title: Serotonin transporter genotype modulates HPA axis output during stress: effect of stress, dexamethasone test and ACTH challenge.
abstract: BACKGROUND
  Studies show that the hypothalamic-pituitary-adrenal (HPA) axis is dysregulated in depression. Some studies suggest that variation in the serotonin transporter genotype (hereafter5HTT) modulates both risk for depression and psychopathological HPA axis responsiveness. Rhesus monkeys are well suited to model such relationships. Rhesus macaque models of human psychopathology have assessed the effect of the serotonin transporter (rh5HTT) on levels of cortisol in stressed subjects. These studies show that that under conditions of stress, heterozygous females (Ls) reared under adversity exhibit high levels of cortisol. Studies have not to our knowledge, however, assessed the potential additive effect on the cortisol response in a number of macaque subjects homozygous for the serotonin transporter short allele (ss). Moreover, little is known about the level of the central or peripheral nervous system at which the5HTTgenotype acts to modulate the cortisol response.
  
  
  METHODS
  This study assesses a relatively large number of subjects homozygous and heterozygous for therh5HTTshort and long alleles (a) during stress; (b) following a dexamethasone suppression test; and (c) following an adrenocorticotropic hormone (ACTH) challenge. Subjects included 190 infant rhesus macaques (Macaca mulatta- 84 males and 106 females; 118 LL, 60 Ls, and 12 ss subjects), obtaining two blood plasma samples during the stress of separation from their mothers. Then on the following day, we obtained a blood sample following a dexamethasone test, and later that day we obtained a blood sample after an ACTH challenge test. Subjects ranged in age between 90 and 128 days, with a mean age of 107 days.
  
  
  RESULTS
  Subjects homozygous for the short allele had significantly higher levels of cortisol across all test conditions, when compared to those homozygous for the long allele, or those heterozygous with Ls alleles. Subsequent analyses showed a high correlation between individual cortisol levels across the three different tests.
  
  
  CONCLUSIONS
  These data suggest that subjects homozygous for the short allele are more likely to show dysregulated cortisol levels in response to stress. Given the correlation in individual responses of the HPA axis across the different tests, our data suggest that the effect of the5HTTgenotype shows some commonality in its regulation of stress, feedback, and ACTH-stimulated cortisol output. Our data suggest that under conditions of stress, the serotonin transporter may modulate HPA axis psychopathology.
authors: Department of Psychology, Brigham Young University, Provo, Utah, USA.
authors: Andrea N
authors: AN
authors: Sorenson
authors: Department of Psychology, California National Primate Research Center, University of California Davis, Davis, CA, USA.
authors: Erin C
authors: EC
authors: Sullivan
authors: Department of Psychology, California National Primate Research Center, University of California Davis, Davis, CA, USA.
authors: Sally P
authors: SP
authors: Mendoza
authors: Department of Psychology, California National Primate Research Center, University of California Davis, Davis, CA, USA.
authors: John P
authors: JP
authors: Capitanio
authors: Department of Psychology, Brigham Young University, Provo, Utah, USA.
authors: J Dee
authors: JD
authors: Higley
keywords: HPA axis; Nonhuman primate; Rhesus monkey; Serotonin; cortisol; depression; dexamethasone; serotonin transporter genotype; stress