Genetic and environmental determinants of stress responding

Alcohol Research: Current Reviews

Volumn 34, Issue 4, 2012, Pages 484-494

  Clarke, Toni Kim ^a   Nymberg, Charlotte ^b   Schumann, Gunter ^b  

^a UNIVERSITY OF PENNSYLVANIA   (United States)

^b KING'S COLLEGE LONDON   (United Kingdom)

Author keywords

Alcohol and other drug use initiation; Alcohol dependence; Alcohol use and abuse; Alcoholism; Animal studies; Biological development; Brain; Corticotropin releasing factor system; Environmental factors; Genetic factors; Human studies; Hypothalamic pituitary adrenal axis; Literature review; Neurobiology; Risk factors; Stress; Stress response

Indexed keywords

DOPAMINE;

ANIMAL; BRAIN; GENETICS; GENOTYPE ENVIRONMENT INTERACTION; HUMAN; MENTAL STRESS; PATHOPHYSIOLOGY; PHYSIOLOGY; REVIEW; RISK FACTOR; SOCIAL ENVIRONMENT;

ANIMALS; BRAIN; DOPAMINE; GENE-ENVIRONMENT INTERACTION; HUMANS; RISK FACTORS; SOCIAL ENVIRONMENT; STRESS, PSYCHOLOGICAL;

EID: 84870041146     PISSN: 21683492     EISSN: 21694796     Source Type: Journal    
DOI: None     Document Type: Review

References (99)

1. Ariza Cardenal, C., and Nebqt Adell, M. Factors associated with problematic alcohol consumption in schoolchil-dren. Journal of Adolescent Health 27:425-433, 2000. PMiD: 11090745
2. Armbruster, D.; Mueller, A.; Moser, D.A.; et al. Interaction effect of D4 dopamine receptor gene and serotonin transporter promoter polymorphism on the cortisol stress response. Behavioral Neuroscience 123:1288-1295, 2009. PMiD: 20001112
3. Badanich, K.A.; Maldonado, A.M.; and Kirstein, C. L. Chronic ethanol exposure during adolescence increases basal dopamine in the nucleus accumbens septi during adulthood. Alcoholism: Clinical and Experimental Research 31:895-900, 2007. PMiD: 17391340
4. Barbier, E.; Houchi, H.; Warnault, V.; et al. Effects of prena-tal and postnatal maternal ethanol on offspring response to alcohol and psychostimulants in Long Evans rats. Neuroscience 161:427-440, 2009. PMiD: 19348874
5. Barr, C.S., and Goldman, D. Non-human primate models of inheritance vulnerability to alcohol use disorders. Addiction Biology 11:374-385, 2006. PMiD: 16961765
6. Barr, C.S.; Schwandt, M.; Lindell, S.G.; et al. Association of a functional polymorphism in the mu-opioid receptor gene with alcohol response and consumption in male rhesus macaques. Archives of General Psychiatry 64:369-376, 2007. PMiD: 17339526
7. Barr, C.S.; Schwandt, M.L.; Lindell, S.G.; etal. Variation at the mu-opioid receptor gene (OPRM1) influences attachment behavior in infant primates. Proceedings of the National Academy of Sciences of the United States of America 105:5277-5281, 2008. PMiD: 18378897
8. Bava, S., and Tapert, S.F. Adolescent brain development and the risk for alcohol and other drug problems. Neuropsychology Review 20:398-413, 2010. PMiD: 20953990
9. Bjorntorp, P. Do stress reactions cause abdominal obe-sity and comorbidities? Obesity Reviews 2:73-86, 2001. PMiD: 12119665
10. Blomever, D.; Treutlein, J.; Esser, G.; et al. Interaction between CRHR1 gene and stressful life events predicts adolescent heavy alcohol use. Biological Psychiatry 63:146-151, 2008. PMiD: 17597588
11. Campbell, J.C.; Szumlinski, K.K.; and Kippin, T.E. Contribution of early environmental stress to alcoholism vulnerability. Alcohol 43:547-554, 2009. PMiD: 19913199
12. Clarke, T.K.; Dempster, E.; Dochertv, S.J.; et al. Multiple polymorphisms in genes of the adrenergic stress system confer vulnerability to alcohol abuse. Addiction Biology 17:202-208, 2012. PMiD: 21070505
13. Clarke, T.K.; Laucht, M.; Ridinger, M.; et al. KCNJ6 is asso-ciated with adult alcohol dependence and involved in gene X early life stress interactions in adolescent alco-hol drinking. Neuropsychopharmacology 36:1142-1148, 2011. PMiD: 21307845
14. Copeland, W.E.; Sun, H.; Costello, E.J.; et al. Child mu- opioid receptor gene variant influences parent-child relations. Neuropsychopharmacology 36:1165-1170, 2011.PMID: 21326192
15. Desrivieres, S.; Lourdusamv, A.; Muller, C.; etal. Glucocorticoid receptor (NR3C1) gene polymorphisms and onset of alcohol abuse in adolescents. Addiction Biology 16:510-513, 2011. PMiD: 20731635
16. Di Chiara, G., and Imperato, A. Drugs abused by humans preferentially increase synaptic dopamine concentra-tions in the mesolimbic system of freely moving rats. Proceedings of the National Academy of Sciences of the United States of America 85:5274-5278, 1988. PMiD: 2899326
17. Diana, M.; Pistis, M.; Carboni, S.; et al. Profound decrement of mesolimbic dopaminergic neuronal activity during ethanol withdrawal syndrome in rats: Electrophysiological and biochemical evidence. Proceedings of the National Academy of Sciences of the United States of America 90:7966-7969, 1993. PMiD: 8367449
18. Dick, D.M.; Pagan, J.L.; Viken, R.; etal. Changing environ-mental influences on substance use across develop-ment. Twin Research and Human Genetics 10:315-326, 2007. PMiD: 17564520
19. Dillon, D.G.; Holmes, A.J.; Birk, J.L.; et al. Childhood adversity is associated with left basal ganglia dysfunc-tion during reward anticipation in adulthood. Biological Psychiatry 66:206-213, 2009. PMiD: 19358974
20. Ducci, F.; Rov, A.; Shen, P.H.; et al. Association of sub-stance use disorders with childhood trauma but not African genetic heritage in an African American cohort. American Journal of Psychiatry 166:1031-1040, 2009. PMiD: 19605534
21. Enoch, M.A.; Hodgkinson, C.A.; Vuan, Q.; et al. The influ-ence of GABRA2, childhood trauma, and their interac-tion on alcohol, heroin, and cocaine dependence. Biological Psychiatry 67:20-27, 2010. PMiD: 19833324
22. Fahlke, C.; Engel, J.A.; Eriksson, C.J.; et al. Involvement of corticosterone in the modulation of ethanol consumption in the rat. Alcohol 11:195-202, 1994.PMID: 8060519
23. Fahlke, C.; Lorenz, J.G.; Long, J.; et al. Rearing experi-ences and stress-induced plasma cortisol as early risk factors for excessive alcohol consumption in nonhuman primates. Alcoholism: Clinical and Experimental Research 24:644-650, 2000. PMiD: 10832905
24. Finley, J.C., Jr.; o-'Leary, M.; wester, D.; et al. A genetic polymorphism of the alpha2-adrenergic receptor increas-es autonomic responses to stress. Journal of Applied Physiology 96:2231-2239, 2004. PMiD: 14742450
25. Flint, J., and Munafo, M.R. Forum: Interactions between gene and environment. Current Opinion in Psychiatry 21:315-317, 2008. PMiD: 18520729
26. Fullgrabe, M.W.; Vengeliene, V.; and Spanagel, R. influence of age at drinking onset on the alcohol deprivation effect and stress-induced drinking in female rats. Pharmacology, Biochemistry, and Behavior 86:320-326, 2007. PMiD: 17098280
27. Gass, J.T., and Olive, M.F. Glutamatergic substrates of drug addiction and alcoholism. Biochemical Pharmacology 75:218-265, 2008. PMiD: 17706608
28. George, D.T.; Gilman, J.; Hersh, J.; et al. Neurokinin 1 recep-tor antagonism as a possible therapy for alcoholism. Science 319:1536-1539, 2008. PMiD: 18276852
29. Giedd, J.N. The anatomy of mentalization: A view from developmental neuroimaging. Bulletin of the Menninger Clinic 67:132-142, 2003. PMiD: 14604098
30. Gower, W.R., Jr. Mechanism of glucocorticoid action. Journal of the Florida Medical Association 80:697-700,PMiD: 8270904
31. Grant, B.F., and Dawson, D.A. Age at onset of alcohol use and its association with DSM-IV alcohol abuse and dependence: Results from the National Longitudinal Alcohol Epidemiologic Survey. Journal of Substance Abuse 9:103-110, 1997. PMiD: 9494942
32. Gresch, P.J.; Sved, A.F.; Zigmond, M.J.; and Finlay, J. M. Stress-induced sensitization of dopamine and nore-pinephrine efflux in medial prefrontal cortex of the rat. Journal of Neurochemistry 63:575-583, 1994. PMiD: 8035182
33. Habib, K.E.; Gold, P.W.; and Chrousos, G. P. Neuro-endocrinology of stress. Endocrinology and Metabolism Clinics of North America 30:695-728, 2001. PMiD: 11571937
34. Hawkins, J.D.; Graham, J.W.; Maguin, E.; et al. Exploring the effects of age of alcohol use initiation and psy-chosocial risk factors on subsequent alcohol misuse. Journal of Studies on Alcohol 58:280-290, 1997. PMiD: 9130220
35. Heath, A.C.; Bucholz, K.K.; Madden, P.A.; et al. Genetic and environmental contributions to alcohol dependence risk in a national twin sample: Consistency of findings in women and men. Psychological Medicine 27:1381-1396, 1997. PMiD: 9403910
36. Hopfer, C.J.; Crowley, T.J.; and Hewitt, J.K. Review of twin and adoption studies of adolescent substance use. Journal of the American Academy of Child and Adolescent Psychiatry 42:710-719, 2003. PMiD: 12921479
37. Huizenga, N.A.; Koper, J.W.; De Lange, P.; etal. A polymor-phism in the glucocorticoid receptor gene may be asso-ciated with an increased sensitivity to glucocorticoids in vivo. Journal of Clinical Endocrinology and Metabolism 83:144-151, 1998. PMiD: 9435432
38. Jahng, J.W.; Ryu, V.; Yoo, S.B.; et al. Mesolimbic dopaminergic activity responding to acute stress is blunted in adolescent rats that experienced neonatal maternal separation. Neuroscience 171:144-152, 2010. PMiD:20828601
39. Kalsbeek, A.; Voorn, P.; Buijs, R.M.; et al. Development of the dopaminergic innervation in the prefrontal cortex of the rat. Journal of Comparative Neurology 269:58-72, 1988. PMiD: 3361004
40. Karvonen, S. Regional differences in drinking among Finnish adolescents. Addiction 90:57-64, 1995. PMiD: 7888980
41. Kendler, K.S.; Gardner, C.; and Dick, D.M. Predicting alco-hol consumption in adolescence from alcohol-specific and general externalizing genetic risk factors, key envi-ronmental exposures and their interaction. Psychological Medicine 41:1507-1516, 2011. PMiD: 20942993
42. Koob, G.F. A role for brain stress systems in addiction. Neuron 59:11-34, 2008. PMiD: 18614026.
43. Koob, G.F. The role of CRF and CRF-related peptides in the dark side of addiction. Brain Research 1314:3-14, 2010. PMiD: 19912996
44. Koob, G.F., and Le Moal, M. Addiction and the brain antireward system. Annual Review of Psychology 59:29-53, 2008. PMiD: 18154498
45. Kuzhikandathil, E.V.; Yu, W.; and Oxford, G.S. Human dopamine D3 and D2L receptors couple to inward recti-fier potassium channels in mammalian cell lines. Molecular and Cellular Neurosciemces 12:390-402, 1998. PMiD: 9888991
46. Latendresse, S.J.; Rose, R.J.; Viken, R.J.; et al. Parenting mechanisms in links between parents-' and adolescents-' alcohol use behaviors. Alcoholism: Clinical and Experimental Research 32:322-330, 2008. PMiD: 1162066
47. Laucht, M.; Treutlein, J.; Schmid, B.; et al. impact of psy-chosocial adversity on alcohol intake in young adults: Moderation by the LL genotype of the serotonin trans-porter polymorphism. Biological Psychiatry 66:102-109, 2009. PMiD: 19358979
48. Le, A.D.; Harding, S.; Juzytsch, W.; et al. The role of corti- cotrophin-releasing factor in stress-induced relapse to alcohol-seeking behavior in rats. Psychopharmacology (Berlin) 150:317-324, 2000. PMiD: 10923760
49. Linkowski, p.; Van Onderbergen, a.; Kerkhofs, M.; et al.Twin study of the 24-h cortisol profile: Evidence for genetic control of the human circadian clock. American Journal of Physiology 264(2 Pt. 1):E173-E181, 1993. PMiD: 8447383
50. Malcolm, R.J. GABA systems, benzodiazepines, and sub-stance dependence. Journal of Clinical Psychiatry 64(Suppl. 3):36-40, 2003. PMiD: 12662132
51. McGue, M.; Elkins, I.; and Iacono, W.G. Genetic and envi-ronmental influences on adolescent substance use and abuse. American Journal Medical Genetics 96:671-677, 2000. PMiD: 11054776
52. Meikle, A.W.; Stringham, J.D.; Woodward, M.G.; and Bishop, D.T. Heritability of variation of plasma cortisol levels. Metabolism 37:514-517, 1988. PMiD: 2967419
53. Moffitt, T.E. Adolescence-limited and life-course-persis-tent antisocial behavior: A developmental taxonomy. Psychological Review 100:674-701, 1993. PMiD: 8255953
54. Moffitt, T.E.; Caspi, A.; Harrington, H.; and Milne, B.J. Males on the life-course-persistent and adolescence-lim-ited antisocial pathways: Follow-up at age 26 years. Development and Psychopathology 14:179-207, 2002.PMiD:11893092
55. Nelson, E.C.; Agrawal, A.; Pergadia, M.L.; et al. H2 haplo-type at chromosome 17q21.31 protects against child-hood sexual abuse-associated risk for alcohol consump-tion and dependence. Addiction Biology 15:1-11, 2010. PMiD: 19878140
56. Newman, T.K.; Parker, C.C.; Suomi, S.J.; et al. DRD1 5-'UTR variation, sex and early infant stress influence ethanol consumption in rhesus macaques. Genes, Brain, and Behavior 8:626-630, 2009. PMiD: 19563515
57. Ortiz, j.; Fitzgerald, L.W.; Lane, s.; et al. Biochemical adaptations in the mesolimbic dopamine system in response to repeated stress. Neuropsychopharmacology 14:443-452, 1996. PMiD: 8726755
58. Oslin, D.W.; Berrettini, W.; Kranzler, H.R.; et al. A func-tional polymorphism of the mu-opioid receptor gene is associated with naltrexone response in alcohol-depen-dent patients. Neuropsychopharmacology 28:1546-1552, 2003. PMiD: 12813472
59. Oswald, L.M., and Wand, G.S. Opioids and alcoholism. Physiology & Behavior 81:339-358, 2004. PMiD: 15159175
60. Pagan, J.L.; Rose, R.J.; Viken, R.J.; etal. Genetic and envi-ronmental influences on stages of alcohol use across adolescence and into young adulthood. Behavior Genetics 36:483-497, 2006. PMiD: 16586152
61. Pascual, M.; Boix, J.; Felipo, V.; and Guerri, C. Repeated alcohol administration during adolescence causes changes in the mesolimbic dopaminergic and gluta- matergic systems and promotes alcohol intake in the adult rat. Journal of Neurochemistry 108:920-931,PMiD: 19077056
62. Peters, J.; Bromberg, U.; Schneider, S.; et al. Lower ventral striatal activation during reward anticipation in adoles-cent smokers. American Journal of Psychiatry 168:540-549, 2011. PMiD: 21362742
63. Philpot, R., and Kirstein, C. Developmental differences in the accumbal dopaminergic response to repeated ethanol exposure. Annals of the New York Academy of Sciences 1021:422-426, 2004. PMiD: 15251921
64. Piazza, P.V.; Rouge-Pont, F.; Deminiere, J.M.; etal. Dopaminergic activity is reduced in the prefrontal cortex and increased in the nucleus accumbens of rats predis-posed to develop amphetamine self-administration.Brain Research 567:169-174, 1991. PMiD: 1726140
65. Pilowsky, D.J.; Keyes, K.M.; and Hasin, D.S. Adverse child-hood events and lifetime alcohol dependence. American Journal of Public Health 99:258-263, 2009. PMiD: 19059847
66. Prescott, C.A., and Kendler, K.S. Genetic and environ-mental contributions to alcohol abuse and dependence in a population-based sample of male twins. American Journal of Psychiatry 156:34-40, 1999. PMID:9892295
67. Ramchandani, V.A.; Umhau, J.; Pavon, F.J.; et al. A genetic determinant of the striatal dopamine response to alco-hol in men. Molecular Psychiatry 16:809-817, 2011. PMiD: 20479755
68. Ray, L.A., and Hutchison, K.E. A polymorphism of the mu- opioid receptor gene (OPRM1) and sensitivity to the effects of alcohol in humans. Alcoholism: Clinical and Experimental Research 28:1789-1795, 2004. PMiD: 15608594
69. Rivier, C. Alcohol stimulates ACTH secretion in the rat: Mechanisms of action and interactions with other stim-uli. Alcoholism: Clinical and Experimental Research 20:240-254, 1996. PMiD: 8730214
70. Rivier, C., and Lee, S. Acute alcohol administration stimu-lates the activity of hypothalamic neurons that express corticotropin-releasing factor and vasopressin. Brain Research 726:1-10, 1996. PMiD: 8836539
71. Robinson, T.E., and Berridge, K.C. The neural basis of drug craving: An incentive-sensitization theory of addiction. Brain Research. Brain Research Reviews 18:247-291,PMID: 8401595
72. Rodrigues, A.J.; Leao, P.; Carvalho, M et al. Potential pro-gramming of dopaminergic circuits by early life stress. Psychopharmacology (Berlin) 214:107-120, 2011. PMiD: 21088961
73. Rosenberg, D.R., and Lewis, D.A. Changes in the dopamin-ergic innervation of monkey prefrontal cortex during late postnatal development: A tyrosine hydroxylase immuno- histochemical study. Biological Psychiatry 36:272-277, 2005 PMID: 7986893
74. Saccone, S.F.; Hinrichs, A.L.; Saccone, N.L.; et al. Cholinergic nicotinic receptor genes implicated in a nicotine dependence association study targeting 348 candidate genes with 3713 sNPs. Human Molecular Genetics 16:36-49, 2007. PMiD: 17135278.
75. Schein, J.C.; Hunter, D.D.; and Roffler-Tarlov, S. Girk2 expression in the ventral midbrain, cerebellum, and olfactory bulb and its relationship to the murine muta-tion weaver. Developmental Biology 204:432-450, 1998.PMID: 9882481
76. schmid, B.; Blomeyer, D.; Becker, K. et al. The interaction between the dopamine transporter gene and age at onset in relation to tobacco and alcohol use among 19- year-olds. Addiction Biology 14:489-499, 2009. PMiD: 19740369
77. Schmid, B.; Blomeyer, D.; Treutlein, J. et al. Interacting effects of CRHR1 gene and stressful life events on drink-ing initiation and progression among 19-year-olds. International Journal of Neuropsychopharmacology 13:703-714, 2010. PMiD: 19607758
78. Schuckit, M.A.; Anthenelli, R.M.; Bucholz, K.K. et al. The time course of development of alcohol-related problems in men and women. Journal of Studies on Alcohol 56:218-225, 1995. PMiD: 7760569
79. Schumann, G.; Loth, E.; Banaschewski, T. et al. The IMA-GEN study: Reinforcement-related behaviour in normal brain function and psychopathology. Molecular Psychiatry 15:1128-1139, 2010. PMiD: 21102431
80. Shaham, Y., and stewart, J. Exposure to mild stress enhances the reinforcing efficacy of intravenous heroin self-administration in rats. Psychopharmacology (Berlin) 114:523-527, 1994. PMiD: 7855213
81. Siegmund, s.; Vengeliene, V.; singer, M.V., and spanagel, R. Influence of age at drinking onset on long-term ethanol self-administration with deprivation and stress phases. Alcoholism: Clinical and Experimental Research 29:1139-1145, 2005. PMiD: 16046868
82. Simons, S.S., Jr.; Oshima, H.; and szapary, D. Higher levels of control: Modulation of steroid hormone-regulated gene transcription. Molecular Endocrinology 6:995-1002, 1992. PMiD: 1324423
83. Soderpalm, B.; Lof, E.; and Ericson, M. Mechanistic stud-ies of ethanol-'s interaction with the mesolimbic dopamine reward system. Pharmacopsychiatry 42(suppl. 1): s87-s94, 2009. PMiD: 19434560
84. Spanagel, R. Alcoholism: A systems approach from molecular physiology to addictive behavior. Physiology Reviews 89:649-705, 2009. PMiD: 19342616
85. Spear, L.P. The adolescent brain and age-related behav-ioral manifestations. Neuroscience and Biobehavioral Reviews 24:417-463, 2000. PMiD: 10817843
86. Stevens, A.; Ray, D.W.; Zeggini, E. et al. Glucocorticoid sensitivity is determined by a specific glucocorticoid receptor haplotype. Journal of Clinical Endocrinology and Metabolism 89:892-897, 2004. PMiD: 14764810
87. Swanson, L.W.; sawchenko, P.E.; Rivier, J.; and Vale, W.W. Organization of ovine corticotropin-releasing factor immunoreactive cells and fibers in the rat brain: An immunohistochemical study. Neuroendocrinology 36:165-186. 1983. PMiD: 6601247
88. szot, P.; White, s.s.; Veith, R.C.; and Rasmussen, D.D. Reduced gene expression for dopamine biosynthesis and transport in midbrain neurons of adult male rats exposed prenatally to ethanol. Alcoholism: Clinical and Experimental Research 23:1643-1649, 1999. PMiD: 10549997
89. Treutlein, J.; Kissling, C.; Frank, J. et al. Genetic associa-tion of the human corticotropin releasing hormone receptor 1 (CRHR1) with binge drinking and alcohol intake patterns in two independent samples. Molecular Psychiatry 11:594-602, 2006. 16550213
90. Tupala, E., and Tiihonen, J. Dopamine and alcoholism: Neurobiological basis of ethanol abuse. Progress in Neuro-psychopharmacology & Biological Psychiatry 28:1221-1247, 2004. PMiD: 15588749
91. Uhart, M., and Wand, G.S. Stress, alcohol and drug inter-action: An update of human research. Addiction Biology 14:43-64, 2009. PMiD: 18855803
92. Uhart, M.; Oswald, L.; McCaul, M.E. et al. Hormonal responses to psychological stress and family history of alcoholism. Neuropsychopharmacology 31:2255-2263, 2006. PMiD: 16554744
93. Waltman, C.; McCaul, M.E.; and Wand, G.S. Adrenocorticotropin responses following administration of ethanol and ovine corticotropin-releasing hormone in the sons of alcoholics and control subjects. Alcoholism: Clinical and Experimental Research 18:826-830, 1994. 7978091
94. Weiss, F.; Parsons, L.H.; Schulteis, G. et al. Ethanol self-administration restores withdrawal-associated deficien-cies in accumbal dopamine and 5-hydroxytryptamine release in dependent rats. Journal of Neuroscience 16:3474-3485, 1996. PMiD: 8627380
95. Wu, P.; Bird, H.R.; Liu, X.; et al. Trauma, posttraumatic stress symptoms, and alcohol-use initiation in children. Journal of Studies on Alcohol and Drugs 71:326-334,PMID: 20409425
96. Wust, S.; van Rossum, E.F.; Federenko, I.S.; et al. Common polymorphisms in the glucocorticoid receptor gene are associated with adrenocortical responses to psychoso-cial stress. Journal of Clinical Endocrinology and Metabolism 89:565-573, 2004. PMiD: 14764763
97. Zhang, H.; Kranzler, H.R.; Weiss, R.D.; etal. Pro-opiome- lanocortin gene variation related to alcohol or drug dependence: Evidence and replications across family- and population-based studies. Biological Psychiatry 66:128-136, 2009. PMiD: 19217079
98. Zimmermann, U.; spring, K.; Kunz-Ebrecht, S.R.; et al. Effect of ethanol on hypothalamic-pituitary-adrenal system response to psychosocial stress in sons of alcohol- dependent fathers. Neuropsychopharmacology 29:1156-1165, 2004a. PMiD: 15100697
99. Zimmermann, U.; spring, K.; Wittchen, H.U.; et al. Arginine vasopressin and adrenocorticotropin secretion in response to psychosocial stress is attenuated by ethanol in sons of alcohol-dependent fathers. Journal of Psychiatric Research 38:385-393, 2004b. PMiD: 15203290