Hostname: page-component-8448b6f56d-m8qmq Total loading time: 0 Render date: 2024-04-18T22:53:54.726Z Has data issue: false hasContentIssue false
  • English
  • Français

Association between the recombinant human serotonin transporter linked promoter region polymorphism and behavior in rhesus macaques during a separation paradigm

Published online by Cambridge University Press:  11 October 2007

Simona Spinelli ,
Melanie L. Schwandt ,
Stephen G. Lindell ,
Timothy K. Newman ,
Markus Heilig ,
Stephen J. Suomi ,
J. Dee Higley ,
David Goldman  and
Christina S. Barr
Simona Spinelli
Affiliation:
National Institute on Alcohol Abuse and Alcoholism
Melanie L. Schwandt
Affiliation:
National Institute on Alcohol Abuse and Alcoholism
Stephen G. Lindell
Affiliation:
National Institute on Alcohol Abuse and Alcoholism
Timothy K. Newman
Affiliation:
National Institute on Alcohol Abuse and Alcoholism
Markus Heilig
Affiliation:
National Institute on Alcohol Abuse and Alcoholism
Stephen J. Suomi
Affiliation:
National Institute of Child Health and Human Development
J. Dee Higley
Affiliation:
Brigham Young University
David Goldman
Affiliation:
National Institute on Alcohol Abuse and Alcoholism
Christina S. Barr*
Affiliation:
National Institute on Alcohol Abuse and Alcoholism
*
Address correspondence and reprint request to: Christina S. Barr, Laboratory of Clinical and Translational Studies, Primate Section, National Institute on Alcohol Abuse and Alcoholism, NIH Animal Center, P.O. Box 529, Poolesville, MD 20837; E-mail: cbarr@mail.nih.gov.
Get access Rights & Permissions [Opens in a new window]

Abstract

Human studies have suggested an association between a variable length polymorphism in the serotonin transporter gene promoter region and vulnerability to anxiety and depression. Relative to the long (l) allele, the short (s) allele increases the risk of developing depression in individuals exposed to stressful life events. An orthologue of the human variant is present in rhesus macaques and allows for studies in animals exposed to stress. Here, we used an established model of early life stress exposure, in which rhesus macaques are raised without adults in a group of peers (peer-only reared [PR]), or with their mothers. At 6 months of age, animals were subjected to 4-day long social separations for 4 consecutive weeks, with 3 days of reunion in between. Data were collected during both the acute (Day 1) and chronic phases (Days 2–4) of separation. Behavioral factors were separately extracted for each phase of separation. For acute separation, the behavioral factors generated were despair and behavioral pathology and, for the chronic phase despair, agitation, and behavioral pathology. During both phases of social separation, PR l/s animals were more likely to exhibit pathological behaviors, whereas PR l/l monkeys show higher levels of despair compared to the other three groups. These findings indicate that early stress affects the behavioral response to separation differently as a function of recombinant human serotonin transporter linked polymorphic repeat genotype and suggest that carriers of the s allele are not only more anxious but may also be more vulnerable to developing behavioral pathology in the face of chronic adversity.

Type
Research Article
Information
Development and Psychopathology , Volume 19 , Issue 4 , Fall 2007 , pp. 977 - 987
Copyright
Copyright © Cambridge University Press 2007

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Barr, C. S., & Goldman, D. (2006). Non-human primate models of inheritance vulnerability to alcohol use disorders. Addiction Biology, 11, 374–385.CrossRefGoogle ScholarPubMed
Barr, C. S., Newman, T. K., Becker, M. L., Champoux, M., Lesch, K. P., Suomi, S. J., et al. (2003). Serotonin transporter gene variation is associated with alcohol sensitivity in rhesus macaques exposed to early-life stress. Alcoholism: Clinical and Experimental Research, 27, 812–817.CrossRefGoogle ScholarPubMed
Barr, C. S., Newman, T. K., Becker, M. L., Parker, C. C., Champoux, M., Lesch, K. P., et al. (2003). The utility of the non-human primate: Model for studying gene by environment interactions in behavioral research. Genes, Brain, and Behavior, 2, 336–340.CrossRefGoogle ScholarPubMed
Barr, C. S., Newman, T. K., Lindell, S., Shannon, C., Champoux, M., Lesch, K. P., et al. (2004). Interaction between serotonin transporter gene variation and rearing condition in alcohol preference and consumption in female primates. Archives of General Psychiatry, 61, 1146–1152.CrossRefGoogle ScholarPubMed
Barr, C. S., Newman, T. K., Shannon, C., Parker, C., Dvoskin, R. L., Becker, M. L. et al. , (2004). Rearing condition and rh5-HTTLPR interact to influence limbic–hypothalamic–pituitary–adrenal axis response to stress in infant macaques. Biological Psychiatry, 55, 733–738.CrossRefGoogle ScholarPubMed
Barr, C. S., Schwandt, M. L., Newman, T. K., & Higley, J. D. (2004). The use of adolescent nonhuman primates to model human alcohol intake: Neurobiological, genetic, and psychological variables. Annals of the New York Academy of Science, 1021, 221–233.CrossRefGoogle ScholarPubMed
Bennett, A. J., Lesch, K. P., Heils, A., Long, J. C., Lorenz, J. G., Shoaf, S. E., et al. (2002). Early experience and serotonin transporter gene variation interact to influence primate CNS function. Molecular Psychiatry, 7, 118–122.CrossRefGoogle ScholarPubMed
Berton, O., & Nestler, E. J. (2006). New approaches to antidepressant drug discovery: Beyond monoamines. Nature Reviews Neuroscience, 7, 137–151.CrossRefGoogle ScholarPubMed
Caspi, A., McClay, J., Moffitt, T. E., Mill, J., Martin, J., Craig, I. W., et al. (2002). Role of genotype in the cycle of violence in maltreated children. Science, 297, 851–854.CrossRefGoogle ScholarPubMed
Caspi, A., Sugden, K., Moffitt, T. E., Taylor, A., Craig, I. W., Harrington, H., et al. (2003). Influence of life stress on depression: Moderation by a polymorphism in the 5-HTT gene. Science, 301, 386–389.CrossRefGoogle ScholarPubMed
Champoux, M., Bennett, A., Shannon, C., Higley, J. D., Lesch, K. P., & Suomi, S. J. (2002). Serotonin transporter gene polymorphism, differential early rearing, and behavior in rhesus monkey neonates. Molecular Psychiatry, 7, 1058–1063.CrossRefGoogle ScholarPubMed
Clark, A. B., & Ehlinger, T. J. (1987). Pattern and adaptation in individual behavioral differences. Perspectives in Ethology, 7, 1–47.Google Scholar
De Bellis, M. D. (2005). The psychobiology of neglect. Child Maltreatment, 10, 150–172.CrossRefGoogle ScholarPubMed
Feldman, S., & Weidenfeld, J. (1998). The excitatory effects of the amygdala on hypothalamo–pituitary–adrenocortical responses are mediated by hypothalamic norepinephrine, serotonin, and CRF-41. Brain Research Bulletin, 45, 389–393.CrossRefGoogle ScholarPubMed
Fontenot, M. B., Padgett, E. E. R., Dupuy, A. M., Lynch, C. R., De Petrillo, P. B., & Higley, J. D. (2005). The effects of fluoxetine and buspirone on self-injurious and stereotypic behavior in adult male rhesus macaques. Comparative Medicine, 55, 67–74.Google ScholarPubMed
Garner, J. P. (2005). Stereotypies and other abnormal repetitive behaviors: Potential impact on validity, reliability, and replicability of scientific outcomes. Institute for Laboratory Animal Research Journal, 46, 106–117.Google ScholarPubMed
Gordon, H. W. (2002). Early environmental stress and biological vulnerability to drug abuse. Psychoneuroendocrinology, 27, 115–126.CrossRefGoogle ScholarPubMed
Gross, C., & Hen, R. (2004). The developmental origins of anxiety. Nature Reviews Neuroscience, 5, 545–552.CrossRefGoogle ScholarPubMed
Hamet, P., & Tremblay, J. (2005). Genetics and genomics of depression. Metabolism, 54(5, Suppl. 1), 10–15.CrossRefGoogle ScholarPubMed
Heinz, A., Jones, D. W., Mazzanti, C., Goldman, D., Ragan, P., Hommer, D., et al. (2000). A relationship between serotonin transporter genotype and in vivo protein expression and alcohol neurotoxicity. Biological Psychiatry, 47, 643–649.CrossRefGoogle ScholarPubMed
Higley, J. D., Mehlman, P. T., Taub, D. M., Higley, S. B., Suomi, S. J., Vickers, J. H., et al. (1992). Cerebrospinal fluid monoamine and adrenal correlates of aggression in free-ranging rhesus monkeys. Archives of General Psychiatry, 49, 436–441.CrossRefGoogle ScholarPubMed
Higley, J. D., Suomi, S. J., & Linnoila, M. (1991). CSF monoamine metabolite concentrations vary according to age, rearing, and sex, and are influenced by the stressor of social separation in rhesus monkeys. Psychopharmacology (Berlin), 103, 551–556.CrossRefGoogle ScholarPubMed
Hu, X. Z., Lipsky, R. H., Zhu, G., Akhtar, L. A., Taubman, J., Greenberg, B. D., et al. (2006). Serotonin transporter promoter gain-of-function genotypes are linked to obsessive–compulsive disorder. American Journal of Human Genetics, 7, 815–826.CrossRefGoogle Scholar
Hugo, C., Seier, J., Mdhluli, C., Daniels, W., Harvey, B. H., Du Toit, D., et al. (2003). Fluoxetine decreases stereotypic behavior in primates. Progress in Neuropsychopharmacology and Biological Psychiatry, 27, 639–643.CrossRefGoogle ScholarPubMed
Lesch, K. P., Bengel, D., Heils, A., Sabol, S. Z., Greenberg, B. D., Petri, S., et al. (1996). Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science, 274, 1527–1531.CrossRefGoogle ScholarPubMed
Levinson, D. F. (2006). The genetics of depression: A review. Biological Psychiatry, 60, 84–92.CrossRefGoogle Scholar
Lowry, C. A. (2002). Functional subsets of serotonergic neurones: Implications for control of the hypothalamic–pituitary–adrenal axis. Journal of Neuroendocrinology, 14, 911–923.CrossRefGoogle ScholarPubMed
Manor, I., Eisenberg, J., Tyano, S., Sever, Y., Cohen, H., Ebstein, R. P., et al. (2001). Family-based association study of the serotonin transporter promoter region polymorphism (5-HTTLPR) in attention deficit hyperactivity disorder. American Journal of Medical Genetics, 105, 91–95.3.0.CO;2-V>CrossRefGoogle ScholarPubMed
McDougle, C. J., Epperson, C. N., Price, L. H., & Gelernter, J. (1998). Evidence for linkage disequilibrium between serotonin transporter protein gene (SLC6A4) and obsessive compulsive disorder. Molecular Psychiatry, 3, 270–273.CrossRefGoogle ScholarPubMed
Mineka, S., & Suomi, S. J. (1978). Social separation in monkeys. Psychological Bulletin, 85, 1376–1400.CrossRefGoogle ScholarPubMed
Nemeroff, C. B., & Owens, M. J. (2002). Treatment of mood disorders. Nature Neuroscience, 5(Suppl.), 1068–1070.CrossRefGoogle ScholarPubMed
Shannon, C., Champoux, M., & Suomi, S. J. (1998). Rearing condition and plasma cortisol in rhesus monkey infants. American Journal of Primatology, 46, 311–321.3.0.CO;2-L>CrossRefGoogle ScholarPubMed
Suomi, S. J. (1991). Early stress and adult emotional reactivity in rhesus monkeys. Ciba Foundation Symposium, 156, 171–183.Google ScholarPubMed
Suomi, S. J. (1997). Early determinants of behaviour: Evidence from primate studies. British Medical Bulletin, 53, 170–184.CrossRefGoogle ScholarPubMed
Thadani, P. V. (2002). The intersection of stress, drug abuse and development. Psychoneuroendocrinology, 27, 221–230.CrossRefGoogle ScholarPubMed
Vazquez, D. M., Eskandari, R., Zimmer, C. A., Levine, S., & Lopez, J. F. (2002). Brain 5-HT receptor system in the stressed infant rat: Implications for vulnerability to substance abuse. Psychoneuroendocrinology, 27, 245–272.CrossRefGoogle ScholarPubMed
Weld, K. P., Mench, J. A., Woodward, R. A., Bolesta, M. S., Suomi, S. J., & Higley, J. D. (1998). Effect of tryptophan treatment on self-biting and central nervous system serotonin metabolism in rhesus monkeys (Macaca mulatta). Neuropsychopharmacology, 19, 314–321.CrossRefGoogle ScholarPubMed