck were significantly lower than group O with balicatib treatment, except that periosteal bone formation rates (Ps.BFR) were significantly higher. Ps.BFR in mid-femur was also significantly increased by treatment. Balicatib partially prevented ovariectomy-induced changes in bone mass, inhibited bone turnover at most sites, and had an unexpected stimulatory effect on periosteal bone formation.

Balicatib, a cathepsin K inhibitor, stimulates periosteal bone formation in monkeys

Balicatib, an inhibitor of the osteoclastic enzyme cathepsin K, was tested in ovariectomized monkeys, a model for osteoporosis. As expected, ovariectomy-induced bone mass changes were partially prevented by balicatib treatment. Bone turnover was significantly decreased at most sites, but unlike most bone resorption inhibitors, periosteal bone formation rates were increased. Selective inhibitors of the osteoclastic enzyme cathepsin K have potential in osteoporosis treatment. This study evaluated the efficacy of balicatib (AAE581), a novel inhibitor of human cathepsin K, on bone mass and dynamic histomorphometric endpoints in ovariectomized monkeys. Eighty adult female Macaca fascicularis underwent bilateral ovariectomies and were dosed twice daily by oral gavage with balicatib at 0, 3, 10, and 50 mg/kg for 18 months (groups O, L, M, H, respectively). Approximately 1 month after treatment initiation, the 50 mg/kg dose was decreased to 30 mg/kg. Twenty animals underwent sham-ovariectomies (group S). Bone mass was measured at 3-6 month intervals. At 18 months, vertebra and femur were collected for histomorphometry. In both spine and femur, group O animals lost bone mineral density (BMD), and all other groups gained BMD between 0 and 18 months. In balicatib-treated animals, BMD change in the spine was intermediate between group S and O, with groups L and M significantly different from group O. In femur, all three doses of balicatib significantly increased BMD gain relative to group O, and group mean values were also higher than group S. Most histomorphometric indices of bone turnover in vertebra and femoral neck were significantly lower than group O with balicatib treatment, except that periosteal bone formation rates (Ps.BFR) were significantly higher. Ps.BFR in mid-femur was also significantly increased by treatment. Balicatib partially prevented ovariectomy-induced changes in bone mass, inhibited bone turnover at most sites, and had an unexpected stimulatory effect on periosteal bone formation.

Chronic maternal methanol inhalation in nonhuman primates ( Macaca fascicularis): reproductive performance and birth outcome

The present study was designed to characterize maternal reproductive performance and early offspring effects following exposure to methanol (MeOH) vapor in a nonhuman primate model. The two-cohort study design used 48 adult female Macaca fascicularis (24/cohort) monkeys exposed to 0, 200, 600, or 1800 ppm MeOH vapor for approximately 2.5 h/day, 7 days/week prior to breeding and throughout pregnancy. Maternal body weight measurement, clinical observations and health assessments were conducted routinely throughout the study. Menstrual cyclicity was monitored during the pre-breeding and breeding periods and timed matings were conducted with nonexposed males. Females were monitored closely during the last month of pregnancy. At birth, infant physical characteristics were measured and a newborn health assessment was conducted. Methanol exposure did not alter menstrual cycles, the number of breedings to conception or conception rate. A total of 34 live-born infants were delivered (control=8, 200 ppm=9, 600 ppm=8, 1800 ppm=9). One female each in the control and 600-ppm group delivered a stillborn infant and a cesarean section (C-section) was required to deliver a hydrocephalic infant who died in utero in the maternal 1800-ppm group. Although not statistically significant, five MeOH-exposed females were C-sectioned due to pregnancy complications such as uterine bleeding and prolonged unproductive labor. These complications were not observed in the control group. The mean length of pregnancy in the MeOH-exposed groups was significantly decreased by 6 to 8 days when compared to controls. There were no MeOH-related effects on offspring birthweight or newborn health status. The consistent reduction in length of pregnancy observed in the MeOH females may reflect a treatment effect on the fetal neuroendocrine system. Given that the fetal hypothalamic–-pituitary–adrenal axis controls pregnancy length in most species, these results suggest a modest but significant effect of MeOH on the biochemical events that control the timing of birth.

Chronic maternal methanol inhalation in nonhuman primates ( Macaca fascicularis): Exposure and toxicokinetics prior to and during pregnancy

Toxicokinetic studies were conducted following daily inhalation exposure to methanol vapor prior to and throughout pregnancy in adult female Macaca fascicularis monkeys. They were part of a larger study to investigate the effects of chronic methanol exposure on maternal reproductive performance and early offspring effects. In a two-cohort study design, 48 females (24/cohort) were assigned to parallel exposure groups at 0 (control), 200, 600, or 1800 ppm methanol vapor for approximately 2.5 h/day, 7 days/week throughout breeding and pregnancy. Blood methanol at 30 min postexposure was monitored biweekly. The time course for the clearance of blood MeOH concentrations following exposure was characterized on four occasions: twice during the prebreeding period and during mid- and late pregnancy. Average blood methanol concentrations at 30 min postexposure were 5, 11, and 35 μg/ml across all four toxicokinetic studies in the 200, 600 and 1800 ppm groups, respectively. Blood concentrations in the 200 ppm group were barely above basal (preexposure) blood methanol concentrations or those observed in the control group (approximately 3 μg/ml). Nonlinear elimination kinetics were observed in most of the 1800 ppm group females. There was a decrease in elimination half-life (7–20%) and an increase in clearance (30%) after 3-months of daily MeOH exposure compared to the initial exposure. There were no statistically significant changes in the first-order blood methanol half-life or clearance during pregnancy, but the mean distribution volume per kilogram body weight decreased by 22% and 17% in the 600 and 1800 ppm groups. Plasma formate levels did not differ between the methanol and control exposure groups. Plasma formate and serum folate concentrations increased slightly over the course of this study in both the exposed and control groups but these increases were not related to methanol exposure.

Characterization of the discriminative stimulus effects of GABA(A) receptor ligands in Macaca fascicularis monkeys under different ethanol training conditions.

The current study was designed to extend our knowledge of the GABA(A) receptor system in mediating discriminative stimulus effects of ethanol in non-human primates. To characterize the discriminative stimulus effects of ethanol, pentobarbital, midazolam, muscimol and morphine in male and female monkeys under different ethanol training conditions. Adult male (n=8) and female (n=10) Macaca fascicularis monkeys were divided into four groups and trained to discriminate 1.0 g/kg ethanol (n=8) versus water or 2.0 g/kg ethanol (n=10) versus water in a 2x2 design with training dose and sex as main group factors. Solutions were administered intragastrically (20% ethanol w/v) and responding was maintained under a fixed-ratio schedule of food reinforcement. Dose-response determinations of ethanol, pentobarbital, midazolam, muscimol and morphine were made under the training condition of 30 min pretreatment interval. The ethanol pretreatment interval in training sessions was then increased to 60 min and the effects of ethanol, pentobarbital and midazolam were redetermined. Training dose influenced the ED50 of ethanol to produce substitution under both pretreatment intervals and pentobarbital to produce substitution under the 30-min pretreatment training interval. There were no group differences in sensitivity to midazolam. The potency of the ligands to produce ethanol substitution was consistent across groups with midazolam>pentobarbital>ethanol. There were no sex differences in substitution of the ligands for ethanol. Blood ethanol concentrations at the onset of ethanol training sessions were higher in the 2.0 g/kg groups and under longer pretreatment times, but were not different on the basis of sex. Pentobarbital and midazolam produce ethanol-like discriminative stimulus effects in male and female cynomolgus monkeys suggesting a significant GABA(A) component mediating the behavioral effects of ethanol. There was limited evidence that training dose of ethanol influenced substitution pattern of the GABA(A) ligands in cynomolgus monkeys, unlike previous findings in rats. Finally, there appear to be no sex differences in the profile of GABA(A) mechanisms involved in the discriminative stimulus effects of ethanol.

Elastic properties and masticatory bone stress in the macaque mandible.

One important limitation of mechanical analyses with strain gages is the difficulty in directly estimating patterns of stress or loading in skeletal elements from strain measurements. Because of the inherent anisotropy in cortical bone, orientation of principal strains and stresses do not necessarily coincide, and it has been demonstrated theoretically that such differences may be as great as 45 degrees (Cowin and Hart, 1990). Likewise, relative proportions of stress and strain magnitudes may differ. This investigation measured the elastic properties of a region of cortical bone on both the buccal and lingual surfaces of the lower border of the macaque mandible. The elastic property data was then combined with macaque mandibular strain data from published and a new in vivo strain gage experiment to determine directions and magnitudes of maximum and minimum principal stresses. The goal was to compare the stresses and strains and assess the differences in orientation and relative magnitude between them. The main question was whether these differences might lead to different interpretations of mandibular function. Elastic and shear moduli, and Poisson's ratios were measured using an ultrasonic technique from buccal and lingual cortical surfaces in 12 macaque mandibles. Mandibular strain gage data were taken from a published set of experiments (Hylander, 1979), and from a new experiment in which rosette strain gauges were fixed to the buccal and lingual cortices of the mandibular corpus of an adult female Macaca fascicularis, after which bone strain was recorded during mastication. Averaged elastic properties were combined with strain data to calculate an estimate of stresses in the mandibular corpus. The elastic properties were similar to those of the human mandibular cortex. Near its lower border, the macaque mandible was most stiff in a longitudinal direction, less stiff in an inferosuperior direction, and least stiff in a direction normal to the bone's surface. The lingual aspect of the mandible was slightly stiffer than the buccal aspect. Magnitudes of stresses calculated from average strains ranged from a compressive stress of -16.00 GPa to a tensile stress of 8.84 GPa. The orientation of the principal stresses depended on whether the strain gage site was on the working or balancing side. On the balancing side of the mandibles, maximum principal stresses were oriented nearly perpendicular to the lower border of the mandible. On the working side of the mandibles, the orientation of the maximum principal stresses was more variable than on the balancing side, indicating a larger range of possible mechanisms of loading. Near the lower border of the mandible, differences between the orientation of stresses and strains were 12 degrees or less. Compared to ratios between maximum and minimum strains, ratios between maximum and minimum stresses were more divergent from a ratio of 1.0. Results did not provide any major reinterpretations of mandibular function in macaques, but rather confirmed and extended existing work. The differences between stresses and strains on the balancing side of the mandible generally supported the view that during the power stroke the mandible was bent and slightly twisted both during mastication and transducer biting. The calculated stresses served to de-emphasize the relative importance of torsion. On the working side, the greater range of variability in the stress analysis compared to the strain analysis suggested that a more detailed examination of loadings and stress patterns in each individual experiment would be useful to interpret the results. Torsion was evident on the working side; but in a number of experiments, further information was needed to interpret other superimposed regional loading patterns, which may have included parasagittal bending and reverse parasagittal bending.

Autometallographic determination of inorganic mercury distribution in the cortex of the calcarine sulcus of the monkey Macaca fascicularis following long-term subclinical exposure to methylmercury and mercuric chloride.

The distribution of accumulated inorganic mercury deposits in the cortex of the calcarine sulcus of adult female Macaca fascicularis following long-term subclinical exposure to methyl-mercury (MeHg) and mercuric chloride (inorganic mercury-IHg) has been determined by autometallography. Four groups of monkeys were exposed to MeHg (50 micrograms Hg/kg body wt/day) by mouth for 6, 12, and 18 months or 12 months followed by 6 months without exposure (clearance group). A fifth group of monkeys was administered inorganic mercury (as HgCl2; 200 micrograms Hg/kg body wt/day) for 3 months by constant rate intravenous infusion via an indwelling catheter. Staining of IHg deposits in the MeHg-exposed groups increased for all cell types with increased length of exposure. The astrocytes and microglia in the MeHg exposure groups contained the largest deposits of IHg. Neurons in the 6-month MeHg exposure group were either not labeled or contained very fine deposits of IHg. The frequency of labeled neurons increased somewhat in the 12-month and clearance exposure groups. Virtually all neurons in the 18-month exposure group contained labeled deposits of IHg; however, these total deposits were considerably smaller than those present within the astrocytes and microglia. The majority of endothelial cells and pericytes did not contain notable mercury deposits, although scattered individual cells were heavily labeled. Labeled oligodendrocytes were relatively rare in all MeHg-exposed groups. Gitter cells, primarily located in a perivascular position, were common in the 12-month, 18-month, and clearance groups and many of these were found to be heavily labeled. The staining of mercury deposits in the IHg-exposed animals was low compared to the MeHg-exposed groups. The astrocytes and microglia were the primary cell types labeled. It is concluded that the astrocytes, and possibly microglia, are the primary location of the demethylation of MeHg into IHg within the cortex of the calcarine sulcus.

Increases in the Number of Reactive Glia in the Visual Cortex of Macaca fascicularis Following Subclinical Long-Term Methyl Mercury Exposure

The number of neurons, astrocytes, reactive glia, oligodendrocytes, endothelia, and pericytes in the cortex of the calcarine sulcus of adult female Macaca fascicularis following long-term subclinical exposure to methyl mercury (MeHg) and mercuric chloride (inorganic mercury; IHg) has been estimated by use of the optical volume fractionator stereology technique. Four groups of monkeys were exposed to MeHg (50 μg Hg/kg body wt/day) by mouth for 6, 12, 18, and 12 months followed by 6 months without exposure (clearance group). A fifth group of monkeys was administered IHg (as HgCl2; 200 μg Hg/kg body wt/day) by constant rate intravenous infusion via an indwelling catheter for 3 months. Reactive glia showed a significant increase in number for every treatment group, increasing 72% in the 6-month, 152% in the 12-month, and 120% in the 18-month MeHg exposed groups, and the number of reactive glia in the clearance group remained elevated (89%). The IHg exposed group showed a 165% increase in the number of reactive glia. The IHg exposed group and the clearance group had low levels of MeHg present within the tissue; however, the level of IHg was elevated in both groups. These results suggest that the IHg may be responsible for the increase in reactive glia. All other cell types, including the neurons, showed no significant change in number at the prescribed exposure level and durations. The identities of the reactive glial cells and the implications for the long-term function and survivability of the neurons due to changes in the glial population following subclinical long-term exposure to mercury are discussed.

Stability of social status rankings of female cynomolgus monkeys, of varying reproductive condition, in different social groups.

In order test the hypothesis that adult female macaques display a tendency to attain a certain level of social status independent of the social situation, the social status rankings of 41 wild-caught adult female Macaca fascicularis were determined in different social groups. About one-third of the females were intact and housed with vasectomized males. About one-third of the females were ovariectomized and housed with intact males, and the remaining females were intact and housed with intact males in order to allow pregnancy to occur. Within each of these experimental groups, females were housed in social groups of 4-6 females and 1 male, and the constituency of these groups was changed every 3 months for 22 months. Thus, females lived in eight different social groups. The correlations between the social status rankings of individual females while living in different social groups were positive and significant. The majority of the females were either stable dominants or stable subordinates in 75% of the groups in which they lived, which was a significant proportion of the study population. The stability of social status rankings was higher in the ovariectomized than in the pregnant and intact groups; however, this was not a significant difference. In the context of the results of previous studies, these findings suggest that the social status of an individual is the result of both the immediate social environment and some inherent characteristic(s) of the individual that promotes the likelihood that under most social circumstances an individual will display a predictable level of social status.

Kinetics of methyl mercury in blood and brain during chronic exposure in the monkey Macaca fascicularis.

The disposition parameters derived from a compartmental model kinetic analysis of blood Hg levels in nonpregnant, adult female Macaca fascicularis given daily doses of MeHg did not vary with either dosage level (50, 70 or 90 micrograms MeHg/kg b.wt.day) or duration of exposure (up to 507 day). In contrast, blood clearance of Hg in pregnant females was dose-dependent; it being higher at the 90 micrograms MeHg/kg b.wt.day than at the lower dosage levels. Hg levels in the brain of adult fascicularis relative to blood Hg also increased at the highest level of exposure. Blood Hg half-life in neonate fascicularis was similar to half-life in their mothers (adults). Finally, the regional distribution of mercury in the brains of adult and neonate fascicularis exposed to low and intermediate levels of MeHg resembles the reported distribution of mercury in the brains of adult and neonate humans environmentally exposed to MeHg. Consequently, M. fascicularis may be an especially appropriate animal model for studying the neurotoxic mechanisms of chronic methyl mercury exposure.

Adrenal responsiveness and social status in intact and ovariectomized Macaca fascicularis.

Plasma cortisol (F) response to intravenous adrenocorticotropin (ACTH) infusion (following dexamethasone suppression) was examined in adult female Macaca fascicularis that had been living for 22 months in social groups consisting of four to six females and one male. A portion of these females were ovariectomized (n = 21), while the rest were reproductively intact (n = 23). The social behavior of all animals was monitored with a focal sampling procedure, and dominance ranks were determined on the basis of fight outcomes. Further, intact females were swabbed vaginally to determine onset of menstruation and were sampled for plasma progesterone (P) every three days during the luteal phase of their cycles. Among the results was that the plasma F response to ACTH infusion was greater in subordinate animals than in dominants (P < .02). Subordinates and dominants did not, however, differ in plasma F measured at baseline. It was found further that plasma F concentrations were greater in ovariectomized than in intact females at baseline and following ACTH injection (P < .01). Finally, there was an appreciable elevation in plasma F across all animals during the 15- and 30-minute post-ACTH injection measurements (P < .01). Subsequent analyses of data from intact females showed interrelationships among dominance rank, reproductive function (indicated by luteal phase plasma P concentrations), adrenal size, and adrenal response to ACTH infusion. These data indicated that subordinate females were at a reproductive disadvantage compared to dominants, a result that may have been mediated, in part, by the increased adrenal size and enhanced adrenal responsiveness of subordinate females.

Habituation and rehabituation of the electrodermal orienting reflex in Macaca fascicularis monkeys as a function of stimulus variability

Two groups of six adult female Macaca fascicularis monkeys received repeated presentations of either a fixed pure tone or a tone that varied in frequency from trial to trial, until their skin conductance response habituated. The monkeys were then rehabituated with a new, unchanging stimulus. The monkeys showed a small but insignificant tendency towards retention of habituation, but no savings in either SCR magnitude or latency scores. The habituation-retardation effect, seen in humans’ trials-to-criterion data and to some extent in SCR magnitude and latency measures in Cebus monkeys, was suggested in the macaques’ trials data but not in their magnitude or latency data. A significant accelerative change in heart rate was elicited by the tones, unlike the decelerative response seen in humans, Macaca arctoides, and Cebus monkeys. The Macaca fascicularis monkeys showed a change toward HR deceleration with repeated, unchanging stimulation, but not with varying stimulation. Also, a shift in auditory frequency following habituation resulted in a HR increase following initial habituation to a fixed stimulus, but not following habituation to variable stimuli. It could not be determined whether the difference in HR response between the present macaques and previously studied Cebus monkeys was due to species or sex, since the macaques in this study were all female, while the Cebus monkeys in our earlier study were all male. Both species appear to provide some support for the matching model of habituation.