Individual differences in basal cisternal cerebrospinal fluid 5-HIAA and HVA in monkeys. The effects of gender, age, physical characteristics, and matrilineal influences.

We examined the effects of gender, age, weight, length, body shape (ectomorphy), and matrilineal influences on cisternal cerebrospinal fluid 5-hydroxyindoleacetic acid (CSF 5-HIAA) and homovanillic acid (HVA) in 78 socially living adult and adolescent vervet monkeys. CSF 5-HIAA and the 5-HIAA:HVA ratio were higher (by 27% and 18%, respectively) in females. In both sexes, CSF 5-HIAA and the 5-HIAA:HVA ratio increased with age. Neither weight nor length were independently related to CSF 5-HIAA or HVA; however, shape correlated with CSF 5-HIAA and HVA in males (higher in thin, long subjects). Male offspring had CSF 5-HIAA concentrations and 5-HIAA:HVA ratios that were significantly closer to their mothers than did age-matched, maternally unrelated males. Repeated measures of CSF 5-HIAA and HVA in another 22 males living in unvarying settings showed that individual differences in these measures persisted over time. The data underscore the impact of gender, age, and matrilineal relationships on individual differences in CSF monoamine metabolites and highlight the importance of controlling for age and gender in neuropharmacological investigations of clinical populations.

Menstrual cycle and social behavior in vervet monkeys.

We assessed the relationship between social behavior and the menstrual cycle in 11 adult female vervet monkeys (Cercopithecus aethiops sabaeus) living in an established, stable social group. The findings indicated that fluctuations in ovarian steroids are accompanied by behavioral changes in vervet monkeys. A significant increase in aggressive action, avoidance of social overtures, and retreats from threat occurred during the late luteal phase. However, the social environment can greatly affect behavior independent of the phase of the menstrual cycle. The 10 nondominant (or subordinate) individuals not only exhibited behavioral changes across their own menstrual cycles, but also were responsive to the dominant female's cycle. During the dominant female's late luteal phase, subordinate females significantly increased aggression and decreased social activity. Some of behavioral patterns in female vervet monkeys are therefore relatively independent of direct hormonal modulation and support the contention of the dominant female as the driving force for behavioral changes related to aggression and social interaction. The differential effect of hormones and social status and other environmental factors on behavior has not been critically evaluated in human studies of the premenstrual syndrome. The present study suggests that it is important to assess which behavioral patterns in women are hormonally mediated and which are dependent on the environment.

Application of positron emission tomography to determine cerebral glucose utilization in conscious infant monkeys.

Cerebral glucose metabolism has been used as a marker of cerebral maturation and neuroplasticity. In studies addressing these issues in young non-human primates, investigators have used positron emission tomography (PET) and [18F]2-fluoro-2-deoxy-D-glucose (FDG) to calculate local cerebral metabolic rates of glucose (1CMRG1c). Unfortunately, these values were influenced by anesthesia. In order to avoid this confounding factor, we have established a method that permits reliable measurements in young conscious vervet monkeys using FDG-PET. Immature animals remained in a conscious, resting state during the initial 42 min of FDG uptake as they were allowed to cling to their anesthetized mothers. After FDG uptake, animals were anesthetized and placed in the PET scanner with data acquisition beginning at 60 min post-FDG injection. FDG image sets consisted of 30 planes separated by 1.69 mm, parameters sufficient to image the entire monkey brain. Our method of region-of-interest (ROI) analysis was assessed within and between raters and demonstrated high reliability (P < 0.001). To illustrate that our method was sensitive to developmental changes in cerebral glucose metabolism, quantitative studies of young conscious monkeys revealed that infant monkeys 6-8 months of age exhibited significantly higher 1CMRG1c values (P < 0.05) in all regions examined, except sensorimotor cortex and thalamus, compared to monkeys younger than 4 months of age. This method provided high resolution images and 1CMRG1c values that were reliable within age group. These results support the application of FDG-PET to investigate questions related to cerebral glucose metabolism in young conscious non-human primates.

Serotonergic mechanisms promote dominance acquisition in adult male vervet monkeys.

In a counter-balanced, cross-over study, we examined the contributions of serotonergic systems to the acquisition of social dominance in adult male vervet monkeys. Subjects were members of 12 social groups, each containing 3 adult males, at least 3 adult females, and their offspring. Animals were observed in 5 intervals including a first baseline, a first experimental, a second baseline, a second experimental, and a third baseline period. At the end of the first baseline period, the dominant male was removed from each group. In each group, one of the two remaining subordinate males was selected at random for treatment and during the first experimental period, 6 of the 12 treated males received drugs that enhanced serotonergic activity (3 were given tryptophan 40 mg/kg/day and 3 fluoxetine 2 mg/kg/day). The other 6 treated males received drugs that reduced serotonergic function (3 were given fenfluramine 2 mg/kg/day and 3 cyproheptadine 60 micrograms/kg/day). At the end of the first experimental period, the original dominant male was returned to his group and the second baseline period began. In all instances, the originally dominant male regained his dominant position. The second experimental period began with the dominant male again being removed and, the 12 treated males were given the treatment they had not received in the first experimental period. At the start of the third 12-week baseline period, the original dominant male was returned to his group and resumed his dominant status. When the 12 treated subjects received tryptophan or fluoxetine, they became dominant in all instances. When they received fenfluramine or cyproheptadine, their vehicle-treated cage mates became dominant. The sequence of the behavioral changes shown by the treated males as they acquired dominance status paralleled those seen in naturalistic conditions. These observations support the distinction between dominance and aggression and strongly suggest that when hierarchical relationships are uncertain, serotonergic mechanisms may mediate the behaviors which permit a male to attain high dominance status.

Dynamic changes in cerebral glucose metabolism in conscious infant monkeys during the first year of life as measured by positron emission tomography.

Recently, advances in spatial resolution have provided the opportunity to utilize positron emission tomography (PET) to examine local cerebral metabolic rates for glucose (lCMR(glc)) in large animals noninvasively, thereby allowing repeated lCMR(glc) measurements in the same animal. Previous studies have attempted to describe the ontogeny of cerebral glucose metabolism in anesthetized nonhuman primates using [18F]fluorodeoxyglucose (FDG) and PET. However, the use of sedation during the tracer uptake period may influence lCMR(glc). This study was conducted to describe lCMR(glc) in conscious infant vervet monkeys (Cercopithecus aethiops sabaeus) during the first year of life utilizing FDG-PET. Cross-sectional studies (n=23) displayed lowest and highest lCMR(glc) in all structures at the 2-3 and 8-9 month age groups, respectively. The metabolic pattern suggested an increase in lCMR(glc) values between 2 and 8 months of age with decreased metabolism observed at 10-12 months of age in all regions. Peak lCMR(glc) values at 8 months were an average of 84+/-24% higher than values seen at the youngest age examined quantitatively (2-3 months). The regions of greatest and smallest increases in lCMR(glc) at 8 months were the cerebellar hemispheres (90%) and the thalamus (39%), respectively. Longitudinal analysis in 4 animals supported this developmental pattern, demonstrating the ability to detect changes in cerebral glucose metabolism within animals and the potential for FDG-PET in nonhuman primate models of brain maturation. By determining the normative profile of lCMR(glc) during development in monkeys, future application of FDG-PET will provide the opportunity to longitudinally assess the effects of environmental or pharmacological intervention on the immature brain.

Developmental changes in brain metabolism in sedated rhesus macaques and vervet monkeys revealed by positron emission tomography.

The present positron emission tomography study used 2-deoxy-2[18F]fluoro-D-glucose to examine age-related changes in local cerebral metabolic rates for glucose (LCMRglc) in sedated rhesus macaques and vervet monkeys. Nineteen vervet monkeys were scanned in a cross-sectional design, which consisted of three age groups (birth to 59 d, 60-179 d, 180 d to adult) that captured the developmental period of greatest synaptic density within the second group. Two rhesus and two vervet monkeys were also examined longitudinally. Subjects were sedated throughout the procedure with a combination of ketamine and midazolam. Longitudinal and cross-sectional analyses of 20 brain regions indicated lowest LCMRglc in rhesus and vervet monkeys < 2 months of age (about 60% of adult levels). These metabolic rates more than doubled to approximately 155% of adult levels after the second postnatal month, coincident with transient synaptic overproduction and increased sociobehavioral activity. LCMRglc remained high until 6 months postnatally, coincident with continued dendritic growth and the emerging sociobehavioral independence of the young monkey. After 6 months, LCMRglc decreased gradually to adult levels. Thus, the period between 2 and 6 months is a time of peak metabolic activity, which coincides with increased histologic and behavioral activity in the developing monkey.