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Social subordination in female macaques represents a well-described model of chronic psychosocial stress. Additionally, a length polymorphism (5- HTTLPR) in the regulatory region of the serotonin (5- HT) transporter (5- HTT) gene ( SLC6A4) is present in rhesus macaques, which has been linked to adverse outcomes similar to that described in humans with an analogous 5- HTTLPR polymorphism. The present study determined the effects of social status and the 5- HTTLPR genotype on 5- HT1 A receptor binding potential (5- HT1 A BPND) in brain regions implicated in emotional regulation and stress reactivity in ovariectomised female monkeys, and then assessed how these effects were altered by 17β-oestradiol ( E2) treatment. Areas analysed included the prefrontal cortex [anterior cingulate ( ACC); medial prefrontal cortex (m PFC); dorsolateral prefrontal cortex; orbitofrontal prefrontal cortex], amygdala, hippocampus, hypothalamus and raphe nucleui. Positron emission tomography using p-[18 F] MPPF was performed to determine the levels of 5- HT1 A BPND under a non- E2 and a 3-week E2 treatment condition. The short variant (s-variant) 5- HTTLPR genotype produced a significant reduction in 5- HT1A BPND in the m PFC regardless of social status, and subordinate s-variant females showed a reduction in 5- HT1 A BPND within the ACC. Both these effects of 5- HTTLPR were unaffected by E2. Additionally, E2 reduced 5- HT1 A BPND in the dorsal raphe of all females irrespective of psychosocial stress or 5- HTTLPR genotype. Hippocampal 5- HT1 A BPND was attenuated in subordinate females regardless of 5- HTTLPR genotype during the non- E2 condition, an effect that was normalised with E2. Similarly, 5- HT1 A BPND in the hypothalamus was significantly lower in subordinate females regardless of 5- HTTLPR genotype, an effect reversed with E2. Taken together, the data indicate that the effect of E2 on modulation of central 5 HT1 A BPND may only occur in brain regions that show no 5- HTTLPR genotype-linked control of 5- HT1 A binding. [ABSTRACT FROM AUTHOR]

Psychosocial stress exposure is linked to the disruption of emotional regulation that can manifest as anxiety and depression. Women are more likely to suffer from such psychopathologies than men, indicating that sex-based differences in gonadal steroids may be a key factor in the aetiology of stress-induced adverse health outcomes. Oestradiol (E2) positively influences mood and cognition in females, an effect likely related to the ability of E2 to modulate the serotonin and dopamine neurotransmitter systems. Furthermore, genetic variation as a result of the polymorphism in the promoter region of the gene ( SLC6A4) encoding the serotonin transporter (5 HTTLPR) also can influence the ability of E2 to modulate behaviour and physiology. However, it remains uncertain whether exposure to social stress interacts with the 5 HTTLPR to influence E2-induced changes in behaviour and physiology. The present study used ovariectomised adult female rhesus monkeys to investigate acute and chronic effects of E2 on central monoamine metabolite concentrations using cerobrospinal fluid sampling. We further assessed how E2-induced changes in monoamine metabolite levels are modified by the unpredictable stress of social subordination and the 5 HTTLPR polymorphism. Levels of the serotonin metabolite 5-hydroxyindoleacetic acid decreased significantly during chronic E2 treatment only in dominant females with the long promoter length of SLC6A4. Chronic administration of E2 decreased levels of the dopamine metabolite dihydrophenylacetic acid in a manner independent of the social status, 5 HTTLPR genotype, or their interactions. Overall levels of dopamine and serotonin metabolites were increased in subordinate females, although this effect of social stress was not influenced by 5 HTTLPR genotype. Together, these data emphasise how E2 can modulate central neurotransmitter systems and indicate that social subordination in female monkeys is a valid model for examining how chronic psychosocial stress alters sensitivity to E2. Future studies are necessary to elaborate how changes in central neurotransmitter metabolism affect behaviour and physiology as a result of E2 and prolonged exposure to stress. [ABSTRACT FROM AUTHOR]

Highlights: [•] Social subordination alters GABAARs binding in estradiol-treated female monkeys. [•] Status effect on GABAAR is site specific, only seen in the prefrontal cortex. [•] CRH receptor antagonism reverses status differences in GABAAR binding. [•] Implicates the stress axis in the dysregulation of GABAAR in subordinate females. [•] Provides mechanism by which subordination alters the actions of estradiol. [ABSTRACT FROM AUTHOR]