OPRM1 gene variation influences hypothalamic-pituitary-adrenal axis function in response to a variety of stressors in rhesus macaques

Abstract

The endogenous opioid system is involved in modulating a number of behavioral and physiological systems, including the hypothalamic-pituitary-adrenal (HPA) axis. In humans, a functional variant in the OPRM1 gene (OPRM1 A118G) is associated with a number of outcomes, including attenuated HPA axis responses to stress. A nonsynonymous variant (OPRM1 C77G) in the rhesus macaque has been shown to have similar effects in vivo to the human variant. The current study investigated whether OPRM1 C77G influences HPA axis response to stress in rhesus macaques. We analyzed plasma adrenocorticotropic hormone (ACTH) and cortisol levels measured in response to three different stressors: (1) maternal separation in infant subjects at 6 months of age, (2) acute ethanol administration in adolescent subjects at 4 years of age, and (3) postpartum HPA axis function in adult rhesus macaque females. For the maternal separation paradigm, ACTH and cortisol levels were determined at baseline as well as peak levels during each of 4 consecutive separation episodes. For the acute ethanol administration paradigm, hormone levels were determined at baseline and again at 5 min, 10 min, and 60 min following the ethanol infusion. For postpartum sampling, hormone levels were determined at postpartum days 7, 14, 21, 30, 60, 90, 120, and 150. Infants carrying the 77G allele exhibited lower levels of cortisol across all 4 separation episodes. Furthermore, adolescents carrying the 77G allele exhibited lower cortisol levels at 5 and 10 min following acute ethanol administration. Adult females with prior reproductive experience and who carry the 77G allele exhibited lower cortisol levels across the postpartum period. No significant genotype effects were found for ACTH, although there were some trends for lower ACTH levels in 77G allele carriers. These data are consistent with human studies that have demonstrated attenuated cortisol responses to stress among carriers of the OPRM1 118G allele, lending further support to the argument that the rhesus and human allelic variants are functionally similar. Our results also suggest that OPRM1 variation may influence coping style, as well as alcohol-induced and postpartum levels of HPA axis activity and, as such, may modify vulnerability to alcohol use disorders and postpartum depression.

Figure 1

Peak cortisol response to maternal separation as a function of OPRM1 genotype in six month old rhesus macaque infants. Values are given as mean ± SEM. Peak cortisol responses were determined by comparing values at hour 1 and hour 2 of separation on the Monday of each separation week, When data were analyzed using only the hour 2 values for all subjects (the time point for which most subjects exhibited the peak response), the results were the same. S1 = week 1 separation, S2 = week 2 separation, S3 = week 3 separation, S4 = week 4 separation.

Figure 2

Cortisol response to acute alcohol administration as a function of OPRM1 genotype in the adolescent/young adult rhesus macaques. Values are given as mean ± SEM.

Figure 3

Cortisol levels in rhesus macaque mothers as a function of OPRM1 genotype. Values are given as mean ± SEM. (A) Primiparous (first-time) mothers. * indicates a significant difference (p < 0.05) from day 7 and day 14 in primaparous mothers according to Newman-Keuls post-hoc tests. (B) Multiparous mothers.