Sexual dichotomy of an interaction between early adversity and the serotonin transporter gene promoter variant in rhesus macaques

Abstract

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.

Fig. 1.

Effects of rh5-HTTLPR genotype (l/l or l/s), rearing condition (MR or PR), and sex (male or female) on ACTH responses to acute stress in infant rhesus macaques. (A) Values listed are mean plasma levels of ACTH in pg/ml ± SEM determined at baseline (Stress –, 2 and 6 months) and after stress (Stress +,3,4, and 5 months). (B–D) Shown are serum ACTH levels for Basal-1 (B), stress (C), and Basal-2 (D) testing conditions. During both baseline conditions, PR animals had lower levels of ACTH. After stress, there were interactions between rearing and genotype and among rearing, genotype, and sex. (*, P < 0.05; **, P < 0.01; ***, P < 0.005).

Fig. 2.

Effects of rh5-HTTLPR genotype (l/l or l/s), rearing condition (MR or PR), and sex (male or female) on cortisol responses to acute stress in infant rhesus macaques. (A) Values listed are mean plasma levels of cortisol in μg/dl ± SEM determined at baseline (Stress –, 2 and 6 months) and after stress (Stress +,3,4, and 5 months). (B–D) Shown are serum cortisol levels for Basal-1 (B), stress (C), and Basal-2 (D) testing conditions. There were main effects of rearing condition and of rh5-HTTLPR genotype on cortisol. In addition, there was an interaction among sex, rearing condition, and rh5-HTTLPR, such that female PR l/s animals had lower levels of cortisol.