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Aberrant functioning of the hypothalamic-pituitary-adrenal (HPA) axis is a hallmark of conditions such as depression, anxiety disorders, and post-traumatic stress disorder. Early-life adversity and genetic variation can interaction to disrupt HPA axis regulation, potentially contributing to certain forms of psychopathology. This study employs a rhesus macaque model to investigate how early parental neglect interacts with a single nucleotide polymorphism within the promoter region of the corticotropin-releasing hormone (CRH-248) gene, impacting the development of the HPA axis. For the initial six months of life, 307 rhesus monkey infants ( n  = 146 females, n  = 161 males) were either reared with their mothers (MR) in conditions emulating the natural environment (control group) or raised without maternal care in groups with constant or 3-hours daily access to same-aged peers (NR). Blood samples collected on days 30, 60, 90, and 120 of life under stressful conditions were assayed for plasma cortisol and adrenocorticotropic hormone (ACTH) concentrations. Findings revealed that NR subjects exhibited a significant blunting of both ACTH and cortisol concentrations. Notably, there was a gene-by-environment interaction observed for ACTH and cortisol levels, with NR subjects with the polymorphism displaying higher ACTH concentrations and lower cortisol concentrations. To the extent that these results generalize to humans, they suggest that early parental neglect may render individuals vulnerable to HPA axis dysfunction, a susceptibility that is modulated by CRH-248 genotype-a gene-by-environment interaction that leaves a lasting developmental signature.

Studies show that maternal behaviors are mediated by the bivariate serotonin transporter (5-HTT) genotype, although the findings are mixed, with some studies showing that mothers with the s allele exhibit increased maternal sensitivity, while other studies show that mothers with the s allele show decreased maternal sensitivity. Nonhuman primate studies offer increased control over extraneous variables and may contribute to a better understanding of the effects of the 5-HTT genotype on maternal sensitivity. This study assesses the influence of 5-HTT genotype variation on maternal sensitivity in parenting in 125 rhesus macaque mothers (Macaca mulatta) during the first three-months of their infants' lives, an age well before typical infants undergo weaning. Mothers were genotyped for the 5-HTT genotype and maternal behaviors were collected, including neglectfulness, sensitivity, and premature rejections during undisturbed social interactions. Results showed that mothers homozygous for the s allele rejected their infants the most and restrained their infants the least, an indication that mothers with the s allele are more likely to neglect their infants' psychological and physical needs. These findings suggest that, at an age when an infant's needs are based on warmth, security, and protection, mothers with an s allele exhibit less sensitive maternal behaviors. High rates of rejections and low rates of restraints are behaviors that typically characterize premature weaning and are inappropriate for their infant's young age. This study is an important step in understanding the etiology of variability in maternal warmth and care, and further suggests that maternal 5-HTT genotype should be examined in studies assessing genetic influences on variation in maternal sensitivity, and ultimately, mother-infant attachment quality., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Wood et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

While non-suicidal self-injury (NSSI) occurs in the general population at a surprisingly high rate, with higher rates among certain clinical  populations, its etiology is not well-understood. Consequently, the DSM-5 lists NSSI as requiring further research. This study utilizes a translational model of naturally-occurring NSSI to assess the role of early parental neglect and variation in the serotonin transporter genotype (5-HTT) in the etiology of NSSI. Subjects (N = 161) were rhesus macaques (Macaca mulatta) reared in one of three conditions (mother-reared (MR), peer-reared (PR), or surrogate peer-reared (SPR)), and classified as NSSI (n = 18) or non-NSSI (n = 143). Subjects were genotyped for 5-HTT and their behaviors were recorded during an ecologically-meaningful, stress-evoking, intruder paradigm. Two weeks prior to testing, blood samples were obtained and assayed for plasma cortisol and adrenocorticotropic hormone (ACTH) concentrations. NSSI subjects were more likely to be SPR, paralleling human studies showing that individuals that exhibit NSSI tend to have experienced abuse or neglect early in life. Results also indicated that variation in the 5-HTT genotype differentiated the NSSI subjects. NSSI subjects that were homozygous for the L allele exhibited high plasma ACTH and high rates of stress-induced stereotypies; whereas NSSI subjects with the s allele exhibited impulsive behaviors, including frequently approaching the potentially dangerous intruder, high rates of aggressive vocal threats, and more activity. These results suggest that there may be different 5-HTT genotype-mediated NSSI typologies and that both early experiences and variation in the 5-HTT genotype may be important factors in understanding the etiology of NSSI., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

A μ-opioid receptor (OPRM1) single-nucleotide-polymorphism, found in both humans and rhesus macaques mediates the mother-infant attachment bond. Because mothers treat their sons and daughters differently, it is somewhat surprising that the role of infant sex has not been assessed in the context of a maternal-OPRM1-genotype-by-infant-sex interaction. The present study investigates the effect of maternal-OPRM1-genotype and infant sex on mother-infant behaviors. Over the first 6 months of offspring life, mother-infant behavioral data assessing attachment quality was collected twice weekly from a large number of rhesus monkey mother-infant pairs ( N = 161 dyads; n = 64 female infants, n = 97 male infants). Mothers were genotyped for OPRM1 variation. Factor analysis of the observed behaviors showed two factors: Attachment (maternal-infant cradling, rejections, and infant approaches and leaves), and Maternal Restraints (mother restrains infant, preventing exploration). Further analyses showed a two-way, maternal-genotype-by-infant-sex interaction for both factors. For Attachment, mothers with the CC genotype cradled and restrained (Maternal Restraints) their female infants more and rejected them less, when compared to female infants of CG mothers. Perhaps as a consequence, female infants of CC genotype mothers approached and left their mothers less often, when compared to female infants of CG mothers, likely an indication that female infants from mothers with CG genotype play a greater role in maintaining the mother-infant bond than do female infants from CC genotype mothers. This finding may also indicate a more secure attachment in infants from CC genotype mothers. Unlike female infants, on average, the mother-infant relationship of dyads with a male infant was largely undifferentiated by maternal genotype. These findings suggest that, in contrast to female infants from CG mothers, CC mothers and their female infants appear to have a closer mother-infant relationship which may portend close life-long bonds, as mothers and female offspring remain together throughout life. Male offspring appear to have a more aloof mother-infant bond regardless of OPRM1-genotype. The results of this study indicate that maternal-OPRM1 variation mediates mother-infant attachment behaviors for female infants and has less effect for male infants. This suggests that offspring sex should be included in studies investigating the effect of maternal-OPRM1 genotype on the mother-infant attachment relationship., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wood, Baron, Schwandt, Lindell, Barr, Suomi and Higley.)

A variety of studies show that parental absence early in life leads to deleterious effects on the developing CNS. This is thought to be largely because evolutionary-dependent stimuli are necessary for the appropriate postnatal development of the young brain, an effect sometimes termed the "experience-expectant brain," with parents providing the necessary input for normative synaptic connections to develop and appropriate neuronal survival to occur. Principal among CNS systems affected by parental input are the monoamine systems. In the present study, N = 434 rhesus monkeys (233 males, 201 females) were reared in one of two conditions: as mother-reared controls (MR; n = 269) or without adults with 24-h access to same-aged peers (PR; n = 165). When subjects were six-months-old, they underwent a separation paradigm involving 4, sequential, four-day social separations from their mothers or peers, with each separation followed by three-day reunions with their mothers or their peers. Prior to the separation paradigm, baseline cisternal CSF samples were obtained, as well as at the end of each the four social separations, and after final separation, during a recovery period. CSF was assayed for concentrations of monoamine metabolites and a blood sample was genotyped for the serotonin transporter (5-HTT) genotype. Replicating earlier landmark findings, PR subjects with the s allele exhibited lower baseline concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), when compared to PR subjects homozygous for the L allele. MR subjects were undifferentiated by genotype. PR subjects exhibited lower CSF 5-HIAA concentrations during baseline, but higher CSF 5-HIAA during social separations, when compared to MR subjects. There were rearing effects for the dopamine metabolite homovanillic acid (HVA) and for the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG), with PR subjects showing higher HVA and lower MHPG when compared to MR subjects. These findings indicate that there are long-term deficits in the response of monoamines following early maternal absence. The results of this study confirm and extend earlier findings that early parental absence has deleterious consequences for the development of the monoamine systems, and that these consequences are modulated by the 5-HTT genotype., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wood, Gabrielle, Hunter, Skowbo, Schwandt, Lindell, Barr, Suomi and Higley.)

The second-to-fourth digit ratio (2D:4D ratio) is considered a postnatal proxy measure for the degree of prenatal androgen exposure (PAE), which is the primary factor responsible for masculinizing the brain of a developing fetus. Some studies suggest that the organizational effects of PAE may extend to the hypothalamic-pituitary-adrenal (HPA) axis response to stress. This study investigates the relationship between 2D:4D ratio and HPA axis functioning using a rhesus monkey ( Macaca mulatta ) model. Subjects were N = 268 (180 females, 88 males) rhesus monkey infants (3-4 months of age). Plasma cortisol concentrations were assayed from two blood samples obtained during a 25-h experimental social separation stressor at 2- and 7-h post-separation. Subjects' 2D:4D ratio was measured later in life ( M age = 6.70 years). It was hypothesized that infant rhesus monkeys that exhibited a more masculine-like 2D:4D ratio would show lower levels of circulating cortisol after a social separation and relocation stressor. The results showed that there was a sex difference in the left-hand 2D:4D ratio. The results also showed that there was an overall sex difference in cortisol concentrations and that female, but not male, monkeys that exhibited a more masculine-like right- and left-hand 2D:4D ratio exhibited lower mean stress-induced cortisol concentrations early in life. These findings suggest that higher levels of prenatal androgens in females, as measured by 2D:4D ratio, may be related to an attenuated HPA axis stress-response, as measured by plasma cortisol levels. To the extent that these findings generalize to humans, they suggest that the organizational effects of PAE extend to the infant HPA axis, modulating the HPA axis response, particularly in females., (Copyright © 2020 Wood, Jarman, Cash, Baxter, Capitanio and Higley.)

Prenatal androgen exposure (PAE) plays a pivotal role in masculinizing the developing body and brain, and extreme exposure may contribute to autism, anxiety disorder and schizophrenia. One commonly used biomarker for PAE is the pointer-to-ring-finger digit length (2D:4D) ratio. Although this biomarker is widely used in human studies, relatively few studies have investigated 2D:4D ratio in nonhuman primates, particularly rhesus macaques ( Macaca mulatta ), one of the most commonly used animals in biomedical research. Thus far, data suggest that sexual dimorphism in 2D:4D ratio may be in the opposite direction in some monkey species, when compared to the pattern exhibited by humans and great apes. Using a large sample size, we investigated whether rhesus monkeys' 2D:4D ratio shows the same sex-differentiated pattern present in other Old World monkey species. We also investigated whether individual differences in 2D:4D ratio are associated with the social dominance rank of subjects' mothers during pregnancy, and the social dominance rank the subjects attained as adults. Subjects were 335 rhesus monkeys between 3 years and 24 years of age ( M = 6.6). Maternal dominance rank during pregnancy and subjects' adult dominance rank were categorized into tertiles (high, middle and low). Results showed that, across both hands, male rhesus monkeys exhibited higher 2D:4D ratio than females, a pattern consistent with other monkey species and a reversal from the pattern typically observed in humans and apes. This sex difference was modulated by maternal dominance rank, with female offspring of high-ranking and middle-ranking mothers exhibiting masculinized 2D:4D ratio, indicating that maternal dominance rank during pregnancy may influence levels of PAE. There was no association between subjects' 2D:4D ratio and the social dominance rank they attained as adults. These findings show a consistent sex difference in Old World monkeys' 2D:4D ratio that diverges from the pattern observed in apes and humans, and suggest maternal social dominance rank modulates PAE in rhesus monkeys.

Adaptations to stress can occur through epigenetic processes and may be a conduit for informing offspring of environmental challenge. We employed ChIP-sequencing for H3K4me3 to examine effects of early maternal deprivation (peer-rearing, PR) in archived rhesus macaque hippocampal samples (male, n = 13). Focusing on genes with roles in stress response and behavior, we assessed the effects of rearing on H3K4me3 binding by ANOVA. We found decreased H3K4me3 binding at genes critical to behavioral stress response, the most robust being the oxytocin receptor gene OXTR , for which we observed a corresponding decrease in RNA expression. Based on this finding, we performed behavioral analyses to determine whether a gain-of-function nonsynonymous OXTR SNP interacted with early stress to influence relevant behavioral stress reactivity phenotypes ( n = 194), revealing that this SNP partially rescued the PR phenotype. PR infants exhibited higher levels of separation anxiety and arousal in response to social separation, but infants carrying the alternative OXTR allele did not exhibit as great a separation response. These data indicate that the oxytocin system is involved in social-separation response and suggest that epigenetic down-modulation of OXTR could contribute to behavioral differences observed in PR animals. Epigenetic changes at OXTR may represent predictive adaptive responses that could impart readiness to respond to environmental challenge or maintain proximity to a caregiver but also contribute to behavioral pathology. Our data also demonstrate that OXTR polymorphism can permit animals to partially overcome the detrimental effects of early maternal deprivation, which could have translational implications for human psychiatric disorders., Competing Interests: The authors declare no conflict of interest., (Copyright © 2017 the Author(s). Published by PNAS.)

Background: Studies show that the hypothalamic-pituitary-adrenal (HPA) axis is dysregulated in depression. Some studies suggest that variation in the serotonin transporter genotype (hereafter 5HTT ) modulates both risk for depression and psychopathological HPA axis responsiveness. Rhesus monkeys are well suited to model such relationships. Rhesus macaque models of human psychopathology have assessed the effect of the serotonin transporter ( rh5HTT ) on levels of cortisol in stressed subjects. These studies show that that under conditions of stress, heterozygous females (Ls) reared under adversity exhibit high levels of cortisol. Studies have not to our knowledge, however, assessed the potential additive effect on the cortisol response in a number of macaque subjects homozygous for the serotonin transporter short allele (ss). Moreover, little is known about the level of the central or peripheral nervous system at which the 5HTT genotype acts to modulate the cortisol response., Methods: This study assesses a relatively large number of subjects homozygous and heterozygous for the rh5HTT short and long alleles (a) during stress; (b) following a dexamethasone suppression test; and (c) following an adrenocorticotropic hormone (ACTH) challenge. Subjects included 190 infant rhesus macaques ( Macaca mulatta - 84 males and 106 females; 118 LL, 60 Ls, and 12 ss subjects), obtaining two blood plasma samples during the stress of separation from their mothers. Then on the following day, we obtained a blood sample following a dexamethasone test, and later that day we obtained a blood sample after an ACTH challenge test. Subjects ranged in age between 90 and 128 days, with a mean age of 107 days., Results: Subjects homozygous for the short allele had significantly higher levels of cortisol across all test conditions, when compared to those homozygous for the long allele, or those heterozygous with Ls alleles. Subsequent analyses showed a high correlation between individual cortisol levels across the three different tests., Conclusions: These data suggest that subjects homozygous for the short allele are more likely to show dysregulated cortisol levels in response to stress. Given the correlation in individual responses of the HPA axis across the different tests, our data suggest that the effect of the 5HTT genotype shows some commonality in its regulation of stress, feedback, and ACTH-stimulated cortisol output. Our data suggest that under conditions of stress, the serotonin transporter may modulate HPA axis psychopathology.

Background: As a model organism in biomedicine, the rhesus macaque (Macaca mulatta) is the most widely used nonhuman primate. Although a draft genome sequence was completed in 2007, there has been no systematic genome-wide comparison of genetic variation of this species to humans. Comparative analysis of functional and nonfunctional diversity in this highly abundant and adaptable non-human primate could inform its use as a model for human biology, and could reveal how variation in population history and size alters patterns and levels of sequence variation in primates., Results: We sequenced the mRNA transcriptome and H3K4me3-marked DNA regions in hippocampus from 14 humans and 14 rhesus macaques. Using equivalent methodology and sampling spaces, we identified 462,802 macaque SNPs, most of which were novel and disproportionately located in the functionally important genomic regions we had targeted in the sequencing. At least one SNP was identified in each of 16,797 annotated macaque genes. Accuracy of macaque SNP identification was conservatively estimated to be >90%. Comparative analyses using SNPs equivalently identified in the two species revealed that rhesus macaque has approximately three times higher SNP density and average nucleotide diversity as compared to the human. Based on this level of diversity, the effective population size of the rhesus macaque is approximately 80,000 which contrasts with an effective population size of less than 10,000 for humans. Across five categories of genomic regions, intergenic regions had the highest SNP density and average nucleotide diversity and CDS (coding sequences) the lowest, in both humans and macaques. Although there are more coding SNPs (cSNPs) per individual in macaques than in humans, the ratio of dN/dS is significantly lower in the macaque. Furthermore, the number of damaging nonsynonymous cSNPs (have damaging effects on protein functions from PolyPhen-2 prediction) in the macaque is more closely equivalent to that of the human., Conclusions: This large panel of newly identified macaque SNPs enriched for functionally significant regions considerably expands our knowledge of genetic variation in the rhesus macaque. Comparative analysis reveals that this widespread, highly adaptable species is approximately three times as diverse as the human but more closely equivalent in damaging variation.

Background: Rodent studies show that neurogenesis is necessary for mediating the salutary effects of antidepressants. Nonhuman primate (NHP) studies may bridge important rodent findings to the clinical realm since NHP-depression shares significant homology with human depression and kinetics of primate neurogenesis differ from those in rodents. After demonstrating that antidepressants can stimulate neurogenesis in NHPs, our present study examines whether neurogenesis is required for antidepressant efficacy in NHPs. MATERIALS/METHODOLOGY: Adult female bonnets were randomized to three social pens (N = 6 each). Pen-1 subjects were exposed to control-conditions for 15 weeks with half receiving the antidepressant fluoxetine and the rest receiving saline-placebo. Pen-2 subjects were exposed to 15 weeks of separation-stress with half receiving fluoxetine and half receiving placebo. Pen-3 subjects 2 weeks of irradiation (N = 4) or sham-irradiation (N = 2) and then exposed to 15 weeks of stress and fluoxetine. Dependent measures were weekly behavioral observations and postmortem neurogenesis levels., Results: Exposing NHPs to repeated separation stress resulted in depression-like behaviors (anhedonia and subordinance) accompanied by reduced hippocampal neurogenesis. Treatment with fluoxetine stimulated neurogenesis and prevented the emergence of depression-like behaviors. Ablation of neurogenesis with irradiation abolished the therapeutic effects of fluoxetine. Non-stressed controls had normative behaviors although the fluoxetine-treated controls had higher neurogenesis rates. Across all groups, depression-like behaviors were associated with decreased rates of neurogenesis but this inverse correlation was only significant for new neurons in the anterior dentate gyrus that were at the threshold of completing maturation., Conclusion: We provide evidence that induction of neurogenesis is integral to the therapeutic effects of fluoxetine in NHPs. Given the similarity between monkeys and humans, hippocampal neurogenesis likely plays a similar role in the treatment of clinical depression. Future studies will examine several outstanding questions such as whether neuro-suppression is sufficient for producing depression and whether therapeutic neuroplastic effects of fluoxetine are specific to antidepressants.

A powerful convergence of genetics, neuroimaging and epidemiological research has identified the biological pathways mediating individual differences in complex behavioral processes and the related risk for disease. Orthologous genetic variation in non-human primates (NHPs) represents a unique opportunity to characterize the detailed molecular and cellular mechanisms that bias behaviorally and clinically relevant brain function. We report that a rhesus macaque orthologue of a common polymorphism of the serotonin transporter gene (rh5-HTTLPR) has strikingly similar effects on behavior and brain morphology to those in humans. Specifically, the rh5-HTTLPR (S)hort allele broadly affects cognitive choice behavior and brain morphology without observably affecting the 5-hydroxytryptamine (5-HT) transporter or 5-HT(1A) concentrations in vivo. Collectively, our findings indicate that 5-HTTLPR-associated behavioral effects reflect genotype-dependent biases in cortical development rather than static differences in serotonergic signaling mechanisms. Moreover, these data highlight the vast potential of NHP models in advancing our understanding of human genetic variation affecting behavior and neuropsychiatric disease liability.

Platelet monoamine oxidase B (MAO-B) has been proposed to be a biological marker for the properties of monoamine systems, with low activity being associated with vulnerability for high scores on personality traits such as sensation seeking, monotony avoidance, and impulsiveness, as well as for vulnerability for alcoholism. In the present study, platelet MAO-B activity was analysed in 78 rhesus macaques, and its relation to voluntary alcohol intake and behaviours after intravenous alcohol administration was observed. Monkeys with low platelet MAO-B activity had low levels of 5-hydroxyindole acetic acid in cerebrospinal fluid and showed excessive aggression after alcohol administration. A novel finding was that animals with low platelet MAO-B activity showed less intoxication following alcohol administration. As we have shown previously, they also voluntarily consumed more alcohol. We here replicate results from studies on both humans and non-human primates, showing the utility of platelet MAO as a marker for risk behaviours and alcohol abuse. Furthermore, we link platelet MAO activity to alcohol sensitivity.

Corticotropin-releasing factor (CRF), encoded by the CRH gene, is a key integrator of stress responses, and, as such, CRH gene variation may contribute to individual differences in susceptibility to stress-related pathology. In rhesus macaques, a single nucleotide polymorphism (SNP) is found within the CRH promoter (-248C--> T). Here, we assessed whether this variant influenced stress responding and, because increased CRF system activity drives alcohol drinking in rodents, we examined whether it predicted voluntary alcohol consumption as a function of prior stress exposure. Using a hypothalamic nuclear extract, we showed that the -248 T allele resulted in increased DNA protein interactions relative to the C allele. In vitro, the T allele resulted in CRH promoter activity that was higher following both stimulation with forskolin and treatment with dexamethasone. Endocrine and behavioral responses to social separation stress (release of ACTH and cortisol, and suppression of environmental exploration, respectively) were higher among carriers of the T allele, particularly among those exposed to early adversity in the form of peer rearing. We also found that T allele carriers with a history of early life adversity consumed more alcohol in a limited-access paradigm. Our data suggest that CRH promoter variation that confers increased stress reactivity increases the risk for alcohol use disorders in stress-exposed individuals.

The mesolimbic dopamine system plays an important role in mediating a variety of behaviors and is involved in mediating the reinforcing effects of ethanol. Genes encoding dopamine receptor subtypes are thus good candidate loci for understanding the genetic etiologies of susceptibility to alcohol dependence and its antecedent behavioral phenotypes. We tested whether variation in DRD1 influences alcohol consumption in rhesus macaques and whether its influence is mediated by sex and early rearing experience. We genotyped a single nucleotide polymorphism (-111 G/T) in the 5'UTR of DRD1 in 96 subjects raised with their mothers until 6 months of age (n = 43) or in peer-only groups (n = 53). As young adults they underwent a 7-week voluntary ethanol consumption experiment. anova revealed a significant main effect of sex (F(1,95) = 6.3, P = 0.014) and an interaction between genotype, sex and rearing on ethanol consumption (F(7,95) = 4.63, P = 0.0002). Maternally deprived males heterozygous for the T allele consumed significantly more ethanol (P > t

In a variety of species, development of attachment to a caregiver is crucial for infant survival and partly mediated by the endogenous opioids. Functional mu-opioid receptor gene polymorphisms are present in humans (OPRM1 A118G) and rhesus macaques (OPRM1 C77G). We hypothesized that rhesus infants carrying a gain-of-function OPRM1 77G allele would experience increased reward during maternal contact and would, therefore, display increased measures of attachment. We collected behavioral data from rhesus macaques (n = 97) during early infancy and at 6 months of age, across four cycles of maternal separation (4 days) and reunion (3 days). Animals were genotyped for the OPRM1 C77G polymorphism, and the effects of this allele on attachment-related behaviors were analyzed. Infants carrying the G allele exhibited higher levels of attachment behavior during early infancy. During prolonged periods of maternal separation, although infant macaques homozygous for the C allele exhibited decreases in their levels of distress vocalization with repeated separation, this response persisted in G allele carriers. The OPRM1 77G allele also affected social preference during reunion. C/G infants spent increasing amounts of time in social contact with their mothers as a function of repeated separation and were less likely to interact with other individuals in the social group, a pattern not observed among infants with the C/C genotype. These findings suggest a role for OPRM1 variation in the expression of attachment behavior in human subjects, especially as a function of separation from the caregiver.

In human and nonhuman primates, structural variants of the gene encoding the serotonin transporter [5-hydroxytryptamine transporter (5-HTT)] affect the transcription and functional efficacy of 5-HTT. Prior work has shown that structural variants differentially affect function of the amygdala and ventromedial prefrontal cortex (VMPFC), regions important for the regulation and expression of emotion. However, relatively little is known about the impact of 5-HTT allelic variants on cognition. To address this question, we tested rhesus monkeys carrying orthologous structural variants of 5-HTT on a battery of tasks that assess cognitive flexibility, reward processing, and emotion. Here we show that rhesus monkeys carrying two copies of the short allele (SS) of the rhesus 5-HTT gene-linked polymorphic region (rh5-HTTLPR) show significantly reduced cognitive flexibility as measured by two tasks in the battery: object discrimination reversal learning and instrumental extinction. Monkeys with the SS genotype also displayed alterations in socioemotional behavior. Genotype variation was not related to visual perceptual abilities, valuation of food rewards, or the ability to express a wide range of defensive responses. Although emotional alterations associated with 5-HTT variation have been described as the primary phenotype, the present study reports differences in at least one type of cognitive flexibility, which has not been described previously. Because behaviors modulated by the 5-HTTLPR are a subset of those dependent on the VMPFC, analysis of structural and functional correlates of gene variation in this region may inform the nature of the genetic modulation of cognition.

Peer-reared (PR) rhesus monkeys with early maternal separation later exhibit aggressiveness, impaired impulse control, alcohol abuse, and low CSF 5-hydroxyindoleacetic acid. This study compared regional brain serotonin transporter (SERT) binding between nine PR and seven mother-reared rhesus monkeys with [11C]DASB positron emission tomography (PET) imaging. Parametric images of binding potential (BP) (which is proportional to Bmax/KD, in which Bmax is transporter density and KD is dissociation constant) and relative blood flow (R1) were generated by the two-parameter multilinear reference tissue model. R1 images were used for coregistration and normalization of PET parametric data to the magnetic resonance imaging template space. Group BP differences were analyzed voxelwise by Student's t test in SPM2. Region of interest-based parameter values were also calculated to obtain the magnitude of regional BP differences between the two groups. For the PR group, SERT BP was decreased by 10-23% across a range of brain areas consisting of the raphe, thalamus, hypothalamus, caudate and putamen, globus pallidum, anterior cingulate gyrus, and medial temporal regions, including amygdala and hippocampus (cluster-level corrected p = 0.002). For the latter three regions, BP was decreased in the right hemisphere. These results agree with the hypothesis that early maternal deprivation affects the development of the serotonergic system and suggest that decreased serotonergic innervations in the critical brain regions may explain some of the behavioral and biochemical abnormalities in PR monkeys.

Alcohol abuse constitutes a major cohort among HIV-infected individuals. The precise effect of alcohol addiction on HIV pathogenesis remains inconclusive, however. This study was designed to determine the effect of alcohol dependence on virus replication and CD4 profiles in simian immunodeficiency virus/simian-HIV-infected rhesus macaques. A group of 3 male Indian rhesus macaques was adapted to a self-drinking model of alcohol consumption, whereas another group of 3 macaques was provided a Nutrasweet solution. After 7 weeks of alcohol consumption, the alcohol-dependent animals along with controls were intravenously inoculated with a mixture of SHIV(KU), SHIV(89.6)P, and SIV/17E-Fr. These animals were followed for a period of 24 weeks for complete blood cell counts, CD4 cell profiles, and viral loads in the blood and cerebral compartments. The alcohol and control groups showed comparable peak viral loads in the blood. The plasma viral load in the alcohol group was 31- to 85-fold higher than that in the control group at weeks 18 through 24 after infection, however. The pattern of cerebrospinal fluid viral replication was also comparable during the acute phase; however, the virus continued to replicate in the brain of alcohol-dependent animals, whereas it became undetectable in the controls. The extent of CD4 cell loss in the alcohol group was significantly higher than that in the control animals at week 1 after infection.

The effects of two serotonergic agents--fluoxetine, a serotonin (5-HT) reuptake inhibitor, and buspirone, a 5-HT 1a agonist--on rates of self-injurious and stereotypic behavior were examined in 15 adult male Macaca mulatta. All animals received a placebo for 2 weeks followed by either buspirone or fluoxetine for 12 weeks. Behavior was monitored using a focal sampling technique throughout the study and for 2 weeks post-study. Cerebrospinal fluid (CSF) samples and body weights were obtained pre-study, at the ends of placebo and treatment phases, and post-study. Fluoxetine and buspirone were significantly effective in reducing rates of self-biting during treatment weeks 1 to 8 and self-directed stereotypic behavior during weeks 5 to 12 and post-treatment. No significant effect of either treatment on hair-plucking, stereotypic pacing, saluting, or head tossing was identified. The duration of neutral behavior increased, and rates of scratching and yawning decreased in the buspirone-treated condition. In the fluoxetine-treated condition, rates of yawning, scratching, and self-directed grooming were higher overall compared with those of buspirone-treated animals, and rates of scratching increased significantly (P < 0.05) in weeks 9 to 12; these findings suggest that animals in the fluoxetine-treated condition experienced higher levels of anxiety throughout the study. In both treatment conditions, concentrations of CSF 5-HIAA (5-HT metabolite) were significantly lower (P < 0.05) than placebo concentrations. Fluoxetine and buspirone may be efficacious for treatment of self-injurious and self-directed stereotypic behavior in macaques. Further studies are required to determine the optimal dosages and treatment length.

CRH is a main regulator of the stress response. This neuropeptide and its specific receptors, CRHR-1 and CRHR-2, are disseminated throughout the central nervous system. There is a significant interspecies difference in the distribution of CRHR within the central nervous system. CRH-R1 antagonists may attenuate stress-related behavior in rats without compromising adrenal function, but few studies have addressed the same question in higher mammals. Antalarmin (AA) is a specific CRHR-1 antagonist suitable for oral administration. Social separation is a potent stressor for rhesus monkeys. Therefore, we sought to investigate the hormonal responses to chronic administration of AA using a primate stress model. Eight preadolescent (4-6 kg) male rhesus monkeys received AA (20 mg/kg.d) or placebo (PBO) orally. All animals were on a regular day/light cycle and were fed with standard monkey chow daily. The study (114 d) was comprised of the following consecutive phases: adaptation, baseline, separation (stress), recovery, and cross-over. During social separation, solid panels separated the individuals. Cerebrospinal fluid (CSF) and femoral venous blood samples were obtained once a week on the fourth day of separation under ketamine anesthesia. Serum samples were also obtained 1 and 2 h after separation. CSF samples were assayed for CRH, AA, norepinephrine (NE) and epinephrine (EPI). Plasma was assayed for ACTH, cortisol, NE, and EPI. AA was detected in the plasma of each monkey while they were taking the active drug and in none of the animals on PBO. Among the behaviors assessed, environmental exploration, a behavior inhibited by stress, was increased during AA administration. However, AA at this dose did not affect other anxiety-related behavioral end points, including self-directed behavior, vocalization, or locomotion. We also observed that: 1) ACTH decreased between adaptation and baseline, indicating that the animals had adjusted to the novel environment; 2) ACTH and cortisol increased significantly after social separation, indicating that social separation was an adequate model for acute stress; 3) NE and EPI increased significantly during acute stress in the AA and PBO groups (P < 0.005, NE; P < 0.001, EPI); 4) after chronic stress, by d 4 of separation, ACTH levels were no longer significantly different from baseline, and NE and EPI remained slightly elevated when compared with baseline (P < 0.05, NE; P < 0.01, EPI); and 5) all the animals remained healthy and gained the expected weight during the study. In summary, oral chronic administration of a specific CRH-R1 antagonist to rhesus monkeys does not blunt the sympathoadrenal response to stress while increasing environmental exploration, a behavior that is normally suppressed during stressful events. Taken together, these findings suggest that CRHR-1 antagonists may be a valid treatment for stress-related disorders.

A polymorphism in the human serotonin transporter gene promoter (5-HTTLPR) is associated with anxiety and increased risk for developing depression in the face of adversity. Here, we report that among infant rhesus macaques, an orthologous polymorphism (rh5-HTTLPR) interacts with adversity in the form of peer rearing to influence adrenocorticotropic hormone (ACTH) response to stress and, further, that this interaction is sexually dichotomous. ACTH responses to separation are higher in l/s than in l/l males. In females, however, it is only among those with a history of adversity that the s allele is associated with increased ACTH responses to stress. Of interest, peer-reared animals, in particular females carrying the s allele, also exhibit lower cortisol responses to stress, a pattern that has been recognized in association with certain stress-related neuropsychiatric disorders. By extension, our findings suggest the intriguing possibility that human females carrying the 5-HTTLPR s allele could be more vulnerable to the effects of early adversity. This interactive effect may underlie the increased incidence of certain stress-related disorders in women.

Ghrelin stimulates release of GH from the pituitary, stimulates appetite, and may influence metabolic processes in other tissues expressing the GH secretagogue receptor. Ghrelin can thus influence behaviors and endocrine pathways contributing to weight gain. In this study we characterized the ghrelin gene from the rhesus monkey and analyzed the association of plasma ghrelin levels with metabolic and endocrine markers. Rhesus ghrelin is 97, 91, and 96% homologous to the human cDNA, gene, and peptide, respectively. Ghrelin expression was highest in the stomach with lower levels found in muscle and duodenum. In these tissues, ghrelin expression in calorie-restricted and obese animals was about 40-99% lower than in lean animals. In addition, ghrelin expression in muscle was fairly high and may allow this tissue to contribute significantly to plasma levels. Fasting plasma ghrelin concentrations were also inversely correlated with body mass index and exhibited a nonlinear association with age with increased levels in younger and older monkeys and lower levels in middle-aged monkeys. Although a significant inverse correlation between fasting plasma ghrelin and fasting insulin levels were found, iv glucose and insulin administration did not significantly alter ghrelin levels. These studies demonstrate that ghrelin levels are influenced by age-related factors and adiposity in the rhesus monkey. These similarities between the rhesus monkey and human ghrelin genes and plasma ghrelin responses suggest a unique opportunity to study the mechanisms regulating ghrelin secretion and gene expression in different tissues in normal and disease states using this model system.

Previous research has shown that offspring of females with low cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) concentrations are less likely to survive the first year of life than are offspring of females with high CSF 5-HIAA concentrations. In addition, studies of free-ranging rhesus macaque males have suggested that individuals with low CSF 5-HIAA concentrations suffer reduced reproductive success relative to their high serotonin counterparts. We examined CSF concentrations of the monoamine metabolites 5-HIAA and homovanillic acid (HVA), and plasma cortisol concentrations as predictors of first-time adult reproductive potential, maternal behavior, and overall social interactions in two groups of captive female rhesus macaques and their first offspring. Repeated CSF and blood samples were obtained from adult females in two social groups, and focal observations were performed for both new mothers and infants during the first month following parturition. We found that the reproductively aged nulliparous females who failed to give birth to their first offspring showed significantly lower CSF 5-HIAA concentrations than those females who gave birth. Among those females that gave birth to offspring, females with low CSF 5-HIAA concentrations and females with high plasma cortisol concentrations were overly protective and restrictive with their infants. CSF HVA concentration was not associated with reproductive output, social behavior, aggression, or mother-infant interactions in this sample of rhesus macaque females. We conclude that low CNS serotonin activity and high stress, measured by high plasma cortisol, are correlated with reduced reproductive success and patterns of high maternal restrictiveness in young adult female rhesus macaques.

Variation in the serotonin transporter gene-linked polymorphic region (5-HTTLPR) has been associated with anxiety and harm avoidance and is weakly associated with a number of neuropsychiatric disorders, including Type II alcoholism, which has a high rate of comorbidity with antisocial personality disorder. Studies have also demonstrated interactions between 5-HTLPR variation and environmental stress on the incidence of depression. As in humans, there is a serotonin transporter gene promoter length polymorphism in rhesus macaques that produces similar decreases in transcriptional efficiency. Macaques with histories of early-life stress have been shown to exhibit impulsive aggression, incompetent social behavior and increased behavioral and endocrine responsivity to stress. In this paper, we review studies performed previously in our lab and present preliminary data examining interactions between early rearing and serotonin transporter gene promoter variation on the incidences of play behavior and aggression in infant rhesus macaques. The data presented here highlight the importance of considering gene-environment interactions when studying childhood risk factors for aggression, anxiety and related neuropsychiatric disorders and support the use of the nonhuman primate for studing gene by environment interactions in behavioral research.

We examined the relations among cerebrospinal fluid (CSF) monoamine metabolite concentrations, plasma hormone concentrations, aggression, and impulsive risk-taking behavior in a free-ranging population of female rhesus macaques. We selected 44 juvenile female rhesus macaques as subjects from a population of approximately 3000 macaques that inhabit a 475-acre Sea Island. We obtained CSF and blood samples, and recorded behavioral observations over a subsequent 18-month period. Our results indicate an inverse correlation between CSF concentrations of the major serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), and the frequency of low-intensity restrained aggression typically associated with matrilineal defense of social status. In contrast, previous research with males has shown an inverse correlation between CSF 5-HIAA concentrations and levels of violent unstrained aggression typically associated with traumatic injury and death. We also noted a negative correlation between plasma concentrations of the stress hormone cortisol and the frequency of low-intensity aggressive acts, a finding not reported in our previous studies with males. Further examination revealed a negative correlation between CSF 5-HIAA concentrations and the rate of long dangerous leaps through the forest canopy, suggesting that the relation between low serotonergic functioning and impulsivity may generalize to both female and male primates. These results indicate that females with low CSF 5-HIAA concentrations, like their male counterparts, are at increased risk for impulsive temperament, but that unlike males, females may be buffered from this risk through intersexual differences in life history patterns and social affiliation.

A low level of alcohol intoxication upon initial exposure and impulsive aggressiveness predispose humans to alcoholism. In non-human primates, central serotonin transporter availability and turnover rate were associated with aggressive behavior and a low response to initial alcohol exposure. We assessed the respective effects of these factors on alcohol intake in a free choice paradigm. Serotonin transporter availability in the raphe area, the origin of central serotonergic projections, was measured with single-photon emission computed tomography and the radioligand [(123)I]beta-CIT in 11 rhesus monkeys with low and high central serotonin turnover. The amount of alcohol intake in the 3-month observation period was positively correlated with serotonin transporter availability (R=0.76, P=0.006), but not with aggressiveness (R=0.19, P=0.6) or alcohol response upon first exposure (R=-0.48, P=0.2). In a linear multiple regression analysis with serotonin transporter availability, alcohol response, and aggressiveness as independent variables, 82% of the variance of alcohol intake was explained and serotonin transporter availability emerged as the only statistically significant factor (beta=7.81, P=0.006). These observations indicate that there may be a direct relationship between serotonin transporter availability and alcohol intake after controlling for aggression and alcohol response on first exposure.

Corticotropin-releasing factor (CRF) is a neuropeptide involved in integrating the behavioral, autonomic, and hormonal responses to stress within the central nervous system. Patients suffering from depression have abnormal activity in stress responsive brain regions and elevated cerebrospinal fluid CRF. The DSM-IV criteria for major depressive disorder include behavioral changes such as depressed mood, anhedonia, and psychomotor agitation/retardation. We studied the effects of 434 microgram of CRF given intracerebroventricularly over 40 min in group and individually housed monkeys to examine the role of elevated levels of central CRF on behavior. CRF elicited a wide range of behaviors, which fell into three broad categories: anxiety-like, depressive-like, and externally oriented. Externally oriented behaviors decreased, and anxiety-like behaviors increased regardless of how the animals were housed. Interestingly, increased depressive-like behaviors were only observed when the animals were socially housed. In a separate experiment, we examined the effects of the same dose of CRF on the regional cerebral glucose metabolism of lightly anesthetized monkeys by using positron emission tomography and [(18)F]fluorodeoxyglucose. CRF infusion increased glucose metabolism in the pituitary/infundibulum, the amygdala, and hippocampus. These results indicate that increased central CRF tone affects primate behavior in a context-dependent manner, and that it activates limbic and stress-responsive regions. The fact that intracerebroventricular CRF increases depressive-like behavior in socially housed animals and increases activity in limbic brain regions may help explain the behavioral and metabolic alterations in humans with affective disorders, and this model could therefore have significant value in the development of novel antidepressant treatments.

Docosahexaenoic acid (DHA) is an omega-3 fatty acid that is highly concentrated in CNS tissues. Although breast milk contains the fatty acids DHA and arachidonic acid, infant formulas marketed in North America do not contain these nutrients. The potential deleterious effects of rearing infants with formulas devoid of these nutrients was assessed by comparing nursery-reared rhesus macaque infants (Macaca mulatta) fed standard formula with infants fed standard formula supplemented with physiologically relevant concentrations of DHA (1.0%) and arachidonic acid (1.0%). Neurobehavioral assessments were conducted on d 7, 14, 21, and 30 of life using blinded raters. The 30-min assessment consisted of 45 test items measuring orienting, temperament, reflex capabilities, and motor skills. Plasma concentrations of DHA in standard formula-fed infants were significantly lower than those fed supplemented formula or mother-raised (breast-fed) infants; however, infants fed the supplemented formula exhibited higher arachidonic acid levels than either mother-reared infants or infants fed standard formula. Infant monkeys fed the supplemented formula exhibited stronger orienting and motor skills than infants fed the standard formula, with the differences most pronounced during d 7 and 14. This pattern suggests an earlier maturation of specific visual and motor abilities in the supplemented infants. Supplementation did not affect measures of activity or state control, indicating no effect on temperament. These data support the assertion that preformed DHA and arachidonic acid in infant formulas are required for optimal development.

A polymorphism in the serotonin (5-HT) transporter gene regulatory region (5-HTTLPR) is associated with measures of 5-HT transporter (5-HTT) expression and 5-HT-mediated behaviors in humans. An analogous length variation of the 5-HTTLPR has been reported in rhesus monkeys (rh5-HTTLPR). A retrospective association study was conducted on 115 rhesus macaque infants either homozygous for the long 5HTTLPR variant (l/l) or heterozygous for the short and long form (l/s). To assess contributions of genotype and early rearing environment, 36 mother-reared monkeys (l/l = 26, l/s = 10) and 79 nursery-reared monkeys (l/l = 54, l/s = 25) were assessed on days 7, 14, 21, and 30 of life on a standardized primate neurobehavioral test designed to measure orienting, motor maturity, reflex functioning, and temperament. Both mother-reared and nursery-reared heterozygote animals demonstrated increased affective responding relative to l/l homozygotes. Nursery-reared, but not mother-reared, l/s infants exhibited lower orientation scores than their l/l counterparts. These results demonstrate the contributions of rearing environment and genetic background, and their interaction, in a nonhuman primate model of behavioral development.

Nonhuman primates offer unique opportunities to study the effects of genes, environments, and their interaction, on physiology and complex behavior. We examined genotype and early environment contributions to CNS function in a large sample of rhesus monkeys. In humans, length variation of the serotonin (5-HT) transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR) that results in allelic variation in 5-HTT expression is associated with decreased serotonergic function and 5-HT-mediated psychopathology. We report that an analogous variation of the gene's regulatory region in monkeys interacts with early experience to affect central 5-HT functioning. Monkeys with deleterious early rearing experiences were differentiated by genotype in cerebrospinal fluid concentrations of the 5-HT metabolite, 5-hydroxyindoleacetic acid, while monkeys reared normally were not. These findings demonstrate an environment-dependent effect of the rh5-HTTLPR genotype on CNS 5-HT function and suggest nonhuman primates may provide an important avenue for investigating gene/environment interactions using candidate genes for physiological and behavioral traits.

Some people are more likely than others to become aggressive after consuming alcohol. Researchers studying alcohol use and aggression hope to identify individual differences in behavior and biochemistry that exist among subjects who become aggressive following alcohol consumption. Research with nonhuman primates has shown that individual differences in brain chemistry predict impulsivity, aggression, and alcohol-induced aggression. These differences appear to be associated with early rearing experiences and remain stable throughout the individual's life.

We evaluated the effects of the lipophilic nonpeptide corticotropin-releasing hormone (CRH) type 1 receptor antagonist antalarmin on the behavioral, neuroendocrine, and autonomic components of the stress response in adult male rhesus macaques. After oral administration, significant antalarmin concentrations were detected in the systemic circulation and the cerebrospinal fluid by a mass spectrometry-gas chromatography assay developed specifically for this purpose. Pharmacokinetic and dose-response studies suggested that an oral dose of 20 mg/kg was optimal for behavioral and endocrine effects. We then administered this dose in a double-blind, placebo-controlled fashion to monkeys exposed to an intense social stressor: namely, placement of two unfamiliar males in adjacent cages separated only by a transparent Plexiglas screen. Antalarmin significantly inhibited a repertoire of behaviors associated with anxiety and fear such as body tremors, grimacing, teeth gnashing, urination, and defecation. In contrast, antalarmin increased exploratory and sexual behaviors that are normally suppressed during stress. Moreover, antalarmin significantly diminished the increases in cerebrospinal fluid CRH as well as the pituitary-adrenal, sympathetic, and adrenal medullary responses to stress. We conclude that CRH plays a broad role in the physiological responses to psychological stress in primates and that a CRH type 1 receptor antagonist may be of therapeutic value in human psychiatric, reproductive, and cardiovascular disorders associated with CRH system hyperactivity.

Seasonal changes in cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) concentrations were assessed on multiple occasions in 103 free-ranging male rhesus macaques (Macaca mulatta). At the time of sampling subjects ranged between the ages of 2 and 6 years. CSF samples were collected between the hours of 0900 and 1600 throughout the Fall, Winter, and Spring from 1990 through 1994. Data were analyzed in a general linear mixed model with random intercepts. Results indicated that CSF 5-HIAA concentrations decreased with age. CSF 5-HIAA concentrations were significantly increased in the Fall (October and November), which is the height of the breeding season, with no evidence of differences between Winter and Spring. There was also some evidence that the seasonal variation in CSF 5-HIAA concentrations was blunted in younger, more immature subjects.

Non-human primates will readily consume an alcohol solution for its reinforcing effects when such a solution is palatable, with some subjects consuming alcohol to excess. In this review, we discuss variables that contribute to high alcohol consumption and the behaviours that are correlated with it in a non-human primate model. Developmental and behavioural correlates of central nervous system (CNS) serotonergic activity, as measured by concentrations of the serotonin metabolite 5-hydroxyindol-3-ylacetic acid (5-HIAA) in the cerebrospinal fluid (CSF), were used to investigate neurogenetic influences on alcohol consumption, as well as personality traits that characterize excessive alcohol intake. Inter-individual differences in CSF 5-HIAA concentrations were shown to have trait-like qualities, and with stable inter-individual differences across time and settings. Research has shown numerous similarities between human and non-human primates with respect to Type I- and II-like alcohol abuse and their associated behaviours. In the present series of studies, features characteristic of Type I alcohol misuse, such as high levels of anxiety, hypothalamic-pituitary-adrenal output, and situational stress predicted high alcohol intake. Primates with low CSF 5-HIAA concentrations also exhibited behaviours characteristic of Type II alcohol abuse. Principal among the traits that these subjects exhibited were deficits in impulse control. For example, subjects with low CSF 5-HIAA concentrations engaged in spontaneous behaviours that bring reinforcement but placed them at risk, such as entering food baited traps, jumping from dangerous heights to get from one tree to another, and consuming large amounts of alcohol. They can be characterized by other Type II-like deficits, such as impaired social competence, social alienation, and unrestrained, violent aggression. Non-human primates with low CSF 5-HIAA concentrations also exhibited high intrinsic tolerance following modest intakes of alcohol, and high rates of aggression during intoxication. High preferences for sweet solutions were shown to predict excessive alcohol consumption. Maternal and paternal genetic influences played major roles in producing low CNS serotonin function and excessive alcohol consumption. These genetic influences on serotonin function were exacerbated by early rearing experiences, particularly parental deprivation.

Twelve male, fasted, anesthetized rhesus monkeys were studied with positron emission tomography (PET) and [11C]alpha-methyl-L-tryptophan (alpha MTP) to determine serotonin synthesis rates as described by Diksic et al. (1991). It was expected that the serotonin synthesis rates determined for the whole brain would be correlated with CSF 5-hydroxyindole-3-acetic acid concentrations, a measure of central serotonin turnover, because both measures were obtained at steady state. However, no significant correlation was found. During data analysis, it was noticed that the calculated serotonin synthesis rates were significantly correlated to free plasma tryptophan (TP) concentrations (r = 0.88, p < .001). From repeat scans conducted in six monkeys, it was determined that day-to-day variability in free plasma TP and the percentage of protein binding (average percent difference was 48 and 37%, respectively) produced most of the variability in the calculated serotonin synthesis rates (50%); repeat K images, obtained from the PET data alone, differed by only 11%. Calculated serotonin synthesis rates reported for [11C]alpha MTP PET studies of humans (Nishizawa et al. 1997) and dogs (Diksic et al. 1991) were also highly correlated to reported differences in plasma free TP concentrations. It seems that the [11C]alpha MTP model for the computation of serotonin synthesis rates is very dependent on plasma free TP concentration and that it may not accurately determine actual serotonin synthesis rates.

Unlabelled: Two studies were conducted to examine the effects of oral L-tryptophan (TRP) supplementation as a treatment for self-injurious behavior (SIB) and to investigate behavior and central serotonin turnover of male rhesus monkeys. In Study One, TRP was administered to seven individually housed rhesus monkeys with a recent history of spontaneous SIB. While the monkeys were on TRP treatment (100 mg/kg twice a day), cisternal cerebrospinal fluid (CSF) concentrations of 5-hydroxyindoleacetic acid increased markedly (p = .0013) above baseline (baseline mean = 207.6 pmol/ml +/- 39; TRP mean = 320.3 pmol/ml +/- 83.4), and the duration of self-biting behavior decreased below baseline (p = .03). In Study Two, 14 individually housed rhesus monkeys without a history of SIB were placed on three different doses of TRP in random order (50, 100, and 200 mg/kg twice a day). TRP had no effect on any behavioral or biochemical variables in the normal monkeys., Conclusions: Supplemental tryptophan in well-tolerated doses reduced self-biting and increases serotonin turnover rate in male monkeys with a recent history of SIB. The same doses of TRP do not affect behavior or serotonin metabolism in male monkeys without a history of SIB.

Few studies have investigated longitudinally interindividual stability of cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) concentrations in adult nonhuman primates across time and between baseline and stressful conditions. Furthermore, whereas studies with male macaques consistently have reported a significant, negative correlation between CSF 5-HIAA and rates of spontaneous aggression, wounding, and severe aggression, very few studies have examined this relationship in adult female nonhuman primates. Even fewer studies have investigated correlations between CSF 5-HIAA and competent social behavior, such as social dominance, in female monkeys. In the present study, two social groups of adult rhesus monkeys (Macaca mulatta) were formed by placing 16 females (aged 42 to 180 months, mean age: 68 months) in one of two indoor-outdoor enclosures with one or two adult males. CSF norepinephrine (NE), monoamine metabolites, and behavioral data were collected systematically over a 24-week period. In week 5 of the study, one additional female, not familiar to any of the other subjects, was added to each social group. Thereafter the groups were left undisturbed, and data characterizing spontaneous aggressive wounding and severe wound injuries in the females were collected for an additional year. The results showed that both group introduction and the addition of a new subject into each group resulted in increased monoamine turnover in the animals within the social groups. Interindividual differences in CSF concentrations of each of the monoamine metabolites and NE were highly stable from the baseline period to the stress samplings, and between stress samplings. Females with low CSF 5-HIAA exhibited higher rates of spontaneous aggressive wounding, and they were more likely to be removed from their social groups for aggressive wounding and/or treatment of injuries. CSF NE concentrations also were negatively correlated with rates of spontaneous aggression. In contrast, competitive aggression, i.e. noninjurious aggression used to maintain social dominance ranking, was not correlated with CSF 5-HIAA or NE. Females with above average CSF 5-HIAA prior to and following group formation were more likely to attain and maintain a high social dominance ranking within their social group than females with below average CSF 5-HIAA. The present findings indicate that CNS monoamine functioning in adult female rhesus macaques is traitlike, showing a high degree of interindividual stability across time and setting. These findings also suggest a role for serotonin in controlling impulses that regulate aggression and that competent social behavior among nonhuman primates may require average or above average serotonin functioning.

The genetic similarity to humans of nonhuman primates makes them well suited to serve as models of complex human disorders such as alcoholism. Like humans, nonhuman primates vary with respect to their alcohol consumption, even within the same species. Studies of the origins of high consumption among nonhuman primates have suggested that both genetic and environmental factors play a role in their drinking. In fact, researchers have found some support for multiple subtypes of alcoholism among nonhuman primates.

Twenty-two 50-month-old rhesus monkeys were provided concurrent free access to an aspartame-sweetened 7% ethanol solution and an aspartame-sweetened vehicle before, during, and after social separation. Subjects had been reared for their first 6 months of life either without access to adults but with constant access to age mates (peer reared), a condition producing reduced exploration and increased fear-related behaviors, or as controls with their mothers; thereafter, all subjects received identical treatment. During home-cage periods, for 1 hr each day, 4 days a week, when the ethanol solution and vehicle were freely available, peer-reared subjects consumed significantly more alcohol than mother-reared subjects. When stress was increased via social separation, mother-reared animals increased their alcohol consumption to a level nearly as high as that of peer-reared monkeys. Average individual differences in alcohol consumption were markedly stable over time. In addition, there were strong positive correlations between alcohol consumption and distress behaviors. Biological indices of increased stress, such as plasma cortisol and corticotropin, were higher in peer-reared subjects. Within the peer- and mother-reared groups, these indices were positively correlated with alcohol consumption. The results suggest that early rearing experiences that predispose monkeys to increased fear-related behaviors produce excessive alcohol consumption under normal living conditions. Furthermore, a major challenge such as social separation increases alcohol consumption to levels producing intoxication even in monkeys not particularly vulnerable to stress.

113 rhesus monkeys, representing 4 age classes, 3 matrilines, and immigrant adult males in a 161-member Cayo Santiago-derived troop living in a 2-acre enclosure, were sampled for levels of plasma ACTH and cortisol during a period of capture and brief cage confinement for routine veterinary examination. ACTH levels showed significant decreases over initially high values following capture in all subjects except infants, whereas cortisol levels remained elevated throughout the sampling period. Members of the lowest-ranking matriline had significantly higher ACTH levels than members of the other matrilines and immigrant males. Infants and juveniles exhibited higher cortisol levels than adolescent and adult monkeys. The overall pattern of results was generally consistent with previous findings from laboratory studies, providing not only evidence of generality across conditions and subject populations but also the basis for more detailed subsequent analyses of the relationship between pituitary-adrenocortical responsiveness, behavioral response to challenge, and age-sex-dominance status in wild-born rhesus monkeys.