Individuals vary substantially in their vulnerability to physical and psychosocial stressors. The causes of such variation in susceptibility to stress are poorly understood, but are thought to relate in part to genetic factors. The present study evaluated the extent to which polymorphisms in the gene encoding the serotonin reuptake transporter (5HTTLPR or SERT) modulated physiologic responses to the imposition of psychosocial stress (social reorganization and subordinate social status) in female rhesus monkeys. Forty females, drawn from the middle ranking genealogies of several large social groups, were reorganized into eight groups containing 5 monkeys each; four groups were comprised entirely of animals homogeneous for the long promoter variant in the SERT gene (l/l), while the other four groups had monkeys with at least one allele of the short promoter variant (l/s or s/s). Females were sequentially introduced into these new groups in random order and dominance ranks were established within several days. During the ensuing 6 weeks, dominant monkeys exhibited elevated rates of aggression while subordinates displayed high rates of submission. Notably, females with the s-variant SERT genotype, collapsed across social status positions, exhibited the highest overall rates of both aggression and submission. Although neither social status nor SERT genotype influenced morning cortisol concentrations, glucocorticoid negative feedback was reduced significantly in subordinate compared to dominant females irrespective of genotype. All animals lost weight and abdominal fat across the experiment. However, decreases were greatest in subordinates, regardless of genotype, and least in dominant females with the l/l genotype. Serum concentrations of insulin, glucose, and ghrelin decreased significantly during the group formation process, effects that were independent of genotype or social status. In contrast, social status and genotype interacted to influence changes in serum concentrations of leptin and triiodothyronine (T3), as dominant, l/l females had the highest levels while subordinate s-variant females had the lowest levels. The order in which a female was introduced to her group generally predicted her eventual social rank. However, rank was additionally predicted by pre-experimental T3 and abdominal fat values, but only in the l/l animals. While these findings must be replicated with a larger sample size, the data suggest that the s-variant SERT genotype confers increased vulnerability to the adverse effects of psychosocial stress associated with subordinate status while the l/l genotype benefits the most from the absence of stress conferred by dominant social status. These findings suggest that genetic factors modify the responses of monkeys to social subordination and perhaps other psychosocial stressors.

Increased vulnerability to psychosocial stressors likely predisposes individuals to decreased immune function and inability to control pathogens. While many factors influence the susceptibility to psychosocial stress, genetic polymorphisms may modify individual reactivity to environmental stressors. The present study evaluated how immune function was altered by the interaction of in polymorphisms in the gene that encodes the serotonin reuptake transporter (5HTT) and the psychosocial stress imposed by social subordination in adult female rhesus monkeys. Subjects were dominant and subordinate females that carried both alleles of the long promoter variant (l/l) of the 5HTT gene, and dominant and subordinate that had at least one allele for the short promoter length variant (l/s or s/s, s-variant). Plasma cortisol was higher in subordinate females in response to a social separation paradigm, confirming their increased reactivity to psychosocial stressors. Subordinate females exhibited increased T-cell activation and proliferation regardless of genotype. Despite these higher levels of T-cell proliferation and activation, subordinate females showed significantly lower frequency of T-cells. This latter finding may be due to an increased susceptibility to cell death, as indicated by higher levels of annexin-V+ CD4+ and CD8+ T-cells in s-variant subordinate compared to dominant females. These findings indicate that subordinate rhesus monkeys with the s-variant 5HTT genotype exhibit decreased T-cell numbers perhaps compromising their ability to mount an immune response to pathogens. These data underscore the importance for considering gene polymorphisms that influence emotional reactivity to better understand susceptibility to disease.

The serotonin (5HT) reuptake transporter (SERT) plays a key role in 5HT homeostasis by recycling 5HT into the presynaptic neurons. Recently, polymorphisms in the length of the promoter region of the gene that encodes SERT have been linked to functional differences in reactivity to psychosocial stress, as the short (s) promoter length allele shows reduced transcriptionally activity in vitro and is associated with reduced 5HT activity and increased vulnerability to affective disorders. Given 5HT's important role in appetite regulation, polymorphisms in the SERT gene could also affect metabolic parameters. In addition, since reduced 5HT activity may also predispose females to reproductive deficits, polymorphisms in the SERT gene may help explain individual differences in ovulatory function. The present study, using a rhesus monkey model, tested the hypothesis that the presence of the s-variant allele would be associated with altered metabolic regulation and impaired ovulatory cycles compared with the l/l genotype. Females homozygous for the long allele in the SERT gene (l/l, n = 19) were compared to those with the s-variant allele (l/s or s/s, n = 20). All females had similar social histories. Body weights (P = 0.026) but not heights (P = 0.618) were significantly lower in s-variant compared to l/l females. In addition, both BMI (P = 0.032) and sagittal abdominal diameters (SAD) (P = 0.031), as indices of adiposity, were significantly lower in s-variant females. Consistent with these differences, fasting and non-fasting levels of leptin were significantly lower in s-variant females (P = 0.002). While there were no genotype differences in non-fasting levels of insulin, s-variant females had significantly lower concentrations of insulin during a fast than did l/l females (P = 0.052). Neither glucose, T 3, T 4, nor ghrelin varied significantly between groups during either the fasted or non-fasted condition (P > 0.05). Analysis of a subset of females indicated that significantly fewer s-variant females (62.5%) exhibited ovulatory cycles than l/l females (100%, P < 0.05). However, there were no differences in serum estradiol or progesterone in l/l females and those s-variant females that did ovulate (P > 0.05). In addition, females with the s-variant genotype also had reduced 5HT activity (P = 0.030), assessed from the acute increase in serum prolactin following the administration of the 5HT reuptake inhibitor, citalopram. Finally, s-variant females were significantly less responsive to glucocorticoid negative feedback (P = 0.030) yet more responsive to corticotropin releasing hormone (CRH, P = 0.016) in terms of plasma cortisol than were l/l females. These data indicate that adult female rhesus monkeys with the s-variant polymorphism in the SERT gene exhibit metabolic and reproductive alterations in conjunction with reduced serotonergic responsivity and increased LHPA activity and suggest the possibility that this genotype may predispose females exposed to psychosocial stressors to further metabolic and reproductive def...

Chronic exposure to psychosocial stress may lead to a dysregulation of the limbic-hypothalamic-pituitary-adrenal axis that results in a number of adverse health outcomes. The fat-derived hormone leptin has been indicated as a potential key component to maintaining homeostasis by enhancing glucocorticoid negative feedback. Using an established model of nonhuman primate social stress, notably social subordination, this study examined the effects of continuous leptin administration on cortisol secretion in female rhesus monkeys. The 20 subjects were maintained in stable five-member social groups with established dominance hierarchies. All females were ovariectomized but received estradiol throughout the study to maintain serum concentrations at early follicular phase levels. Three parameters of cortisol secretion were examined in dominant and subordinate females during control and leptin-treatment conditions: diurnal cortisol secretion; response to a dexamethasone suppression test; and response to a brief separation from their social group. We hypothesized that leptin supplementation would attenuate the hypercortisolemia characteristic of subordinate females. During baseline conditions, subordinate female rhesus monkeys had significantly lower levels of serum leptin compared with more dominant monkeys and were less sensitive to glucocorticoid negative feedback. Exogenous administration of leptin improved glucocorticoid negative feedback in subordinate females and decreased morning cortisol in all animals. However, there were no status differences in response to a social separation test and diurnal rhythm in cortisol during baseline conditions. However, leptin administration did not attenuate the increase in cortisol in response to a social separation. The data presented in this study demonstrate that leptin can attenuate several parameters of cortisol secretion in female rhesus monkeys and thus may play a role in the response of the adrenal glands to socio-environmental stimuli.