Social setting, social rank and HPA axis response in cynomolgus monkeys

Abstract

Rationale: Hypothalamic-pituitary-adrenal (HPA) axis activity under different social settings in non-human primates is understudied.

Objective: The aim of this study is to evaluate the response of pituitary-adrenal hormones (adrenocorticotropic hormone (ACTH) and cortisol) to pharmacological challenges of the HPA axis in male cynomolgus macaques under different social settings.

Methods: Male cynomolgus macaques (Macaca fascicularis, n = 11) were individually (A) and socially housed (B) in alternation, over consecutive months, in an ABA design. During each experimental phase, plasma ACTH and cortisol were measured in response to low- and mild-intensity psychological stressors and following administration of saline, naloxone, ovine-corticotropin-releasing factor (oCRF), and dexamethasone.

Results: These data demonstrate that cortisol measured under low stress conditions is sensitive to social rank (dominance hierarchy) and distinguishes dominant from non-dominant animals during both individual and social settings. Administration of naloxone resulted in elevated circulating ACTH and cortisol, while oCRF only increased circulating cortisol. During social housing, the cortisol response to naloxone and oCRF was increased, whereas dexamethasone suppression of ACTH and cortisol remained consistent across all social settings.

Conclusions: Circulating ACTH and cortisol are differentially sensitive to changes in social settings in non-human primates. Cortisol response increased during social housing and could be stimulated by both naloxone and oCRF, whereas ACTH response was generally not influenced by social setting or oCRF but was increased by naloxone. These data show differential adrenal and pituitary response to changes in social settings and a small, but consistent, effect of social dominance.

Keywords: ACTH; Cortisol; HPA axis; Monkey; Social rank.

Fig 1. Low and mild stress

Peak (mean ± SD) ACTH (left) and cortisol (right) collected under low stress (home cage, A) and mild stress (primate chair, B) conditions. The mild stress condition reliably elevated both ACTH and cortisol for all animals across all social ranks and phases. Dominant animals had higher cortisol than intermediate and subordinate animals under the low stress condition (*: p < 0.05). Social housing potentiated the cortisol response to mild stress across all social ranks (#: p < 0.01).

Fig 2. Naloxone challenge

Peak (mean ± SD) ACTH (left) and cortisol (right) following saline (0 μg/kg) and naloxone (125 and 375 μg/kg) challenges. Both doses of naloxone increased ACTH and cortisol compared to saline (a: p < 0.05). The peak cortisol response to naloxone was greatest during the social housing phase (b: p < 0.05) when compared to both individual housed phases. Circles: dominant animals, triangles: non-dominant animals.

Fig 3. ovine-CRF challenge

Peak (mean ± SD) ACTH (left) and cortisol (right) following saline (0 μg/kg) and ovine-CRF (1 μg/kg) challenge. Ovine-CRF increased cortisol compared to saline (a: p < 0.05). The peak cortisol response to ovine-CRF was greatest during the social housing phase (b: p < 0.001). Circles: dominant animals, triangles: non-dominant animals

Fig 4. Dexamethasone suppression

Percent of baseline (mean ± SD) ACTH (left) and cortisol (right) following dexamethasone administration (130 μg/kg) across housing conditions. Dexamethasone reliably suppressed both ACTH and cortisol across social ranks and during all housing conditions.