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Metabolic and reproductive consequences of the serotonin transporter promoter polymorphism (5-HTTLPR) in adult female rhesus monkeys (Macaca mulatta)

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Abstract

The serotonin (5HT) reuptake transporter (SERT) plays a key role in 5HT homeostasis by recycling 5HT into the presynaptic neurons. Recently, polymorphisms in the length of the promoter region of the gene that encodes SERT have been linked to functional differences in reactivity to psychosocial stress, as the short (s) promoter length allele shows reduced transcriptionally activity in vitro and is associated with reduced 5HT activity and increased vulnerability to affective disorders. Given 5HT’s important role in appetite regulation, polymorphisms in the SERT gene could also affect metabolic parameters. In addition, since reduced 5HT activity may also predispose females to reproductive deficits, polymorphisms in the SERT gene may help explain individual differences in ovulatory function. The present study, using a rhesus monkey model, tested the hypothesis that the presence of the s-variant allele would be associated with altered metabolic regulation and impaired ovulatory cycles compared with the l/l genotype. Females homozygous for the long allele in the SERT gene (l/l, n = 19) were compared to those with the s-variant allele (l/s or s/s, n = 20). All females had similar social histories. Body weights (P = 0.026) but not heights (P = 0.618) were significantly lower in s-variant compared to l/l females. In addition, both BMI (P = 0.032) and sagittal abdominal diameters (SAD) (P = 0.031), as indices of adiposity, were significantly lower in s-variant females. Consistent with these differences, fasting and non-fasting levels of leptin were significantly lower in s-variant females (P = 0.002). While there were no genotype differences in non-fasting levels of insulin, s-variant females had significantly lower concentrations of insulin during a fast than did l/l females (P = 0.052). Neither glucose, T 3, T 4, nor ghrelin varied significantly between groups during either the fasted or non-fasted condition (P > 0.05). Analysis of a subset of females indicated that significantly fewer s-variant females (62.5%) exhibited ovulatory cycles than l/l females (100%, P < 0.05). However, there were no differences in serum estradiol or progesterone in l/l females and those s-variant females that did ovulate (P > 0.05). In addition, females with the s-variant genotype also had reduced 5HT activity (P = 0.030), assessed from the acute increase in serum prolactin following the administration of the 5HT reuptake inhibitor, citalopram. Finally, s-variant females were significantly less responsive to glucocorticoid negative feedback (P = 0.030) yet more responsive to corticotropin releasing hormone (CRH, P = 0.016) in terms of plasma cortisol than were l/l females. These data indicate that adult female rhesus monkeys with the s-variant polymorphism in the SERT gene exhibit metabolic and reproductive alterations in conjunction with reduced serotonergic responsivity and increased LHPA activity and suggest the possibility that this genotype may predispose females exposed to psychosocial stressors to further metabolic and reproductive deficits.

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References

  1. I. Lucki, Biol. Psychiat. 44(3), 151 (1998)

    Article  PubMed  Google Scholar 

  2. R. Ursin, Sleep Med. Rev. 6(1), 55 (2002)

    Article  PubMed  Google Scholar 

  3. J.A. Gingrich, M.S. Ansorge, R. Merker, N. Weisstaub, M. Zhou, CNS Spectr. 8(8), 572 (2003)

    PubMed  Google Scholar 

  4. A.C. Swann, J. Clin. Psychiat. 64(Suppl 4), 26 (2003)

    Google Scholar 

  5. E. Sanders-Bush, S.E. Mayer, in Goodman & Gilman’s The Pharmacological Basis of Therapeutics, ed. by L.L. Brubton et al. (The MacGraw-Hill Companies, New York, 2006), p. 297

  6. K.P. Lesch, R. Mossner, Biol. Psychiat. 44(3), 179 (1998)

    Article  PubMed  Google Scholar 

  7. G. Rudnick, J. Clark, Biochim Biophys Acta 1144(3), 249 (1993)

    Article  PubMed  Google Scholar 

  8. A. Heils, A. Teufel, S. Petri, G. Stober, P. Riederer, D. Bengel, K.P. Lesch, J. Neurochem. 66(6), 2621 (1996)

    Article  PubMed  Google Scholar 

  9. K.P. Lesch, U. Balling, J. Gross, K. Strauss, B.L. Wolozin, D.L. Murphy, P. Riederer, J. Neural. Transm. Gen. Sect. 95(2), 157 (1994)

    Article  PubMed  Google Scholar 

  10. C.E. Fiskerstrand, E.A. Lovejoy, J.P. Quinn, FEBS Lett., 458(2), 171 (1999)

    Article  PubMed  Google Scholar 

  11. J.B. Fan, P. Sklar, Mol. Psychiat. 10(10), 928, 891 (2005)

    Google Scholar 

  12. K. Ohara, Y. Suzuki, M. Ochiai, T. Tsukamoto, K. Tani, K. Ohara, Prog. Neuropsychopharmacol. Biol. Psychiat. 23(1), 55 (1999)

    Article  Google Scholar 

  13. K.P. Lesch, J. Meyer, K. Glatz, G. Flugge, A. Hinney, J. Hebebrand, S.M. Klauck, A. Poustka, F. Poustka, D. Bengel, R. Mossner, P. Riederer, A. Heils, J. Neural. Transm. 104(11–12), 1259 (1997)

    Article  PubMed  Google Scholar 

  14. J. Veenstra-VanderWeele, G.M. Anderson, E.H. Cook Jr., Eur. J. Pharmacol. 410(2–3), 165 (2000)

    Article  PubMed  Google Scholar 

  15. J. Melke, M. Landen, F. Baghei, R. Rosmond, G. Holm, P. Bjorntorp, L. Westberg, M. Hellstrand, E. Eriksson, Am. J. Med. Genet. 105(5), 458 (2001)

    Article  PubMed  Google Scholar 

  16. K.P. Lesch, D. Bengel, A. Heils, S.Z. Sabol, B.D. Greenberg, S. Petri, J. Benjamin, C.R. Muller, D.H. Hamer, D.L. Murphy, Science 274(5292), 1527 (1996)

    Article  PubMed  Google Scholar 

  17. A. Caspi, K. Sugden, T.E. Moffitt, A. Taylor, I.W. Craig, H. Harrington, J. McClay, J. Mill, J. Martin, A. Braithwaite, R. Poulton, Science 301(5631), 386 (2003)

    Article  PubMed  Google Scholar 

  18. A. Serretti, R. Calati, L. Mandelli, D. De Ronchi, Curr. Drug. Targets 7(12), 1659 (2006)

    Article  PubMed  Google Scholar 

  19. L. Lanfumey, C. Mannoury La Cour, N. Froger, M. Hamon, Neurochem. Res. 25(9–10), 1199 (2000)

    Article  PubMed  Google Scholar 

  20. A. Holmes, A.R. Hariri, Genes Brain Behav. 2(6), 332 (2003)

    Article  PubMed  Google Scholar 

  21. D.L. Murphy, Q. Li, S. Engel, C. Wichems, A. Andrews, K.P. Lesch, G. Uhl, Brain Res. Bull. 56(5), 487 (2001)

    Article  PubMed  Google Scholar 

  22. A.J. Bennett, K.P. Lesch, A. Heils, J.C. Long, J.G. Lorenz, S.E. Shoaf, M. Champoux, S.J. Suomi, M.V. Linnoila, J.D. Higley, Mol. Psychiat. 7(1), 118 (2002)

    Article  Google Scholar 

  23. M. Champoux, A. Bennett, C. Shannon, J.D. Higley, K.P. Lesch, S.J. Suomi, Mol. Psychiat. 7(10), 1058 (2002)

    Article  Google Scholar 

  24. C.L. Bethea, J.M. Streicher, K. Coleman, F.K. Pau, R. Moessner, J.L. Cameron, Behav. Genet. 34(3), 295 (2004)

    Article  PubMed  Google Scholar 

  25. C.S. Barr, T.K. Newman, C. Shannon, C. Parker, R.L. Dvoskin, M.L. Becker, M. Schwandt, M. Champoux, K.P. Lesch, D. Goldman, S.J. Suomi, J.D. Higley, Biol. Psychiat. 55(7), 733 (2004)

    Article  PubMed  Google Scholar 

  26. C.S. Barr, T.K. Newman, S. Lindell, C. Shannon, M. Champoux, K.P. Lesch, S.J. Suomi, D. Goldman, J.D. Higley, Arch. Gen. Psychiat. 61(11), 1146 (2004)

    Article  PubMed  Google Scholar 

  27. P. Gorwood, Am. J. Pharmacogenomics 4(1), 9 (2004)

    Article  PubMed  Google Scholar 

  28. D. Sundaramurthy, L.F. Pieri, H. Gape, A.F. Markham, D.A. Campbell, Am. J. Med. Genet. 96(1), 53 (2000)

    Article  PubMed  Google Scholar 

  29. G.N. Wade, J.E. Jones, Am. J. Physiol. Regul. Integr. Comp. Physiol. 287(6), R1277–(2004)

    PubMed  Google Scholar 

  30. M.L. Walker, T.P. Gordon, M.E. Wilson, J. Med. Primatol. 11(5), 291 (1982)

    PubMed  Google Scholar 

  31. M.E. Wilson, T.P. Gordon, I.S. Bernstein, J. Med. Primatol., 7(4), 202 (1978)

    PubMed  Google Scholar 

  32. I.S. Bernstein, J. Theor. Biol. 60(2), 459 (1976)

    Article  PubMed  Google Scholar 

  33. I.S. Bernstein, T.P. Gordon, Lab. Anim. Sci. 27(4), 532 (1977)

    PubMed  Google Scholar 

  34. M.L. Walker, M.E. Wilson, T.P. Gordon, Endocrinology 114(4), 1074 (1984)

    Article  PubMed  Google Scholar 

  35. M.E. Wilson, N.S. Pope, T.P. Gordon, Biol. Reprod. 36(4), 975 (1987)

    Article  PubMed  Google Scholar 

  36. M.E. Wilson, J. Endocrinol. 158(2), 247 (1998)

    Article  PubMed  Google Scholar 

  37. M.S. Blank, T.P. Gordon, M.E. Wilson, Acta Endocrinol (Copenh) 102(2), 190 (1983)

    Google Scholar 

  38. J.D. Flory, S.B. Manuck, J.M. Perel, M.F. Muldoon, Psychopharmacology (Berl), 174(3), 376 (2004)

    Article  Google Scholar 

  39. M.F. Muldoon, R.H. Mackey, M.T. Korytkowski, J.D. Flory, B.G. Pollock, S.B. Manuck, J. Clin. Endocrinol. Metab. 91(2), 718 (2006)

    Article  PubMed  Google Scholar 

  40. N. Matsushita, Y. Kato, A. Shimatsu, H. Katakami, N. Yanaihara, H. Imura, Life. Sci. 32(11), 1263 (1983)

    Article  PubMed  Google Scholar 

  41. M.E. Wilson, K. Chikazawa, J. Fisher, D. Mook, K.G. Gould, Biol. Reprod. 71(2), 588 (2004)

    Article  PubMed  Google Scholar 

  42. U. Riserus, J. Arnlov, K. Brismar, B. Zethelius, L. Berglund, B. Vessby, Diabetes Care 27(8), 2041 (2004)

    Article  PubMed  Google Scholar 

  43. R. Whale, D.J. Quested, D. Laver, P.J. Harrison, P.J. Cowen, Psychopharmacology (Berl) 150(1), 120 (2000)

    Article  Google Scholar 

  44. C. Reist, C. Mazzanti, R. Vu, D. Tran, D. Goldman, Am. J. Med. Genet. 105(4), 363 (2001)

    Article  PubMed  Google Scholar 

  45. S.B. Manuck, J.D. Flory, R.E. Ferrell, M.F. Muldoon, Psychoneuroendocrinology 29(5), 651 (2004)

    Article  PubMed  Google Scholar 

  46. J.R. Kaplan, S.B. Manuck, T.B. Clarkson, F.M. Lusso, D.M. Taub, Arteriosclerosis 2(5), 359 (1982)

    PubMed  Google Scholar 

  47. D.H. Abbott, E.B. Keverne, F.B. Bercovitch, C.A. Shively, S.P. Mendoza, W. Saltzman, C.T. Snowdon, T.E. Ziegler, M. Banjevic, T. Garland, R.M. Sapolsky, Horm. Behav. 43(1), 67 (2003)

    Article  PubMed  Google Scholar 

  48. G.E. Torres, R.R. Gainetdinov, M.G. Caron, Nat. Rev. Neurosci. 4(1), 13 (2003)

    Article  PubMed  Google Scholar 

  49. T.A. Mathews, D.E. Fedele, F.M. Coppelli, A.M. Avila, D.L. Murphy, A.M. Andrews, J. Neurosci. Methods 140(1–2), 169 (2004)

    Article  PubMed  Google Scholar 

  50. D. Bengel, D.L. Murphy, A.M. Andrews, C.H. Wichems, D. Feltner, A. Heils, R. Mossner, H. Westphal, K.P. Lesch, Mol. Pharmacol. 53(4), 649 (1998)

    PubMed  Google Scholar 

  51. D.L. Murphy, G.R. Uhl, A. Holmes, R. Ren-Patterson, F.S. Hall, I. Sora, S. Detera-Wadleigh, K.P. Lesch, Genes Brain Behav. 2(6), 350 (2003)

    Article  PubMed  Google Scholar 

  52. A. Heils, A. Teufel, S. Petri, M. Seemann, D. Bengel, U. Balling, P. Riederer, K.P. Lesch, J. Neural. Transm. Gen. Sect. 102(3), 247 (1995)

    Article  PubMed  Google Scholar 

  53. M.J. De Souza, A.A. Luciano, J.C. Arce, L.M. Demers, A.B. Loucks, J. Appl. Physiol. 76(3), 1302 (1994)

    PubMed  Google Scholar 

  54. J. Schulkin, P.W. Gold, B.S. McEwen, Psychoneuroendocrinology, 23(3), 219 (1998)

    Article  PubMed  Google Scholar 

  55. F.G. Graeff, F.S. Guimaraes, T.G. De Andrade, J.F. Deakin, Pharmacol. Biochem. Behav. 54(1), 129 (1996)

    Article  PubMed  Google Scholar 

  56. J.B. Mitchell, W. Rowe, P. Boksa, M.J. Meaney, J. Neurosci. 10(6), 1745 (1990)

    PubMed  Google Scholar 

  57. J.P. Herman, J.G. Tasker, D.R. Ziegler, W.E. Cullinan, Pharmacol. Biochem. Behav. 71(3), 457 (2002)

    Article  PubMed  Google Scholar 

  58. C.S. Barr, T.K. Newman, M.L. Becker, C.C. Parker, M. Champoux, K.P. Lesch, D. Goldman, S.J. Suomi, J.D. Higley, Genes Brain Behav. 2(6), 336 (2003)

    Article  PubMed  Google Scholar 

  59. D. Kaufman, E.L. Smith, B.C. Gohil, M. Banerji, J.D. Coplan, J.G. Kral, L.A. Rosenblum, J. Clin. Endocrinol. Metab. 90(1), 404 (2005)

    Article  PubMed  Google Scholar 

  60. T. Thomas, B. Burguera, L.J. Melton III, E.J. Atkinson, W.M. O’Fallon, B.L. Riggs, S. Khosla, Metabolism 49(10), 1278 (2000)

    Article  PubMed  Google Scholar 

  61. D.L. Williams, D.E. Cummings, J. Nutr. 135(5), 1320 (2005)

    PubMed  Google Scholar 

  62. L. Briatore, G. Andraghetti, R. Cordera, Nutr. Metab. Cardiovasc. Dis. 16(7), 471 (2006)

    Article  PubMed  Google Scholar 

  63. S.C. Woods, Am. J. Physiol. Gastrointest. Liver Physiol 286(1), G7 (2004)

    Article  PubMed  Google Scholar 

  64. D. Richard, Q. Lin, E. Timofeeva, Eur. J. Pharmacol. 440(2–3), 189 (2002)

    Article  PubMed  Google Scholar 

  65. L.K. Heisler, M.A. Cowley, T. Kishi, L.H. Tecott, W. Fan, M.J. Low, J.L. Smart, M. Rubinstein, J.B. Tatro, J.M. Zigman, R.D. Cone, J.K. Elmquist, Ann. N. Y. Acad. Sci. 994, 169 (2003)

    Article  PubMed  Google Scholar 

  66. J.C. Halford, J.A. Harrold, C.L. Lawton, J.E. Blundell, Curr. Drug. Targets 6(2), 201 (2005)

    PubMed  Google Scholar 

  67. V. Hainer, K. Kabrnova, B. Aldhoon, M. Kunesova, M. Wagenknecht, Ann. N. Y. Acad. Sci. 1083, 252 (2006)

    Article  PubMed  Google Scholar 

  68. S. Matsushita, K. Suzuki, M. Murayama, N. Nishiguchi, A. Hishimoto, A. Takeda, O. Shirakawa, S. Higuchi, Am. J. Med. Genet. B. Neuropsychiat. Genet. 128(1), 114 (2004)

    Article  Google Scholar 

  69. R.E. Urwin, B.H. Bennetts, B. Wilcken, P.J. Beumont, J.D. Russell, K.P. Nunn, Neuropsychopharmacology 28(7), 1351 (2003)

    Article  PubMed  Google Scholar 

  70. C.L. Bethea, F.K. Pau, S. Fox, D.L. Hess, S.L. Berga, J.L. Cameron, Fertil. Steril. 83(1), 148 (2005)

    Article  PubMed  Google Scholar 

  71. C.L. Bethea, J.M. Streicher, S.J. Mirkes, R.L. Sanchez, A.P. Reddy, J.L. Cameron, Neuroscience 132(1), 151 (2005)

    Article  PubMed  Google Scholar 

  72. M.P. Warren, J.L. Fried, Endocrinol. Metab. Clin. North. Am. 30(3), 611 (2001)

    Article  PubMed  Google Scholar 

  73. C.K. Welt, J.L. Chan, J. Bullen, R. Murphy, P. Smith, A.M. DePaoli, A. Karalis, C.S. Mantzoros, N. Engl. J. Med. 351(10), 987 (2004)

    Article  PubMed  Google Scholar 

  74. K.M. Breen, F.J. Karsch, Endocrinology 145(2), 692 (2004)

    Article  PubMed  Google Scholar 

  75. M. Ferin, J. Clin. Endocrinol. Metab. 84(6), 1768 (1999)

    Article  PubMed  Google Scholar 

  76. P.D. Finn, M.J. Cunningham, K.Y. Pau, H.G. Spies, D.K. Clifton, R.A. Steiner, Endocrinology 139(11), 4652 (1998)

    Article  PubMed  Google Scholar 

  77. P.D. Finn, M.J. Cunningham, D.G. Rickard, D.K. Clifton, R.A. Steiner, J. Clin. Endocrinol. Metab. 86(1), 422 (2001)

    Article  PubMed  Google Scholar 

  78. S.D. Sullivan, L.C. Howard, A.H. Clayton, S.M. Moenter, Biol. Reprod. 66(6), 1702 (2002)

    Article  PubMed  Google Scholar 

  79. C.S. Barr, T.K. Newman, M. Schwandt, C. Shannon, R.L. Dvoskin, S.G. Lindell, J. Taubman, B. Thompson, M. Champoux, K.P. Lesch, D. Goldman, S.J. Suomi, J.D. Higley, Proc. Natl. Acad. Sci. U. S. A. 101(33), 12358 (2004)

    Article  PubMed  Google Scholar 

  80. J.R. Kaplan, S.B. Manuck, ILAR 45, 89 (2004)

    Google Scholar 

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Acknowledgments

The technical assistance of Jeff Fisher, Juliet Brown, and the Yerkes NPRC Biomarkers Core Lab is greatly appreciated. This work was supported by HD46501 and, in part, RR00165. The Yerkes NPRC is fully accredited by the American Association of Laboratory Animal Care International.

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Hoffman, J.B., Kaplan, J.R., Kinkead, B. et al. Metabolic and reproductive consequences of the serotonin transporter promoter polymorphism (5-HTTLPR) in adult female rhesus monkeys (Macaca mulatta) . Endocr 31, 202–211 (2007). https://doi.org/10.1007/s12020-007-0017-8

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