Metabolic and reproductive consequences of the serotonin transporter promoter polymorphism (5-HTTLPR) in adult female rhesus monkeys (Macaca mulatta)

Abstract

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...

Polymorphisms in the serotonin reuptake transporter gene modify the consequences of social status on metabolic health in female rhesus monkeys

“…This test of glucocorticoid resistance accurately reflects changes in glucocorticoid receptor binding in the hippocampus in response to a chronic stressor in a number of animal models [62,63] and is predictive of stress-induced affective disorders in humans [64]. Although other studies of rhesus macaques show that the s-variant allele in SERT gene is associated with greater LHPA reactivity [24,32], the approach used in the present study did not find differences between subordinate females with the l/l and s-variant genotypes. It is possible that that genotype differences in subordinate females will emerge with time.…”

“…Rather, the increased aggression suggests the s-variant females may be more impulsive in this socially challenging situation. While we did not characterize central 5HT activity, previous studies indicate that the s-variant allele in SERT gene is associated with reduced 5HT tone [32,51,52] and reduced central 5HT activity is associated with increased impulsivity and aggression [53,54] as well as hostility in humans [55,56]. Thus, the significantly higher rates of aggression in s-variant dominants compared to l/l dominant animals and the higher rates of submissive behaviors in s-variant animals suggest a difference in reactivity inherent to these genotypes.…”

“…Dominance status was determined from the outcome of dyadic interactions [35], based on 10 h of observation of each group over a 4-week period. Following confirmation of parity and dominance status, monkeys were screened for SERT polymorphisms [12,32]. Based on these results, we chose 20 females with an l/l genotype and 20 with either an l/s or s/s genotype, as the heterozygote produces a similar phenotype as the homozygous genotype (s/s) on most [20,36] though not all measures [37].…”

“…Females, who had been studied previously in their natal groups [32], were removed from their natal groups to form eight, five-member groups. Four groups were comprised entirely of females with an l/l SERT genotype and four were comprised of monkeys with either the l/s or s/s genotype.…”

“…We recently observed that, among a cohort of adult female rhesus monkeys drawn from the mid-ranking matrilines of several social groups, individuals possessing the short allele variant (l/s or s/s) had lower body weights and adiposity measures, lower serum concentrations of leptin and insulin in response to a fast, and reduced 5HT release in response to provocative stimuli in comparison to their l/l counterparts; animals with the short allele variant also displayed subtle dysregulation of the limbic-hypothalamic-pituitary-adrenal (LHPA) axis [32]. The present study, using this same cohort of animals, was designed to determine whether the foregoing SERT polymorphisms affect the pattern of physiological responsivity to the psychosocial stress, represented here by individual differences in social status produced during new group formation.…”