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


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.

Corresponding author
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:
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This list contains references from the content that can be linked to their source. For a full set of references and notes please see the PDF or HTML where available.

C. S. Barr , & D. Goldman (2006). Non-human primate models of inheritance vulnerability to alcohol use disorders. Addiction Biology, 11, 374385.

C. S. Barr , T. K. Newman , M. L. Becker , M. Champoux , K. P. Lesch , S. J. Suomi , (2003). Serotonin transporter gene variation is associated with alcohol sensitivity in rhesus macaques exposed to early-life stress. Alcoholism: Clinical and Experimental Research, 27, 812817.

C. S. Barr , T. K. Newman , M. L. Becker , C. C. Parker , M. Champoux , K. P. Lesch , (2003). The utility of the non-human primate: Model for studying gene by environment interactions in behavioral research. Genes, Brain, and Behavior, 2, 336340.

C. S. Barr , T. K. Newman , S. Lindell , C. Shannon , M. Champoux , K. P. Lesch , (2004). Interaction between serotonin transporter gene variation and rearing condition in alcohol preference and consumption in female primates. Archives of General Psychiatry, 61, 11461152.

C. S. Barr , T. K. Newman , C. Shannon , C. Parker , R. L. Dvoskin , M. L. Becker , (2004). Rearing condition and rh5-HTTLPR interact to influence limbic–hypothalamic–pituitary–adrenal axis response to stress in infant macaques. Biological Psychiatry, 55, 733738.

C. S. Barr , M. L. Schwandt , T. K. Newman , & J. D. Higley (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, 221233.

A. J. Bennett , K. P. Lesch , A. Heils , J. C. Long , J. G. Lorenz , S. E. Shoaf , (2002). Early experience and serotonin transporter gene variation interact to influence primate CNS function. Molecular Psychiatry, 7, 118122.

O. Berton , & E. J. Nestler (2006). New approaches to antidepressant drug discovery: Beyond monoamines. Nature Reviews Neuroscience, 7, 137151.

A. Caspi , J. McClay , T. E. Moffitt , J. Mill , J. Martin , I. W. Craig , (2002). Role of genotype in the cycle of violence in maltreated children. Science, 297, 851854.

A. Caspi , K. Sugden , T. E. Moffitt , A. Taylor , I. W. Craig , H. Harrington , (2003). Influence of life stress on depression: Moderation by a polymorphism in the 5-HTT gene. Science, 301, 386389.

M. Champoux , A. Bennett , C. Shannon , J. D. Higley , K. P. Lesch , & S. J. Suomi (2002). Serotonin transporter gene polymorphism, differential early rearing, and behavior in rhesus monkey neonates. Molecular Psychiatry, 7, 10581063.

M. D. De Bellis (2005). The psychobiology of neglect. Child Maltreatment, 10, 150172.

S. Feldman , & J. Weidenfeld (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, 389393.

J. P. Garner (2005). Stereotypies and other abnormal repetitive behaviors: Potential impact on validity, reliability, and replicability of scientific outcomes. Institute for Laboratory Animal Research Journal, 46, 106117.

H. W. Gordon (2002). Early environmental stress and biological vulnerability to drug abuse. Psychoneuroendocrinology, 27, 115126.

C. Gross , & R. Hen (2004). The developmental origins of anxiety. Nature Reviews Neuroscience, 5, 545552.

P. Hamet , & J. Tremblay (2005). Genetics and genomics of depression. Metabolism, 54(5, Suppl. 1), 1015.

A. Heinz , D. W. Jones , C. Mazzanti , D. Goldman , P. Ragan , D. Hommer , (2000). A relationship between serotonin transporter genotype and in vivo protein expression and alcohol neurotoxicity. Biological Psychiatry, 47, 643649.

J. D. Higley , P. T. Mehlman , D. M. Taub , S. B. Higley , S. J. Suomi , J. H. Vickers , (1992). Cerebrospinal fluid monoamine and adrenal correlates of aggression in free-ranging rhesus monkeys. Archives of General Psychiatry, 49, 436441.

J. D. Higley , S. J. Suomi , & M. Linnoila (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, 551556.

C. Hugo , J. Seier , C. Mdhluli , W. Daniels , B. H. Harvey , D. Du Toit , (2003). Fluoxetine decreases stereotypic behavior in primates. Progress in Neuropsychopharmacology and Biological Psychiatry, 27, 639643.

K. P. Lesch , D. Bengel , A. Heils , S. Z. Sabol , B. D. Greenberg , S. Petri , (1996). Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science, 274, 15271531.

D. F. Levinson (2006). The genetics of depression: A review. Biological Psychiatry, 60, 8492.

C. A. Lowry (2002). Functional subsets of serotonergic neurones: Implications for control of the hypothalamic–pituitary–adrenal axis. Journal of Neuroendocrinology, 14, 911923.

I. Manor , J. Eisenberg , S. Tyano , Y. Sever , H. Cohen , R. P. Ebstein , (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, 9195.

C. J. McDougle , C. N. Epperson , L. H. Price , & J. Gelernter (1998). Evidence for linkage disequilibrium between serotonin transporter protein gene (SLC6A4) and obsessive compulsive disorder. Molecular Psychiatry, 3, 270273.

S. Mineka , & S. J. Suomi (1978). Social separation in monkeys. Psychological Bulletin, 85, 13761400.

C. B. Nemeroff , & M. J. Owens (2002). Treatment of mood disorders. Nature Neuroscience, 5(Suppl.), 10681070.

C. Shannon , M. Champoux , & S. J. Suomi (1998). Rearing condition and plasma cortisol in rhesus monkey infants. American Journal of Primatology, 46, 311321.

S. J. Suomi (1997). Early determinants of behaviour: Evidence from primate studies. British Medical Bulletin, 53, 170184.

P. V. Thadani (2002). The intersection of stress, drug abuse and development. Psychoneuroendocrinology, 27, 221230.

D. M. Vazquez , R. Eskandari , C. A. Zimmer , S. Levine , & J. F. Lopez (2002). Brain 5-HT receptor system in the stressed infant rat: Implications for vulnerability to substance abuse. Psychoneuroendocrinology, 27, 245272.

K. P. Weld , J. A. Mench , R. A. Woodward , M. S. Bolesta , S. J. Suomi , & J. D. Higley (1998). Effect of tryptophan treatment on self-biting and central nervous system serotonin metabolism in rhesus monkeys (Macaca mulatta). Neuropsychopharmacology, 19, 314321.

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