Rearing condition and rh5-HTTLPR interact to influence limbic-hypothalamic- pituitary-adrenal axis response to stress in infant macaques

Laboratory of Clinical Studies, National Institute of Alcoholism and Alcohol Abuse, National Institutes of Health, Poolesville, Maryland 20837, USA.
Biological Psychiatry (Impact Factor: 10.26). 05/2004; 55(7):733-8. DOI: 10.1016/j.biopsych.2003.12.008
Source: PubMed


In humans and macaques, a promoter polymorphism that decreases transcription of the serotonin transporter gene is associated with anxiety. Serotonin transporter gene disruption in rodents produces anxious animals with exaggerated limbic-hypothalamic-pituitary-adrenal (LHPA) responses to stress. We wanted to determine whether serotonin transporter gene promoter variation (rh-5HTTLPR) and rearing condition would interact to influence endocrine responses to stress in infant rhesus macaques.
Animals were reared with their mothers (MR, n = 141) or in peer-only groups (PR, n = 67). At 6 months of age, adrenocorticotropic hormone (ACTH) and cortisol levels were determined at baseline and during separation stress. Serotonin transporter genotype (l/l and l/s) was determined with polymerase chain reaction followed by gel electrophoresis.
Cortisol levels increased during separation, and there was a main effect of rearing condition, with decreased cortisol levels among PR macaques. Animals with l/s rh5-HTTLPR genotypes had higher ACTH levels than did l/l animals. Adrenocorticotropic hormone levels increased during separation, and there was a separation x rearing x rh5-HTTLPR interaction, such that PR-l/s animals had higher ACTH levels during separation than did other animals studied.
These data demonstrate that serotonin transporter gene variation affects LHPA axis activity and that the influence of rh5-HTTLPR on hormonal responses during stress is modulated by early experience.

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    • "The serotonergic system is a component of the central nervous system associated with differential hypothalamicpituitary-adrenal (HPA) axis responses to stress [1] [2] [3]. The serotonergic system can indirectly modulate the secretion of cortisol and alter feedback regulation of cortisol and the HPA axis [4] [5] [6] [7]. "

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    • "The past several decades of research with NHPs has established the rhesus monkey as a reliable model of alcohol abuse and alcoholism, as they show similar blood alcohol levels, impairment, and withdrawal and relapse symptoms after alcohol consumption (Higley, Mehlman et al. 1996a; Higley, Suomi, Linnoila 1996b; Kornet et al. 1990, 1991; Schwandt et al. 2010). Furthermore, studies with NHPs have repeatedly demonstrated that individuals exposed to adversity (typically in the form of peerrearing ) are more prone to intoxication, alcohol abuse, and excessive aggression than are mother-reared infants (Barr, Schwandt et al. 2004; Fahlke et al. 2000; Heinz et al. 1998; Higley, Hasert et al. 1991), findings that mimic what is known in humans (Caspi and Moffitt 2006; Enoch 2011). "
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    ABSTRACT: This report reviews the scientific literature from the past several decades that focuses on nonhuman primates (NHPs) as models of neuropsychiatric disorders, including anxiety, and alcoholism. In particular, we highlight the approaches, advantages, and disadvantages of the rearing, genetic, and epigenetic methodologies behind these studies as a means of evaluating the application of these methods in assessing disorders in NHPs as models of human disease. Finally, we describe the contributions the NHP studies have made to neuropsychiatric research and areas for future research.
    ILAR journal / National Research Council, Institute of Laboratory Animal Resources 09/2014; 55(2):361-70. DOI:10.1093/ilar/ilu025 · 2.39 Impact Factor
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    • "A wide variety of studies have shown that hypothalamic–pituitary–adrenal (HPA) axis functioning is modulated, at least in part by central nervous system (CNS) serotonin (1–3), and some studies suggest that genetic differences in the serotonin transporter play a role in this serotonin modulation of the HPA axis (4–6). Studies about the serotonin transporter gene effects on the HPA axis in human subjects show that girls in late childhood and early adolescence with one or two copies of the serotonin transporter short allele (Ls, ss, respectively) show high waking cortisol when compared to the female subjects homozygous for the long allele (LL) (7). "
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    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 (hereafter 5HTT) 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 the 5HTT genotype acts to modulate the cortisol response. Methods This study assesses a relatively large number of subjects homozygous and heterozygous for the rh5HTT short 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 the 5HTT genotype 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.
    09/2013; 1:21130. DOI:10.3402/tdp.v1i0.21130
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