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Vol. 31, No. 1-2, 2009
Issue release date: April 2009
Free Access
Dev Neurosci 2009;31:23–35
(DOI:10.1159/000207491)

Third Pathophysiology of Prenatal Cocaine Exposure

Lester B.M. · Padbury J.F.
Warren Alpert Medical School of Brown university, Women and Infants’ Hospital of Rhode Island, Providence, R.I., USA
email Corresponding Author

Abstract

The pathophysiology of the effects of cocaine on fetal development has been described along 2 major pathways: neurochemical effects and vasoconstrictive effects. Following a summary of these effects, we suggest a ‘third pathophysiology’ in which altered fetal programming affects the acute and long-term adverse effects of in utero cocaine exposure. We describe how cocaine as a stressor alters the expression of key candidate genes, increasing exposure to catecholamines and fetal cortisol-altering neuroendocrine (hypothalamic-pituitary-adrenal axis) activity, leading to infant behavioral dysregulation, poor behavioral control and emotion regulation during childhood and phenotypes that confer vulnerability to substance use in adolescence. This model is discussed in relation to follow-up studies of the effects of in utero cocaine exposure and maturational changes in brain development.


 goto top of outline Key Words

  • In utero cocaine exposure
  • Fetal programming
  • Neuroendocrine
  • Stress
  • Behavioral outcome

 goto top of outline Abstract

The pathophysiology of the effects of cocaine on fetal development has been described along 2 major pathways: neurochemical effects and vasoconstrictive effects. Following a summary of these effects, we suggest a ‘third pathophysiology’ in which altered fetal programming affects the acute and long-term adverse effects of in utero cocaine exposure. We describe how cocaine as a stressor alters the expression of key candidate genes, increasing exposure to catecholamines and fetal cortisol-altering neuroendocrine (hypothalamic-pituitary-adrenal axis) activity, leading to infant behavioral dysregulation, poor behavioral control and emotion regulation during childhood and phenotypes that confer vulnerability to substance use in adolescence. This model is discussed in relation to follow-up studies of the effects of in utero cocaine exposure and maturational changes in brain development.

Copyright © 2009 S. Karger AG, Basel


 goto top of outline References
  1. Shurtleff D, Ferre S: Sponsor’s foreword (editorial). ScientificWorldJournal 2007;7 (suppl 2):1–3.
  2. Schenker S, Yang Y, Johnson RF, et al: The transfer of cocaine and its metabolites across the term human placenta. Clin Pharmacol Ther 1993;53:329–339.
  3. Gawin FH, Ellinwood EH Jr: Cocaine and other stimulants: actions, abuse, and treatment. N Engl J Med 1988;318:1173–1182.
  4. Wise R: Neural Mechanisms of the Reinforcing Action of Cocaine. NIDA Research Monograph 50. Rockville, National Institute on Drug Abuse, 1984, pp 15–33.
  5. Goodman L: The Pharmacological Basis of Therapeutics. New York, MacMillan, 1985.
  6. Bzoskie L, Blount L, Kashiwai K, Humme J, Padbury J: The contribution of transporter-dependent uptake to fetal catecholamine clearance. Biol Neonate 1997;71:102–110.
  7. Lau C, Burke S, Slotkin T: Maturation of sympathetic neurotransmission in the rat heart. IX. Development of transsynaptic regulation of cardiac adrenergic sensitivity. J Pharmacol Exp Ther 1982;223:675–680.
  8. Padbury JF, Ludlow JK, Humme JA, Agata Y: Metabolic clearance and plasma appearance rates of catecholamines in preterm and term fetal sheep. Pediatr Res 1986;20:992–995.
  9. Stein H, Oyama K, Martinez A, Chappell B, Padbury J: Plasma epinephrine appearance and clearance rates in fetal and newborn sheep. Am J Physiol 1993;265(part 2):R756–R760.
  10. NIDA: Mechanisms of Cocaine Abuse and Toxicity. Rockville, National Institute on Drug Abuse, 1988.
  11. Kalivas PW, Duffy P, DuMars LA, Skinner C: Behavioral and neurochemical effects of acute and daily cocaine administration in rats. J Pharmacol Exp Ther 1988;245:485–492.
  12. Peris J, Boyson SJ, Cass WA, et al: Persistence of neurochemical changes in dopamine systems after repeated cocaine administration. J Pharmacol Exp Ther 1990;253:38–44.
  13. Kalivas P, Duffy P: Effect of acute and daily cocaine treatment on extracellular dopamine in the nucleus accumbens. Synapse 1990;5:48–58.
  14. Steketee JD, Striplin CD, Murray TF, Kalivas PW: Possible role for G-proteins in behavioral sensitization to cocaine. Brain Res 1991;545:287–291.
  15. Arai S, Morita K, Kitayama S, et al: Chronic inhibition of the norepinephrine transporter in the brain participates in seizure sensitization to cocaine and local anesthetics. Brain Res 1993;964:83–90.
  16. Mead AN, Rocha BA, Donovan DM, Katz JL: Intravenous cocaine induced-activity and behavioural sensitization in norepinephrine-, but not dopamine-transporter knockout mice. Eur J Neurosci 2002;16:514–520.
  17. Kreek MJ: Cocaine, dopamine and the endogenous opioid system. J Addict Dis 1996;15:73–96.
  18. Shippenberg TS, Rea W: Sensitization to the behavioral effects of cocaine: modulation by dynorphin and kappa-opioid receptor agonists. Pharmacol Biochem Behav 1997;57:449–455.
  19. White FJ, Hu XT, Zhang XF, Wolf ME: Repeated administration of cocaine or amphetamine alters neuronal responses to glutamate in the mesoaccumbens dopamine system. J Pharmacol Exp Ther 1995;273: 445–454.
  20. Ye JH, Liu PL, Wu WH, McArdle JJ: Cocaine depresses GABAA current of hippocampal neurons. Brain Res 1997;770(1–2):169–175.
  21. Garg UC, Turndorf H, Bansinath M: Effect of cocaine on macromolecular syntheses and cell proliferation in cultured glial cells. Neuroscience 1993;57:467–472.
  22. Nassogne MC, Evrard P, Courtoy PJ: Selective neuronal toxicity of cocaine in embryonic mouse brain cocultures. Proc Natl Acad Sci USA 1995;92:11029–11033.
  23. Nassogne MC, Evrard P, Courtoy PJ: Selective direct toxicity of cocaine on fetal mouse neurons: teratogenic implications of neurite and apoptotic neuronal loss. Ann NY Acad Sci 1998;846:51–68.
  24. Akbari HM, Whitaker-Azmitia PM, Azmitia EC: Prenatal cocaine decreases the trophic factor S-100 beta and induced microcephaly: reversal by postnatal 5-HT1A receptor agonist. Neurosci Lett 1994;170:141–144.
  25. Gressens P, Gofflot F, Van Maele-Fabry G, et al: Early neurogenesis and teratogenesis in whole mouse embryo cultures: histochemical, immunocytological and ultrastructural study of the premigratory neuronal-glial units in normal mouse embryo and in mouse embryos influenced by cocaine and retinoic acid. J Neuropathol Exp Neurol 1992;51:206–219.
  26. Gressens P, Kosofsky BE, Evrard P: Cocaine-induced disturbances of corticogenesis in the developing murine brain. Neurosci Lett 1992;140:113–116.
  27. Yablonsky-Alter E, Gleser I, Carter C, Juvan M: Effects of prenatal cocaine treatment on postnatal development of neocortex in white mice: immunocytochemistry of calbindin- and paralbumin-positive populations of GABAergic neurons. Soc Neurosci Abstr 1992;18:367.
  28. Steiner H, Gerfen CR: Dynorphin opioid inhibition of cocaine-induced, D1 dopamine receptor-mediated immediate-early gene expression in the striatum. J Comp Neurol 1995;353:200–212.
  29. Steiner H, Gerfen CR: Cocaine-induced c-fos messenger RNA is inversely related to dynorphin expression in striatum. J Neurosci 1993;13:5066–5081.
  30. Bhat RV, Baraban JM: Activation of transcription factor genes in striatum by cocaine: role of both serotonin and dopamine systems. J Pharmacol Exp Ther 1993;267:496–505.
  31. Lester B, Kosofsky B: Effects of drugs of abuse on brain development; in Charney D, Nestler E (eds): Neurobiology of Mental Illness, ed 3. New York, Oxford University Press, 2008.
  32. al-Ghazali W, Chita SK, Chapman MG, Allan LD: Evidence of redistribution of cardiac output in asymmetrical growth retardation. Br J Obstet Gynaecol 1989;96:697–704.

    External Resources

  33. Jensen A, Hohmann M, Kunzel W: Redistribution of fetal circulation during repeated asphyxia in sheep: effects on skin blood flow, transcutaneous PO2, and plasma catecholamines. J Dev Physiol 1987;9:41–55.
  34. Naeye R: Disorders of the Placenta, Fetus and Neonate: Diagnosis and Clinical Significance. St. Louis, Mosby, 1992.
  35. Jansson T: Responsiveness to norepinephrine of the vessels supplying the placenta of growth-retarded fetuses. Am J Obstet Gynecol 1988;158:1233–1237.
  36. Jones CT, Robinson JS: Studies on experimental growth retardation in sheep: plasma catecholamines in fetuses with small placenta. J Dev Physiol 1983;5:77–87.
  37. Lagercrantz H, Sjorquist B, Bremme K, Lunell N, Somell C: Catecholamine metabolites in amniotic fluid as indicators of intrauterine stress. Am J Obstet Gynecol 1980;136:1067–1070.
  38. Bassett JM, Hanson C: Catecholamines inhibit growth in fetal sheep in the absence of hypoxemia. Am J Physiol 1998;274(part 2):R1536–R1545.
  39. Bzoskie L, Blount L, Kashiwai K, Humme J, Padbury J: Placental norepinephrine transporter development in the ovine fetus. Placenta 1997;18:65–70.
  40. Koegler SM, Seidler FJ, Spencer JR, Slotkin TA: Ischemia contributes to adverse effects of cocaine on brain development: suppression of ornithine decarboxylase activity in neonatal rat. Brain Res Bull 1991;27:829–834.
  41. Woods JR Jr, Plessinger MA, Clark KE: Effect of cocaine on uterine blood flow and fetal oxygenation. JAMA 1987;257:957–961.
  42. Reviriego J, Fernandez-Alfonso MS, Marin J: Actions of vasoactive drugs on human placental vascular smooth muscle. Gen Pharmacol 1990;21:719–727.
  43. Zhang L, Dyer DC: Characterization of alpha-adrenoceptors mediating contraction in isolated ovine umbilical vein. Eur J Pharmacol 1991;197:63–67.
  44. Dyer DC: An investigation of the mechanism of potentiation by cocaine of responses to serotonin in sheep umbilical blood vessels. J Pharmacol Exp Ther 1970;175:571–576.
  45. Nair X, Dyer DC: Responses of guinea pig umbilical vasculature to vasoactive drugs. Eur J Pharmacol 1974;27:294–304.
  46. Fox SB, Khong TY: Lack of innervation of human umbilical cord: an immunohistological and histochemical study. Placenta 1990;11:59–62.
  47. Walker DW, McLean JR: Absence of adrenergic nerves in the human placenta. Nature 1971;229:344–345.
  48. Kobayashi K, Morita S, Sawada H, et al: Targeted disruption of the tyrosine hydroxylase locus results in severe catecholamine depletion and perinatal lethality in mice. J Biol Chem 1995;270:27235–27243.
  49. Zhou QY, Quaife CJ, Palmiter RD: Targeted disruption of the tyrosine hydroxylase gene reveals that catecholamines are required for mouse fetal development. Nature 1995;374:640–643.
  50. Thomas SA, Matsumoto AM, Palmiter RD: Noradrenaline is essential for mouse fetal development. Nature 1995;374:643–646.
  51. Thomas SA, Palmiter RD: Examining adrenergic roles in development, physiology, and behavior through targeted disruption of the mouse dopamine beta-hydroxylase gene. Adv Pharmacol 1998;42:57–60.
  52. Whitaker-Azmitia PM, Druse M, Walker P, Lauder JM: Serotonin as a developmental signal. Behav Brain Res 1996;73:19–29.
  53. Yavarone MS, Shuey DL, Tamir H, Sadler TW, Lauder JM: Serotonin and cardiac morphogenesis in the mouse embryo. Teratology 1993;47:573–584.
  54. Shuey DL, Sadler TW, Tamir H, Lauder JM: Serotonin and morphogenesis: transient expression of serotonin uptake and binding protein during craniofacial morphogenesis in the mouse. Anat Embryol (Berl) 1993;187:75–85.
  55. Choi DS, Ward SJ, Messaddeq N, Launay JM, Maroteaux L: 5-HT2B receptor-mediated serotonin morphogenetic functions in mouse cranial neural crest and myocardiac cells. Development 1997;124:1745–1755.
  56. Church MW, Rauch HC: Prenatal cocaine exposure in the laboratory mouse: effects on maternal water consumption and offspring outcome. Neurotoxicol Teratol 1992;14:313–319.
  57. Fantel AG, Macphail BJ: The teratogenicity of cocaine. Teratology 1982;26:17–19.
  58. Bauer CR, Langer JC, Shankaran S, et al: Acute neonatal effects of cocaine exposure during pregnancy. Arch Pediatr Adolesc Med 2005;159:824–834.
  59. Barker DJ, Osmond C, Rodin I, Fall CH, Winter PD: Low weight gain in infancy and suicide in adult life. BMJ 1995;311:1203.
  60. Gluckman PD, Hanson MA: Living with the past: evolution, development, and patterns of disease. Science 2004;305:1733–1736.
  61. Welberg LA, Seckl JR: Prenatal stress, glucocorticoids and the programming of the brain. J Neuroendocrinol 2001;13:113–128.
  62. Barker D: Fetal programming of coronary heart disease. Trends Endocrinol Metab 2002;13:364–368.
  63. McMillen IC, Robinson JS: Developmental origins of the metabolic syndrome: prediction, plasticity, and programming. Physiol Rev 2005;85:571–633.
  64. Barker DJ: The fetal origins of adult hypertension. J Hypertens Suppl 1992;10:S39–S44.
  65. Barker DJ, Osmond C, Golding J, Kuh D, Wadsworth ME: Growth in utero, blood pressure in childhood and adult life, and mortality from cardiovascular disease. BMJ 1989;298:564–567.
  66. Falkner B: Birth weight as a predictor of future hypertension. Am J Hypertens 2002;15:S43–S45.
  67. Rich-Edwards JW, Colditz GA, Stampfer MJ, et al: Birthweight and the risk for type 2 diabetes mellitus in adult women. Ann Intern Med 1999;130(part 1):278–284.
  68. Stein CE, Fall CH, Kumaran K, Osmond C, Cox V, Barker DJ: Fetal growth and coronary heart disease in south India. Lancet 1996;348:1269–1273.
  69. Sallout B, Walker M: The fetal origin of adult diseases. J Obstet Gynaecol 2003;23:555–560.
  70. Phillips D, Barker D, Hales C, Hirst S, Osmond C: Thinness at birth and insulin resistance in adult life. Diabetologia 1994;37:150–154.
  71. Ong KK, Dunger DB: Birth weight, infant growth and insulin resistance. Eur J Endocrinol 2004;151(suppl 3):U131–U139.
  72. Hales CN, Barker DJ, Clark PM, et al: Fetal and infant growth and impaired glucose tolerance at age 64. BMJ 1991;303:1019–1022.
  73. Wals M, Reichart CG, Hillegers MH, et al: Impact of birth weight and genetic liability on psychopathology in children of bipolar parents. J Am Acad Child Adolesc Psychiatry 2003;42:1116–1121.
  74. Allin M, Rooney M, Cuddy M, et al: Personality in young adults who are born preterm. Pediatrics 2006;117:309–316.
  75. Thompson C, Syddall H, Rodin I, Osmond C, Barker DJ: Birth weight and the risk of depressive disorder in late life. Br J Psychiatry 2001;179:450–455.
  76. Gale CR, Martyn CN: Birth weight and later risk of depression in a national birth cohort. Br J Psychiatry 2004;184:28–33.
  77. Matthews SG: Antenatal glucocorticoids and the developing brain: mechanisms of action. Semin Neonatol 2001;6:309–317.
  78. Slotkin TA, Orband-Miller L, Queen KL, Whitmore WL, Seidler FJ: Effects of prenatal nicotine exposure on biochemical development of rat brain regions: maternal drug infusions via osmotic minipumps. J Pharmacol Exp Ther 1987;240:602–611.
  79. Williams MT, Hennessy MB, Davis HN: Stress during pregnancy alters rat offspring morphology and ultrasonic vocalizations. Physiol Behav 1998;63:337–343.
  80. Barbazanges A, Piazza PV, Le Moal M, Maccari S: Maternal glucocorticoid secretion mediates long-term effects of prenatal stress. J Neurosci 1996;16:3943–3949.
  81. Henry C, Kabbaj M, Simon H, Le Moal M, Maccari S: Prenatal stress increases the hypothalamo-pituitary-adrenal axis response in young and adult rats. J Neuroendocrinol 1994;6:341–345.
  82. Maccari S, Piazza PV, Kabbaj M, Barbazanges A, Simon H, Le Moal M: Adoption reverses the long-term impairment in glucocorticoid feedback induced by prenatal stress. J Neurosci 1995;15(part 1):110–116.
  83. Vallee M, Mayo W, Dellu F, Le Moal M, Simon H, Maccari S: Prenatal stress induces high anxiety and postnatal handling induces low anxiety in adult offspring: correlation with stress-induced corticosterone secretion. J Neurosci 1997;17:2626–2636.
  84. Fride E, Dan Y, Feldon J, Halevy G, Weinstock M: Effects of prenatal stress on vulnerability to stress in prepubertal and adult rats. Physiol Behav 1986;37:681–687.
  85. Pfister HP, Muir JL: Prenatal exposure to predictable and unpredictable novelty stress and oxytocin treatment affects offspring development and behavior in rats. Int J Neurosci 1992;62:227–241.
  86. Poltyrev T, Keshet GI, Kay G, Weinstock M: Role of experimental conditions in determining differences in exploratory behavior of prenatally stressed rats. Dev Psychobiol 1996;29:453–462.
  87. Wakshlak A, Weinstock M: Neonatal handling reverses behavioral abnormalities induced in rats by prenatal stress. Physiol Behav 1990;48:289–292.
  88. Takahashi LK, Haglin C, Kalin NH: Prenatal stress potentiates stress-induced behavior and reduces the propensity to play in juvenile rats. Physiol Behav 1992;51:319–323.
  89. Takahashi LK, Turner JG, Kalin NH: Prenatal stress alters brain catecholaminergic activity and potentiates stress-induced behavior in adult rats. Brain Res 1992;574:131–137.
  90. Lambert KG, Kinsley CH, Jones HE, Klein SL, Peretti SN, Stewart KM: Prenatal stress attenuates ulceration in the activity stress paradigm. Physiol Behav 1995;57:989–994.
  91. Weller A, Glaubman H, Yehuda S, Caspy T, Ben-Uria Y: Acute and repeated gestational stress affect offspring learning and activity in rats. Physiol Behav 1988;43:139–143.
  92. Hayashi A, Nagaoka M, Yamada K, Ichitani Y, Miake Y, Okado N: Maternal stress induces synaptic loss and developmental disabilities of offspring. Int J Dev Neurosci 1998;16:209–216.
  93. Szuran T, Zimmermann E, Welzl H: Water maze performance and hippocampal weight of prenatally stressed rats. Behav Brain Res 1994;65:153–155.
  94. Vallee M, MacCari S, Dellu F, Simon H, Le Moal M, Mayo W: Long-term effects of prenatal stress and postnatal handling on age-related glucocorticoid secretion and cognitive performance: a longitudinal study in the rat. Eur J Neurosci 1999;11:2906–2916.
  95. Meaney M, Seckl J: Glucocorticoid programming. Ann NY Acad Sci 2004;1032:63–84.
  96. Roughton EC, Schneider ML, Bromley LJ, Coe CL: Maternal endocrine activation during pregnancy alters neurobehavioral state in primate infants. Am J Occup Ther 1998;52:90–98.
  97. Schneider M, Moore C, Kraemer G: Moderate level alcohol during pregnancy, prenatal stress, or both and limbic-hypothalamic- pituitary-adrenocortical axis response to stress in rhesus monkeys. Child Dev 2004;75:96–109.
  98. Schneider ML: Prenatal stress exposure alters postnatal behavioral expression under conditions of novelty challenge in rhesus monkey infants. Dev Psychobiol 1992;25:529–540.
  99. McEwen BS: Glucocorticoid-biogenic amine interactions in relation to mood and behavior. Biochem Pharmacol 1987;36:1755–1763.
  100. Maes M, Meltzer HY, D’Hondt P, Cosyns P, Blockx P: Effects of serotonin precursors on the negative feedback effects of glucocorticoids on hypothalamic-pituitary-adrenal axis function in depression. Psychoneuroendocrinology 1995;20:149–167.
  101. Meador-Woodruff JH, Greden JF, Grunhaus L, Haskett RF: Severity of depression and hypothalamic-pituitary-adrenal axis dysregulation: identification of contributing factors. Acta Psychiatr Scand 1990;81:364–371.
  102. Nemeroff CB, Widerlov E, Bissette G, et al: Elevated concentrations of CSF corticotropin-releasing factor-like immunoreactivity in depressed patients. Science 1984;226:1342–1344.
  103. van Praag HM: Depression. Lancet 1982;2:1259–1264.
  104. Wadhwa PD, Garite TJ, Porto M, et al: Placental corticotropin-releasing hormone (CRH), spontaneous preterm birth, and fetal growth restriction: a prospective investigation. Am J Obstet Gynecol 2004;191:1063–1069.
  105. Wadhwa PD, Sandman CA, Garite TJ: The neurobiology of stress in human pregnancy: implications for prematurity and development of the fetal central nervous system. Prog Brain Res 2001;133:131–142.
  106. Lou HC, Hansen D, Nordentoft M, et al: Prenatal stressors of human life affect fetal brain development. Dev Med Child Neurol 1994;36:826–832.
  107. van Os J, Selten J: Prenatal exposure to maternal stress and subsequent schizophrenia. Br J Psychiatry 1998;172:324–326.
  108. Field T: Stress and coping from pregnancy through the postnatal period; in Cummings EG, Green AL, Karraker KH (eds): Life-Span Developmental Psychology: Perspectives on Stress and Coping. Hillsdale, Lawrence Erlbaum Associates, 1991, pp 45–59.
  109. Huizink AC, Robles de Medina PG, Mulder EJ, Visser GH, Buitelaar JK: Stress during pregnancy is associated with developmental outcome in infancy. J Child Psychol Psychiatry 2003;44:810–818.
  110. Levy-Shiff R, Dimitrovsky L, Shulman S, et al: Cognitive appraisals, coping strategies, and support resources as correlates of parenting and infant development. Dev Psychobiol 1998;34:1417–1427.
  111. Meijer A: Child psychiatric sequelae of maternal war stress. Acta Psychiatr Scand 1985;72:505–511.
  112. Stott DH: Follow-up study from birth of the effects of prenatal stresses. Dev Med Child Neurol 1973;15:770–787.
  113. Ward AJ: Prenatal stress and childhood psychopathology. Child Psychiatry Hum Dev 1991;22:97–110.
  114. DePietro J: The role of prenatal maternal stress in child development. Curr Dir Psychol Sci 2004;13:71–74.

    External Resources

  115. McEwen BS: Protective and damaging effects of stress mediators. N Engl J Med 1998;338:171–179.
  116. McEwen BS: Early life influences on life-long patterns of behavior and health. Ment Retard Dev Disabil Res Rev 2003;9:149–154.
  117. Nguyen TT, Tseng YT, McGonnigal B, et al: Placental biogenic amine transporters: in vivo function, regulation and pathobiological significance. Placenta 1999;20:3–11.
  118. Meyer JS: Biochemical effects of corticosteroids on neural tissues. Physiol Rev 1985;65:946–1020.
  119. Lopez Bernal A, Craft IL: Corticosteroid metabolism in vitro by human placenta, fetal membranes and decidua in early and late gestation. Placenta 1981;2:279–285.
  120. Benediktsson R, Lindsay RS, Noble J, Seckl JR, Edwards CR: Glucocorticoid exposure in utero: new model for adult hypertension. Lancet 1993;341:339–341.
  121. Murphy VE, Zakar T, Smith R, Giles WB, Gibson PG, Clifton VL: Reduced 11beta-hydroxysteroid dehydrogenase type 2 activity is associated with decreased birth weight centile in pregnancies complicated by asthma. J Clin Endocrinol Metab 2002;87:1660–1668.
  122. Stewart P, Roberson F, Mason J: Type 2 11-hydroxysteroid dehydrogenase messenger RNA and activity in human placenta and fetal membranes: its relationship to birth weight and putative role in fetal steroidogenesis. J Clin Endocrinol Metab 1995;80:885–890.
  123. McTernan CL, Draper N, Nicholson H, et al: Reduced placental 11beta-hydroxysteroid dehydrogenase type 2 mRNA levels in human pregnancies complicated by intrauterine growth restriction: an analysis of possible mechanisms. J Clin Endocrinol Metab 2001;86:4979–4983.
  124. Shams M, Kilby MD, Somerset DA, et al: 11Beta-hydroxysteroid dehydrogenase type 2 in human pregnancy and reduced expression in intrauterine growth restriction. Hum Reprod 1998;13:799–804.
  125. Dave-Sharma S, Wilson R, Harbison M: Extensive personal experience: examination of genotype and phenotype relationships in 14 patients with apparent mineralocorticoid excess. J Clin Endocrinol Metab 1998;83:2244–2254.
  126. Seckl JR, Cleasby M, Nyirenda MJ: Glucocorticoids, 11beta-hydroxysteroid dehydrogenase, and fetal programming. Kidney Int 2000;57:1412–1417.
  127. Edwards CR, Benediktsson R, Lindsay RS, Seckl JR: Dysfunction of placental glucocorticoid barrier: link between fetal environment and adult hypertension? Lancet 1993;341:355–357.
  128. Seckl JR: Glucocorticoids, feto-placental 11 beta-hydroxysteroid dehydrogenase type 2, and the early life origins of adult disease. Steroids 1997;62:89–94.
  129. Gould E, Woolley CS, Cameron HA, Daniels DC, McEwen BS: Adrenal steroids regulate postnatal development of the rat dentate gyrus. II. Effects of glucocorticoids and mineralocorticoids on cell birth. J Comp Neurol 1991;313:486–493.
  130. Gould E, Woolley CS, McEwen BS: Adrenal steroids regulate postnatal development of the rat dentate gyrus. I. Effects of glucocorticoids on cell death. J Comp Neurol 1991;313:479–485.
  131. Bohn MC: Granule cell genesis in the hippocampus of rats treated neonatally with hydrocortisone. Neuroscience 1980;5:2003–2012.
  132. Sarkar S, Tsai SW, Nguyen TT, Plevyak M, Padbury JF, Rubin LP: Inhibition of placental 11beta-hydroxysteroid dehydrogenase type 2 by catecholamines via alpha-adrenergic signaling. Am J Physiol Regul Integr Comp Physiol 2001;281:R1966–R1974.
  133. Bzoskie L, Yen J, Tseng YT, Blount L, Kashiwai K, Padbury JF: Human placental norepinephrine transporter mRNA: expression and correlation with fetal condition at birth. Placenta 1997;18:205–210.
  134. Bottalico B, Larsson I, Brodszki J, et al: Norepinephrine transporter (NET), serotonin transporter (SERT), vesicular monoamine transporter (VMAT2) and organic cation transporters (OCT1, 2 and EMT) in human placenta from pre-eclamptic and normotensive pregnancies. Placenta 2004;25:518–529.
  135. Jacob S, Moley KH: Gametes and embryo epigenetic reprogramming affect developmental outcome: implication for assisted reproductive technologies. Pediatr Res 2005;58:437–446.
  136. Colvis CM, Pollock JD, Goodman RH, et al: Epigenetic mechanisms and gene networks in the nervous system. J Neurosci 2005;25:10379–10389.
  137. Oberlander TF, Weinberg J, Papsdorf M, Grunau R, Misri S, Devlin AM: Prenatal exposure to maternal depression, neonatal methylation of human glucocorticoid receptor gene (NR3C1) and infant cortisol stress responses. Epigenetics 2008;3:97–106.
  138. Kumar A, Choi K, Renthal W, et al: Chromatin remodeling is a key mechanism underlying cocaine-induced plasticity in striatum. Neuron 2005;48:303–314.
  139. Loeber R, Burke JD, Lahey BB, Winters A, Zera M: Oppositional defiant and conduct disorder: a review of the past 10 years, part I. J Am Acad Child Adolesc Psychiatry 2000;39:1468–1484.
  140. Hawkins JD, Graham JW, Maguin E, Abbott R, Hill KG, Catalano RF: Exploring the effects of age of alcohol use initiation and psychosocial risk factors on subsequent alcohol misuse. J Stud Alcohol 1997;58:280–290.
  141. Ellickson PL, Tucker JS, Klein DJ: High-risk behaviors associated with early smoking: results from a 5-year follow-up. J Adolesc Health 2001;28:465–473.
  142. Tarter R, Vanyukov M, Giancola P, et al: Etiology of early age onset substance use disorder: a maturational perspective. Dev Psychopathol 1999;11:657–683.
  143. Brook JS, Whiteman MM, Finch S: Childhood aggression, adolescent delinquency, and drug use: a longitudinal study. J Genet Psychol 1992;153:369–383.
  144. Blackson TC, Butler T, Belsky J, Ammerman RT, Shaw DS, Tarter RE: Individual traits and family contexts predict sons’ externalizing behavior and preliminary relative risk ratios for conduct disorder and substance use disorder outcomes. Drug Alcohol Depend 1999;56:115–131.
  145. Chassin L, Barrera MJ: Substance use escalation and substance use restraint among adolescent children of alcoholics. Psychol Addict Bahav 1993;7:3–20.

    External Resources

  146. Tarter RE, Blackson T, Brigham J, Moss H, Caprara GV: The association between childhood irritability and liability to substance use in early adolescence: a 2-year follow-up study of boys at risk for substance abuse. Drug Alcohol Depend 1995;39:253–261.
  147. Clark DB, Parker AM, Lynch KG: Psychopathology and substance-related problems during early adolescence: a survival analysis. J Clin Child Psychol 1999;28:333–341.
  148. Aytaclar S, Tarter RE, Kirisci L, Lu S: Association between hyperactivity and executive cognitive functioning in childhood and substance use in early adolescence. J Am Acad Child Adolesc Psychiatry 1999;38:172–178.
  149. Giancola P, Martin C, Tarter R, et al: Executive cognitive functioning and aggressive behavior in preadolescent boys at high risk for substance abuse. J Stud Alcohol 1996;57:352–359.
  150. Shoal G, Giancola P: Executive cognitive functioning, negative affectivity, and drug use in adolescent boys with and without a family history of a substance use disorder. J Child Adolesc Subst Abuse 2001;10:111–121.

    External Resources

  151. Tarter RE, Kirisci L, Mezzich A, et al: Neurobehavioral disinhibition in childhood predicts early age at onset of substance use disorder. Am J Psychiatry 2003;160:1078–1085.
  152. Volkow ND, Li TK: Drugs and alcohol: treating and preventing abuse, addiction and their medical consequences. Pharmacol Ther 2005;108:3–17.
  153. Sowell ER, Thompson PM, Toga AW: Mapping changes in the human cortex throughout the span of life. Neuroscientist 2004;10:372–392.
  154. Sowell ER, Thompson PM, Peterson BS, et al: Mapping cortical gray matter asymmetry patterns in adolescents with heavy prenatal alcohol exposure. Neuroimage 2002;17:1807–1819.
  155. Giedd J: Brain development. IX. Human brain growth. Am J Psychiatry 1999;156:4.
  156. Paus T, Zijdenbos A, Worsley K, et al: Structural maturation of neural pathways in children and adolescents: in vivo study. Science 1999;283:1908–1911.
  157. Gogtay N, Giedd JN, Lusk L, et al: Dynamic mapping of human cortical development during childhood through early adulthood. Proc Natl Acad Sci USA 2004;101:8174–8179.
  158. Bauer LO, Hesselbrock VM: P300 decrements in teenagers with conduct problems: implications for substance abuse risk and brain development. Biol Psychiatry 1999;46:263–272.
  159. Giancola P, Tarter R: Executive cognitive functioning and risk for substance abuse. Psychol Sci 1999;10:203–205.

    External Resources

  160. Schweinsburg AD, Paulus MP, Barlett VC, et al: An fMRI study of response inhibition in youths with a family history of alcoholism. Ann NY Acad Sci 2004;1021:391–394.
  161. Fuster JM: Executive frontal functions. Exp Brain Res 2000;133:66–70.
  162. Chambers RA, Taylor JR, Potenza MN: Developmental neurocircuitry of motivation in adolescence: a critical period of addiction vulnerability. Am J Psychiatry 2003;160:1041–1052.
  163. Spear L: Neurobehavioral changes in adolescence. Curr Dir Psychol Sci 2000;9:111–114.

    External Resources

  164. Romeo RD, McEwen BS: Stress and the adolescent brain. Ann NY Acad Sci 2006;1094:202–214.
  165. McEwen BS, De Kloet ER, Rostene W: Adrenal steroid receptors and actions in the nervous system. Physiol Rev 1986;66:1121–1188.
  166. Meaney MJ, Aitken DH: [3H]Dexamethasone binding in rat frontal cortex. Brain Res 1985;328:176–180.
  167. Diorio D, Viau V, Meaney MJ: The role of the medial prefrontal cortex (cingulate gyrus) in the regulation of hypothalamic-pituitary-adrenal responses to stress. J Neurosci 1993;13:3839–3847.
  168. Sanchez MM, Young LJ, Plotsky PM, Insel TR: Distribution of corticosteroid receptors in the rhesus brain: relative absence of glucocorticoid receptors in the hippocampal formation. J Neurosci 2000;20:4657–4668.
  169. Patel PD, Lopez JF, Lyons DM, Burke S, Wallace M, Schatzberg AF: Glucocorticoid and mineralocorticoid receptor mRNA expression in squirrel monkey brain. J Psychiatr Res 2000;34:383–392.
  170. Paule MG, Gillam MP, Allen RR, Chelonis JJ: Effects of chronic in utero exposure to cocaine on behavioral adaptability in rhesus monkey offspring when examined in adulthood. Ann NY Acad Sci 2000;914:412–417.
  171. Chelonis JJ, Gillam MP, Paule MG: The effects of prenatal cocaine exposure on reversal learning using a simple visual discrimination task in rhesus monkeys. Neurotox- icol Teratol 2003;25:437–446.
  172. McEwen BS: Glucocorticoids, depression, and mood disorders: structural remodeling in the brain. Metabolism 2005;54(suppl 1):20–23.

    External Resources

  173. Isgor C, Kabbaj M, Akil H, Watson SJ: Delayed effects of chronic variable stress during peripubertal-juvenile period on hippocampal morphology and on cognitive and stress axis functions in rats. Hippocampus 2004;14:636–648.
  174. Radley JJ, Rocher AB, Miller M, et al: Repeated stress induces dendritic spine loss in the rat medial prefrontal cortex. Cereb Cortex 2006;16:313–320.
  175. Gunnar M, Prudhomme-White B: Salivary cortisol measures in infant and child assessment; in Twarog-Singer L, Zeskind PS (eds): Biobehavioral Assessment of the Infant. New York, Guilford Press, 2001.
  176. Magnano CL, Gardner JM, Karmel BZ: Differences in salivary cortisol levels in cocaine-exposed and noncocaine-exposed NICU infants. Dev Psychobiol 1992;25:93–103.
  177. Jacobson SW, Bihun JT, Chiodo LM: Effects of prenatal alcohol and cocaine exposure on infant cortisol levels. Dev Psychopathol 1999;11:195–208.
  178. Scafidi FA, Field TM, Wheeden A, et al: Cocaine-exposed preterm neonates show behavioral and hormonal differences. Pediatrics 1996;97(part 1):851–855.
  179. Harvey JA: Cocaine effects on the developing brain: current status. Neurosci Biobehav Rev 2004;27:751–764.
  180. Mayes LC: Developing brain and in utero cocaine exposure: effects on neural ontogeny. Dev Psychopathol 1999;11:685–714.
  181. Lester BM, Tronick EZ, LaGasse L, et al: The maternal lifestyle study: effects of substance exposure during pregnancy on neurodevelopmental outcome in 1-month-old infants. Pediatrics 2002;110:1182–1192.
  182. Lester BM, Lagasse L, Seifer R, et al: The Maternal Lifestyle Study (MLS): effects of prenatal cocaine and/or opiate exposure on auditory brain response at one month. J Pediatr 2003;142:279–285.
  183. Miller-Loncar C, Lester BM, Seifer R, et al: Predictors of motor development in children prenatally exposed to cocaine. Neurotoxicol Teratol 2005;27:213–220.
  184. Sheinkopf S, Lester B, LaGasse L, et al: Neonatal irritability, prenatal substance exposure, and later parenting stress. J Pediatr Psychol 2005;31:27–40.
  185. Tronick EZ, Messinger DS, Weinberg MK, et al: Cocaine exposure is associated with subtle compromises of infants’ and mothers’ social-emotional behavior and dyadic features of their interaction in the face-to-face still-face paradigm. Dev Psychol 2005;41:711–722.
  186. Seifer R, LaGasse LL, Lester B, et al: Attachment status in children prenatally exposed to cocaine and other substances. Child Dev 2004;75:850–868.
  187. Bendersky M, Lewis M: Arousal modulation in cocaine-exposed infants. Dev Psychol 1998;34:555–564.
  188. DiPietro J, Suess P, Wheeler J, Smouse P, Newlin D: Reactivity and regulation in cocaine-exposed neonates. Infant Behav Dev 1995;18:407–414.

    External Resources

  189. Gingras JL, O’Donnell KJ, Hume RF: Maternal cocaine addiction and fetal behavioral state. I. A human model for the study of sudden infant death syndrome. Med Hypotheses 1990;33:227–230.
  190. Gingras JL, O’Donnell KJ: State control in the substance-exposed fetus. I. The fetal neurobehavioral profile: an assessment of fetal state, arousal, and regulation competency. Ann NY Acad Sci 1998;846:262–276.
  191. Mayes LC, Bornstein MH, Chawarska K, Granger RH: Information processing and developmental assessments in 3-month-old infants exposed prenatally to cocaine. Pediatrics 1995;95:539–545.
  192. Regalado M, Schechtman V, del Angel A, Bean X: Sleep disorganization in cocaine-exposed neonates. Infant Behav Dev 1995;18:319–327.

    External Resources

  193. Regalado MG, Schechtman VL, Del Angel AP, Bean XD: Cardiac and respiratory patterns during sleep in cocaine-exposed neonates. Early Hum Dev 1996;44:187–200.
  194. Susman EJ: Psychobiology of persistent antisocial behavior: stress, early vulnerabilities and the attenuation hypothesis. Neurosci Biobehav Rev 2006;30:376–389.
  195. Gold PW, Chrousos GP: Organization of the stress system and its dysregulation in melancholic and atypical depression: high vs. low CRH/NE states. Mol Psychiatry 2002;7:254–275.
  196. Richardson GA: Prenatal cocaine exposure: a longitudinal study of development. Ann NY Acad Sci 1998;846:144–152.
  197. Bennett DS, Bendersky M, Lewis M: Children’s intellectual and emotional-behavioral adjustment at 4 years as a function of cocaine exposure, maternal characteristics, and environmental risk. Dev Psychol 2002;38:648–658.
  198. Arendt RE, Short EJ, Singer LT, et al: Children prenatally exposed to cocaine: developmental outcomes and environmental risks at seven years of age. J Dev Behav Pediatr 2004;25:83–90.
  199. LaGasse L, Lester B, Seifer R, et al: Prenatal cocaine exposure and cognitive development at school age. Pediatr Res 2004;55:69.
  200. Lester BM, LaGasse LL, Seifer R: Cocaine exposure and children: the meaning of subtle effects. Science 1998;282:633–634.
  201. Singer LT, Minnes S, Short E, et al: Cognitive outcomes of preschool children with prenatal cocaine exposure. JAMA 2004;291:2448–2456.
  202. Mentis M: In utero cocaine exposure and language development. Semin Speech Lang 1998;19:147–164, quiz 165.
  203. Bandstra ES, Vogel AL, Morrow CE, Xue L, Anthony JC: Severity of prenatal cocaine exposure and child language functioning through age seven years: a longitudinal latent growth curve analysis. Subst Use Misuse 2004;39:25–59.
  204. Lewis BA, Singer LT, Short EJ, et al: Four-year language outcomes of children exposed to cocaine in utero. Neurotoxicol Teratol 2004;26:617–627.
  205. Bandstra ES, Morrow CE, Vogel AL, et al: Longitudinal influence of prenatal cocaine exposure on child language functioning. Neurotoxicol Teratol 2002;24:297–308.
  206. Morrow CE, Bandstra ES, Anthony JC, Ofir AY, Xue L, Reyes MB: Influence of prenatal cocaine exposure on early language development: longitudinal findings from four months to three years of age. J Dev Behav Pediatr 2003;24:39–50.
  207. Loebstein R, Koren G: Pregnancy outcome and neurodevelopment of children exposed in utero to psychoactive drugs: the Motherisk experience. J Psychiatry Neurosci 1997;22:192–196.
  208. Noland JS, Singer LT, Short EJ, et al: Prenatal drug exposure and selective attention in preschoolers. Neurotoxicol Teratol 2005;27:429–438.
  209. Schroder MD, Snyder PJ, Sielski I, Mayes L: Impaired performance of children exposed in utero to cocaine on a novel test of visuospatial working memory. Brain Cogn 2004;55:409–412.
  210. Bandstra ES, Morrow CE, Anthony JC, Accornero VH, Fried PA: Longitudinal investigation of task persistence and sustained attention in children with prenatal cocaine exposure. Neurotoxicol Teratol 2001;23:545–559.
  211. Delaney-Black V, Covington C, Templin T, Ager J, Martier S, Sokol R: Prenatal cocaine exposure and child behavior. Pediatrics 1998;102(part 1):945–950.
  212. Delaney-Black V, Covington C, Templin T, et al: Teacher-assessed behavior of children prenatally exposed to cocaine. Pediatrics 2000;106:782–791.
  213. Mayes L, Snyder PJ, Langlois E, Hunter N: Visuospatial working memory in school-aged children exposed in utero to cocaine. Child Neuropsychol 2007;13:205–218.
  214. Morrow CE, Culbertson JL, Accornero VH, Xue L, Anthony JC, Bandstra ES: Learning disabilities and intellectual functioning in school-aged children with prenatal cocaine exposure. Dev Neuropsychol 2006;30:905–931.
  215. Levine T, Liu J, Das A, et al: Effects of prenatal cocaine exposure on special education in school age children. Pediatrics 2008;122:e83–e91.
  216. Covington C, Nordstrom-Klee B, Delaney-Black V, Templin T, Ager J, Sokol RJ: Development of an instrument to assess problem behavior in first grade students prenatally exposed to cocaine. Part II. Validation. Subst Abus 2001;22:217–233.
  217. Linares TJ, Singer LT, Kirchner HL, et al: Mental health outcomes of cocaine-exposed children at 6 years of age. J Pediatr Psychol 2006;31:85–97.
  218. Accornero VH, Morrow CE, Bandstra ES, Johnson AL, Anthony JC: Behavioral outcome of preschoolers exposed prenatally to cocaine: role of maternal behavioral health. J Pediatr Psychol 2002;27:259–269.
  219. Bada HS, Das A, Bauer CR, et al: Impact of prenatal cocaine exposure on child behavior problems through school age. Pediatrics 2007;119:e348–e359.
  220. Savage J, Brodsky NL, Malmud E, Giannetta JM, Hurt H: Attentional functioning and impulse control in cocaine-exposed and control children at age ten years. J Dev Behav Pediatr 2005;26:42–47.
  221. Wasserman GA, Kline JK, Bateman DA, et al: Prenatal cocaine exposure and school-age intelligence. Drug Alcohol Depend 1998;50:203–210.
  222. Hurt H, Malmud E, Betancourt L, Brodsky NL, Giannetta J: A prospective evaluation of early language development in children with in utero cocaine exposure and in control subjects. J Pediatr 1997;130:310–312.
  223. Pulsifer MB, Radonovich K, Belcher HM, Butz AM: Intelligence and school readiness in preschool children with prenatal drug exposure. Child Neuropsychol 2004;10:89–101.
  224. Warner TD, Behnke M, Eyler FD, et al: Diffusion tensor imaging of frontal white matter and executive functioning in cocaine-exposed children. Pediatrics 2006;118:2014–2024.
  225. Dow-Edwards DL, Benveniste H, Behnke M, et al: Neuroimaging of prenatal drug exposure. Neurotoxicol Teratol 2006;28:386–402.
  226. Avants BB, Hurt H, Giannetta JM, et al: Effects of heavy in utero cocaine exposure on adolescent caudate morphology. Pediatr Neurol 2007;37:275–279.
  227. Neyzi N, Quinn B, Kekatpure D, et al: Automated Segmentation of Brain Structures in a Pediatric Population with Prenatal Cocaine Exposure. San Diego, Society for Neuroscience, 2007.
  228. Hurt H, Giannetta JM, Korczykowski M, et al: Functional magnetic resonance imaging and working memory in adolescents with gestational cocaine exposure. J Pediatr 2008;152:371–377.
  229. Sheinkopf S, Lester B, Sanes J, et al: Functional MRI and response inhibition in children exposed to cocaine in utero. Dev Neurosci, in press.
  230. Rao H, Wang J, Giannetta J, et al: Altered resting cerebral blood flow in adolescents with in utero cocaine exposure revealed by perfusion functional MRI. Pediatrics 2007;120:e1245–e1254.
  231. Smith LM, Chang L, Yonekura ML, et al: Brain proton magnetic resonance spectroscopy and imaging in children exposed to cocaine in utero. Pediatrics 2001;107:227–231.
  232. Wetherington C, Smeriglio V, Finnegan L: Behavioral Studies of Drug-Exposed Offspring: Methodological Issues in Human and Animal Research. NIDA Monograph Series 164. Rockville, National Institute on Drug Abuse, 1998.
  233. Frank DA, Augustyn M, Knight WG, Pell T, Zuckerman B: Growth, development, and behavior in early childhood following prenatal cocaine exposure: a systematic review. JAMA 2001;285:1613–1625.
  234. Lester BM, ElSohly M, Wright LL, et al: The Maternal Lifestyle Study: drug use by meconium toxicology and maternal self-report. Pediatrics 2001;107:309–317.
  235. Blum K, Cull J, Braverman E, Comings D: Reward deficiency syndrome. Am Sci 1996;84:132–145.

    External Resources

  236. Wang GJ, Volkow ND, Logan J, et al: Brain dopamine and obesity. Lancet 2001;357:354–357.
  237. Shankaran S, Das A, Bada H, et al: Prenatal cocaine exposure predicts blood pressure at 9 years of age. Presented at the Pediatric Academic Society Annual Meeting. May 16th, 2005; Washington , DC. http://www.abstracts2view.com/pasall/view.php? nu=PAS5L1_694

 goto top of outline Author Contacts

Barry M. Lester, PhD
Women and Infants’ Hospital of Rhode Island
101 Dudley Street
Providence, RI 02905 (USA)
Tel. +1 401 453 7640, Fax +1 401 453 7646, E-Mail Barry_Lester@Brown.edu


 goto top of outline Article Information

Received: March 24, 2008
Accepted after revision: October 20, 2008
April 17, 2009
Number of Print Pages : 13
Number of Figures : 3, Number of Tables : 0, Number of References : 237


 goto top of outline Publication Details

Developmental Neuroscience

Vol. 31, No. 1-2, Year 2009 (Cover Date: April 2009)

Journal Editor: Levison S.W. (Newark, N.J.)
ISSN: 0378-5866 (Print), eISSN: 1421-9859 (Online)

For additional information: http://www.karger.com/DNE


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

The pathophysiology of the effects of cocaine on fetal development has been described along 2 major pathways: neurochemical effects and vasoconstrictive effects. Following a summary of these effects, we suggest a ‘third pathophysiology’ in which altered fetal programming affects the acute and long-term adverse effects of in utero cocaine exposure. We describe how cocaine as a stressor alters the expression of key candidate genes, increasing exposure to catecholamines and fetal cortisol-altering neuroendocrine (hypothalamic-pituitary-adrenal axis) activity, leading to infant behavioral dysregulation, poor behavioral control and emotion regulation during childhood and phenotypes that confer vulnerability to substance use in adolescence. This model is discussed in relation to follow-up studies of the effects of in utero cocaine exposure and maturational changes in brain development.



 goto top of outline Author Contacts

Barry M. Lester, PhD
Women and Infants’ Hospital of Rhode Island
101 Dudley Street
Providence, RI 02905 (USA)
Tel. +1 401 453 7640, Fax +1 401 453 7646, E-Mail Barry_Lester@Brown.edu


 goto top of outline Article Information

Received: March 24, 2008
Accepted after revision: October 20, 2008
April 17, 2009
Number of Print Pages : 13
Number of Figures : 3, Number of Tables : 0, Number of References : 237


 goto top of outline Publication Details

Developmental Neuroscience

Vol. 31, No. 1-2, Year 2009 (Cover Date: April 2009)

Journal Editor: Levison S.W. (Newark, N.J.)
ISSN: 0378-5866 (Print), eISSN: 1421-9859 (Online)

For additional information: http://www.karger.com/DNE


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Shurtleff D, Ferre S: Sponsor’s foreword (editorial). ScientificWorldJournal 2007;7 (suppl 2):1–3.
  2. Schenker S, Yang Y, Johnson RF, et al: The transfer of cocaine and its metabolites across the term human placenta. Clin Pharmacol Ther 1993;53:329–339.
  3. Gawin FH, Ellinwood EH Jr: Cocaine and other stimulants: actions, abuse, and treatment. N Engl J Med 1988;318:1173–1182.
  4. Wise R: Neural Mechanisms of the Reinforcing Action of Cocaine. NIDA Research Monograph 50. Rockville, National Institute on Drug Abuse, 1984, pp 15–33.
  5. Goodman L: The Pharmacological Basis of Therapeutics. New York, MacMillan, 1985.
  6. Bzoskie L, Blount L, Kashiwai K, Humme J, Padbury J: The contribution of transporter-dependent uptake to fetal catecholamine clearance. Biol Neonate 1997;71:102–110.
  7. Lau C, Burke S, Slotkin T: Maturation of sympathetic neurotransmission in the rat heart. IX. Development of transsynaptic regulation of cardiac adrenergic sensitivity. J Pharmacol Exp Ther 1982;223:675–680.
  8. Padbury JF, Ludlow JK, Humme JA, Agata Y: Metabolic clearance and plasma appearance rates of catecholamines in preterm and term fetal sheep. Pediatr Res 1986;20:992–995.
  9. Stein H, Oyama K, Martinez A, Chappell B, Padbury J: Plasma epinephrine appearance and clearance rates in fetal and newborn sheep. Am J Physiol 1993;265(part 2):R756–R760.
  10. NIDA: Mechanisms of Cocaine Abuse and Toxicity. Rockville, National Institute on Drug Abuse, 1988.
  11. Kalivas PW, Duffy P, DuMars LA, Skinner C: Behavioral and neurochemical effects of acute and daily cocaine administration in rats. J Pharmacol Exp Ther 1988;245:485–492.
  12. Peris J, Boyson SJ, Cass WA, et al: Persistence of neurochemical changes in dopamine systems after repeated cocaine administration. J Pharmacol Exp Ther 1990;253:38–44.
  13. Kalivas P, Duffy P: Effect of acute and daily cocaine treatment on extracellular dopamine in the nucleus accumbens. Synapse 1990;5:48–58.
  14. Steketee JD, Striplin CD, Murray TF, Kalivas PW: Possible role for G-proteins in behavioral sensitization to cocaine. Brain Res 1991;545:287–291.
  15. Arai S, Morita K, Kitayama S, et al: Chronic inhibition of the norepinephrine transporter in the brain participates in seizure sensitization to cocaine and local anesthetics. Brain Res 1993;964:83–90.
  16. Mead AN, Rocha BA, Donovan DM, Katz JL: Intravenous cocaine induced-activity and behavioural sensitization in norepinephrine-, but not dopamine-transporter knockout mice. Eur J Neurosci 2002;16:514–520.
  17. Kreek MJ: Cocaine, dopamine and the endogenous opioid system. J Addict Dis 1996;15:73–96.
  18. Shippenberg TS, Rea W: Sensitization to the behavioral effects of cocaine: modulation by dynorphin and kappa-opioid receptor agonists. Pharmacol Biochem Behav 1997;57:449–455.
  19. White FJ, Hu XT, Zhang XF, Wolf ME: Repeated administration of cocaine or amphetamine alters neuronal responses to glutamate in the mesoaccumbens dopamine system. J Pharmacol Exp Ther 1995;273: 445–454.
  20. Ye JH, Liu PL, Wu WH, McArdle JJ: Cocaine depresses GABAA current of hippocampal neurons. Brain Res 1997;770(1–2):169–175.
  21. Garg UC, Turndorf H, Bansinath M: Effect of cocaine on macromolecular syntheses and cell proliferation in cultured glial cells. Neuroscience 1993;57:467–472.
  22. Nassogne MC, Evrard P, Courtoy PJ: Selective neuronal toxicity of cocaine in embryonic mouse brain cocultures. Proc Natl Acad Sci USA 1995;92:11029–11033.
  23. Nassogne MC, Evrard P, Courtoy PJ: Selective direct toxicity of cocaine on fetal mouse neurons: teratogenic implications of neurite and apoptotic neuronal loss. Ann NY Acad Sci 1998;846:51–68.
  24. Akbari HM, Whitaker-Azmitia PM, Azmitia EC: Prenatal cocaine decreases the trophic factor S-100 beta and induced microcephaly: reversal by postnatal 5-HT1A receptor agonist. Neurosci Lett 1994;170:141–144.
  25. Gressens P, Gofflot F, Van Maele-Fabry G, et al: Early neurogenesis and teratogenesis in whole mouse embryo cultures: histochemical, immunocytological and ultrastructural study of the premigratory neuronal-glial units in normal mouse embryo and in mouse embryos influenced by cocaine and retinoic acid. J Neuropathol Exp Neurol 1992;51:206–219.
  26. Gressens P, Kosofsky BE, Evrard P: Cocaine-induced disturbances of corticogenesis in the developing murine brain. Neurosci Lett 1992;140:113–116.
  27. Yablonsky-Alter E, Gleser I, Carter C, Juvan M: Effects of prenatal cocaine treatment on postnatal development of neocortex in white mice: immunocytochemistry of calbindin- and paralbumin-positive populations of GABAergic neurons. Soc Neurosci Abstr 1992;18:367.
  28. Steiner H, Gerfen CR: Dynorphin opioid inhibition of cocaine-induced, D1 dopamine receptor-mediated immediate-early gene expression in the striatum. J Comp Neurol 1995;353:200–212.
  29. Steiner H, Gerfen CR: Cocaine-induced c-fos messenger RNA is inversely related to dynorphin expression in striatum. J Neurosci 1993;13:5066–5081.
  30. Bhat RV, Baraban JM: Activation of transcription factor genes in striatum by cocaine: role of both serotonin and dopamine systems. J Pharmacol Exp Ther 1993;267:496–505.
  31. Lester B, Kosofsky B: Effects of drugs of abuse on brain development; in Charney D, Nestler E (eds): Neurobiology of Mental Illness, ed 3. New York, Oxford University Press, 2008.
  32. al-Ghazali W, Chita SK, Chapman MG, Allan LD: Evidence of redistribution of cardiac output in asymmetrical growth retardation. Br J Obstet Gynaecol 1989;96:697–704.

    External Resources

  33. Jensen A, Hohmann M, Kunzel W: Redistribution of fetal circulation during repeated asphyxia in sheep: effects on skin blood flow, transcutaneous PO2, and plasma catecholamines. J Dev Physiol 1987;9:41–55.
  34. Naeye R: Disorders of the Placenta, Fetus and Neonate: Diagnosis and Clinical Significance. St. Louis, Mosby, 1992.
  35. Jansson T: Responsiveness to norepinephrine of the vessels supplying the placenta of growth-retarded fetuses. Am J Obstet Gynecol 1988;158:1233–1237.
  36. Jones CT, Robinson JS: Studies on experimental growth retardation in sheep: plasma catecholamines in fetuses with small placenta. J Dev Physiol 1983;5:77–87.
  37. Lagercrantz H, Sjorquist B, Bremme K, Lunell N, Somell C: Catecholamine metabolites in amniotic fluid as indicators of intrauterine stress. Am J Obstet Gynecol 1980;136:1067–1070.
  38. Bassett JM, Hanson C: Catecholamines inhibit growth in fetal sheep in the absence of hypoxemia. Am J Physiol 1998;274(part 2):R1536–R1545.
  39. Bzoskie L, Blount L, Kashiwai K, Humme J, Padbury J: Placental norepinephrine transporter development in the ovine fetus. Placenta 1997;18:65–70.
  40. Koegler SM, Seidler FJ, Spencer JR, Slotkin TA: Ischemia contributes to adverse effects of cocaine on brain development: suppression of ornithine decarboxylase activity in neonatal rat. Brain Res Bull 1991;27:829–834.
  41. Woods JR Jr, Plessinger MA, Clark KE: Effect of cocaine on uterine blood flow and fetal oxygenation. JAMA 1987;257:957–961.
  42. Reviriego J, Fernandez-Alfonso MS, Marin J: Actions of vasoactive drugs on human placental vascular smooth muscle. Gen Pharmacol 1990;21:719–727.
  43. Zhang L, Dyer DC: Characterization of alpha-adrenoceptors mediating contraction in isolated ovine umbilical vein. Eur J Pharmacol 1991;197:63–67.
  44. Dyer DC: An investigation of the mechanism of potentiation by cocaine of responses to serotonin in sheep umbilical blood vessels. J Pharmacol Exp Ther 1970;175:571–576.
  45. Nair X, Dyer DC: Responses of guinea pig umbilical vasculature to vasoactive drugs. Eur J Pharmacol 1974;27:294–304.
  46. Fox SB, Khong TY: Lack of innervation of human umbilical cord: an immunohistological and histochemical study. Placenta 1990;11:59–62.
  47. Walker DW, McLean JR: Absence of adrenergic nerves in the human placenta. Nature 1971;229:344–345.
  48. Kobayashi K, Morita S, Sawada H, et al: Targeted disruption of the tyrosine hydroxylase locus results in severe catecholamine depletion and perinatal lethality in mice. J Biol Chem 1995;270:27235–27243.
  49. Zhou QY, Quaife CJ, Palmiter RD: Targeted disruption of the tyrosine hydroxylase gene reveals that catecholamines are required for mouse fetal development. Nature 1995;374:640–643.
  50. Thomas SA, Matsumoto AM, Palmiter RD: Noradrenaline is essential for mouse fetal development. Nature 1995;374:643–646.
  51. Thomas SA, Palmiter RD: Examining adrenergic roles in development, physiology, and behavior through targeted disruption of the mouse dopamine beta-hydroxylase gene. Adv Pharmacol 1998;42:57–60.
  52. Whitaker-Azmitia PM, Druse M, Walker P, Lauder JM: Serotonin as a developmental signal. Behav Brain Res 1996;73:19–29.
  53. Yavarone MS, Shuey DL, Tamir H, Sadler TW, Lauder JM: Serotonin and cardiac morphogenesis in the mouse embryo. Teratology 1993;47:573–584.
  54. Shuey DL, Sadler TW, Tamir H, Lauder JM: Serotonin and morphogenesis: transient expression of serotonin uptake and binding protein during craniofacial morphogenesis in the mouse. Anat Embryol (Berl) 1993;187:75–85.
  55. Choi DS, Ward SJ, Messaddeq N, Launay JM, Maroteaux L: 5-HT2B receptor-mediated serotonin morphogenetic functions in mouse cranial neural crest and myocardiac cells. Development 1997;124:1745–1755.
  56. Church MW, Rauch HC: Prenatal cocaine exposure in the laboratory mouse: effects on maternal water consumption and offspring outcome. Neurotoxicol Teratol 1992;14:313–319.
  57. Fantel AG, Macphail BJ: The teratogenicity of cocaine. Teratology 1982;26:17–19.
  58. Bauer CR, Langer JC, Shankaran S, et al: Acute neonatal effects of cocaine exposure during pregnancy. Arch Pediatr Adolesc Med 2005;159:824–834.
  59. Barker DJ, Osmond C, Rodin I, Fall CH, Winter PD: Low weight gain in infancy and suicide in adult life. BMJ 1995;311:1203.
  60. Gluckman PD, Hanson MA: Living with the past: evolution, development, and patterns of disease. Science 2004;305:1733–1736.
  61. Welberg LA, Seckl JR: Prenatal stress, glucocorticoids and the programming of the brain. J Neuroendocrinol 2001;13:113–128.
  62. Barker D: Fetal programming of coronary heart disease. Trends Endocrinol Metab 2002;13:364–368.
  63. McMillen IC, Robinson JS: Developmental origins of the metabolic syndrome: prediction, plasticity, and programming. Physiol Rev 2005;85:571–633.
  64. Barker DJ: The fetal origins of adult hypertension. J Hypertens Suppl 1992;10:S39–S44.
  65. Barker DJ, Osmond C, Golding J, Kuh D, Wadsworth ME: Growth in utero, blood pressure in childhood and adult life, and mortality from cardiovascular disease. BMJ 1989;298:564–567.
  66. Falkner B: Birth weight as a predictor of future hypertension. Am J Hypertens 2002;15:S43–S45.
  67. Rich-Edwards JW, Colditz GA, Stampfer MJ, et al: Birthweight and the risk for type 2 diabetes mellitus in adult women. Ann Intern Med 1999;130(part 1):278–284.
  68. Stein CE, Fall CH, Kumaran K, Osmond C, Cox V, Barker DJ: Fetal growth and coronary heart disease in south India. Lancet 1996;348:1269–1273.
  69. Sallout B, Walker M: The fetal origin of adult diseases. J Obstet Gynaecol 2003;23:555–560.
  70. Phillips D, Barker D, Hales C, Hirst S, Osmond C: Thinness at birth and insulin resistance in adult life. Diabetologia 1994;37:150–154.
  71. Ong KK, Dunger DB: Birth weight, infant growth and insulin resistance. Eur J Endocrinol 2004;151(suppl 3):U131–U139.
  72. Hales CN, Barker DJ, Clark PM, et al: Fetal and infant growth and impaired glucose tolerance at age 64. BMJ 1991;303:1019–1022.
  73. Wals M, Reichart CG, Hillegers MH, et al: Impact of birth weight and genetic liability on psychopathology in children of bipolar parents. J Am Acad Child Adolesc Psychiatry 2003;42:1116–1121.
  74. Allin M, Rooney M, Cuddy M, et al: Personality in young adults who are born preterm. Pediatrics 2006;117:309–316.
  75. Thompson C, Syddall H, Rodin I, Osmond C, Barker DJ: Birth weight and the risk of depressive disorder in late life. Br J Psychiatry 2001;179:450–455.
  76. Gale CR, Martyn CN: Birth weight and later risk of depression in a national birth cohort. Br J Psychiatry 2004;184:28–33.
  77. Matthews SG: Antenatal glucocorticoids and the developing brain: mechanisms of action. Semin Neonatol 2001;6:309–317.
  78. Slotkin TA, Orband-Miller L, Queen KL, Whitmore WL, Seidler FJ: Effects of prenatal nicotine exposure on biochemical development of rat brain regions: maternal drug infusions via osmotic minipumps. J Pharmacol Exp Ther 1987;240:602–611.
  79. Williams MT, Hennessy MB, Davis HN: Stress during pregnancy alters rat offspring morphology and ultrasonic vocalizations. Physiol Behav 1998;63:337–343.
  80. Barbazanges A, Piazza PV, Le Moal M, Maccari S: Maternal glucocorticoid secretion mediates long-term effects of prenatal stress. J Neurosci 1996;16:3943–3949.
  81. Henry C, Kabbaj M, Simon H, Le Moal M, Maccari S: Prenatal stress increases the hypothalamo-pituitary-adrenal axis response in young and adult rats. J Neuroendocrinol 1994;6:341–345.
  82. Maccari S, Piazza PV, Kabbaj M, Barbazanges A, Simon H, Le Moal M: Adoption reverses the long-term impairment in glucocorticoid feedback induced by prenatal stress. J Neurosci 1995;15(part 1):110–116.
  83. Vallee M, Mayo W, Dellu F, Le Moal M, Simon H, Maccari S: Prenatal stress induces high anxiety and postnatal handling induces low anxiety in adult offspring: correlation with stress-induced corticosterone secretion. J Neurosci 1997;17:2626–2636.
  84. Fride E, Dan Y, Feldon J, Halevy G, Weinstock M: Effects of prenatal stress on vulnerability to stress in prepubertal and adult rats. Physiol Behav 1986;37:681–687.
  85. Pfister HP, Muir JL: Prenatal exposure to predictable and unpredictable novelty stress and oxytocin treatment affects offspring development and behavior in rats. Int J Neurosci 1992;62:227–241.
  86. Poltyrev T, Keshet GI, Kay G, Weinstock M: Role of experimental conditions in determining differences in exploratory behavior of prenatally stressed rats. Dev Psychobiol 1996;29:453–462.
  87. Wakshlak A, Weinstock M: Neonatal handling reverses behavioral abnormalities induced in rats by prenatal stress. Physiol Behav 1990;48:289–292.
  88. Takahashi LK, Haglin C, Kalin NH: Prenatal stress potentiates stress-induced behavior and reduces the propensity to play in juvenile rats. Physiol Behav 1992;51:319–323.
  89. Takahashi LK, Turner JG, Kalin NH: Prenatal stress alters brain catecholaminergic activity and potentiates stress-induced behavior in adult rats. Brain Res 1992;574:131–137.
  90. Lambert KG, Kinsley CH, Jones HE, Klein SL, Peretti SN, Stewart KM: Prenatal stress attenuates ulceration in the activity stress paradigm. Physiol Behav 1995;57:989–994.
  91. Weller A, Glaubman H, Yehuda S, Caspy T, Ben-Uria Y: Acute and repeated gestational stress affect offspring learning and activity in rats. Physiol Behav 1988;43:139–143.
  92. Hayashi A, Nagaoka M, Yamada K, Ichitani Y, Miake Y, Okado N: Maternal stress induces synaptic loss and developmental disabilities of offspring. Int J Dev Neurosci 1998;16:209–216.
  93. Szuran T, Zimmermann E, Welzl H: Water maze performance and hippocampal weight of prenatally stressed rats. Behav Brain Res 1994;65:153–155.
  94. Vallee M, MacCari S, Dellu F, Simon H, Le Moal M, Mayo W: Long-term effects of prenatal stress and postnatal handling on age-related glucocorticoid secretion and cognitive performance: a longitudinal study in the rat. Eur J Neurosci 1999;11:2906–2916.
  95. Meaney M, Seckl J: Glucocorticoid programming. Ann NY Acad Sci 2004;1032:63–84.
  96. Roughton EC, Schneider ML, Bromley LJ, Coe CL: Maternal endocrine activation during pregnancy alters neurobehavioral state in primate infants. Am J Occup Ther 1998;52:90–98.
  97. Schneider M, Moore C, Kraemer G: Moderate level alcohol during pregnancy, prenatal stress, or both and limbic-hypothalamic- pituitary-adrenocortical axis response to stress in rhesus monkeys. Child Dev 2004;75:96–109.
  98. Schneider ML: Prenatal stress exposure alters postnatal behavioral expression under conditions of novelty challenge in rhesus monkey infants. Dev Psychobiol 1992;25:529–540.
  99. McEwen BS: Glucocorticoid-biogenic amine interactions in relation to mood and behavior. Biochem Pharmacol 1987;36:1755–1763.
  100. Maes M, Meltzer HY, D’Hondt P, Cosyns P, Blockx P: Effects of serotonin precursors on the negative feedback effects of glucocorticoids on hypothalamic-pituitary-adrenal axis function in depression. Psychoneuroendocrinology 1995;20:149–167.
  101. Meador-Woodruff JH, Greden JF, Grunhaus L, Haskett RF: Severity of depression and hypothalamic-pituitary-adrenal axis dysregulation: identification of contributing factors. Acta Psychiatr Scand 1990;81:364–371.
  102. Nemeroff CB, Widerlov E, Bissette G, et al: Elevated concentrations of CSF corticotropin-releasing factor-like immunoreactivity in depressed patients. Science 1984;226:1342–1344.
  103. van Praag HM: Depression. Lancet 1982;2:1259–1264.
  104. Wadhwa PD, Garite TJ, Porto M, et al: Placental corticotropin-releasing hormone (CRH), spontaneous preterm birth, and fetal growth restriction: a prospective investigation. Am J Obstet Gynecol 2004;191:1063–1069.
  105. Wadhwa PD, Sandman CA, Garite TJ: The neurobiology of stress in human pregnancy: implications for prematurity and development of the fetal central nervous system. Prog Brain Res 2001;133:131–142.
  106. Lou HC, Hansen D, Nordentoft M, et al: Prenatal stressors of human life affect fetal brain development. Dev Med Child Neurol 1994;36:826–832.
  107. van Os J, Selten J: Prenatal exposure to maternal stress and subsequent schizophrenia. Br J Psychiatry 1998;172:324–326.
  108. Field T: Stress and coping from pregnancy through the postnatal period; in Cummings EG, Green AL, Karraker KH (eds): Life-Span Developmental Psychology: Perspectives on Stress and Coping. Hillsdale, Lawrence Erlbaum Associates, 1991, pp 45–59.
  109. Huizink AC, Robles de Medina PG, Mulder EJ, Visser GH, Buitelaar JK: Stress during pregnancy is associated with developmental outcome in infancy. J Child Psychol Psychiatry 2003;44:810–818.
  110. Levy-Shiff R, Dimitrovsky L, Shulman S, et al: Cognitive appraisals, coping strategies, and support resources as correlates of parenting and infant development. Dev Psychobiol 1998;34:1417–1427.
  111. Meijer A: Child psychiatric sequelae of maternal war stress. Acta Psychiatr Scand 1985;72:505–511.
  112. Stott DH: Follow-up study from birth of the effects of prenatal stresses. Dev Med Child Neurol 1973;15:770–787.
  113. Ward AJ: Prenatal stress and childhood psychopathology. Child Psychiatry Hum Dev 1991;22:97–110.
  114. DePietro J: The role of prenatal maternal stress in child development. Curr Dir Psychol Sci 2004;13:71–74.

    External Resources

  115. McEwen BS: Protective and damaging effects of stress mediators. N Engl J Med 1998;338:171–179.
  116. McEwen BS: Early life influences on life-long patterns of behavior and health. Ment Retard Dev Disabil Res Rev 2003;9:149–154.
  117. Nguyen TT, Tseng YT, McGonnigal B, et al: Placental biogenic amine transporters: in vivo function, regulation and pathobiological significance. Placenta 1999;20:3–11.
  118. Meyer JS: Biochemical effects of corticosteroids on neural tissues. Physiol Rev 1985;65:946–1020.
  119. Lopez Bernal A, Craft IL: Corticosteroid metabolism in vitro by human placenta, fetal membranes and decidua in early and late gestation. Placenta 1981;2:279–285.
  120. Benediktsson R, Lindsay RS, Noble J, Seckl JR, Edwards CR: Glucocorticoid exposure in utero: new model for adult hypertension. Lancet 1993;341:339–341.
  121. Murphy VE, Zakar T, Smith R, Giles WB, Gibson PG, Clifton VL: Reduced 11beta-hydroxysteroid dehydrogenase type 2 activity is associated with decreased birth weight centile in pregnancies complicated by asthma. J Clin Endocrinol Metab 2002;87:1660–1668.
  122. Stewart P, Roberson F, Mason J: Type 2 11-hydroxysteroid dehydrogenase messenger RNA and activity in human placenta and fetal membranes: its relationship to birth weight and putative role in fetal steroidogenesis. J Clin Endocrinol Metab 1995;80:885–890.
  123. McTernan CL, Draper N, Nicholson H, et al: Reduced placental 11beta-hydroxysteroid dehydrogenase type 2 mRNA levels in human pregnancies complicated by intrauterine growth restriction: an analysis of possible mechanisms. J Clin Endocrinol Metab 2001;86:4979–4983.
  124. Shams M, Kilby MD, Somerset DA, et al: 11Beta-hydroxysteroid dehydrogenase type 2 in human pregnancy and reduced expression in intrauterine growth restriction. Hum Reprod 1998;13:799–804.
  125. Dave-Sharma S, Wilson R, Harbison M: Extensive personal experience: examination of genotype and phenotype relationships in 14 patients with apparent mineralocorticoid excess. J Clin Endocrinol Metab 1998;83:2244–2254.
  126. Seckl JR, Cleasby M, Nyirenda MJ: Glucocorticoids, 11beta-hydroxysteroid dehydrogenase, and fetal programming. Kidney Int 2000;57:1412–1417.
  127. Edwards CR, Benediktsson R, Lindsay RS, Seckl JR: Dysfunction of placental glucocorticoid barrier: link between fetal environment and adult hypertension? Lancet 1993;341:355–357.
  128. Seckl JR: Glucocorticoids, feto-placental 11 beta-hydroxysteroid dehydrogenase type 2, and the early life origins of adult disease. Steroids 1997;62:89–94.
  129. Gould E, Woolley CS, Cameron HA, Daniels DC, McEwen BS: Adrenal steroids regulate postnatal development of the rat dentate gyrus. II. Effects of glucocorticoids and mineralocorticoids on cell birth. J Comp Neurol 1991;313:486–493.
  130. Gould E, Woolley CS, McEwen BS: Adrenal steroids regulate postnatal development of the rat dentate gyrus. I. Effects of glucocorticoids on cell death. J Comp Neurol 1991;313:479–485.
  131. Bohn MC: Granule cell genesis in the hippocampus of rats treated neonatally with hydrocortisone. Neuroscience 1980;5:2003–2012.
  132. Sarkar S, Tsai SW, Nguyen TT, Plevyak M, Padbury JF, Rubin LP: Inhibition of placental 11beta-hydroxysteroid dehydrogenase type 2 by catecholamines via alpha-adrenergic signaling. Am J Physiol Regul Integr Comp Physiol 2001;281:R1966–R1974.
  133. Bzoskie L, Yen J, Tseng YT, Blount L, Kashiwai K, Padbury JF: Human placental norepinephrine transporter mRNA: expression and correlation with fetal condition at birth. Placenta 1997;18:205–210.
  134. Bottalico B, Larsson I, Brodszki J, et al: Norepinephrine transporter (NET), serotonin transporter (SERT), vesicular monoamine transporter (VMAT2) and organic cation transporters (OCT1, 2 and EMT) in human placenta from pre-eclamptic and normotensive pregnancies. Placenta 2004;25:518–529.
  135. Jacob S, Moley KH: Gametes and embryo epigenetic reprogramming affect developmental outcome: implication for assisted reproductive technologies. Pediatr Res 2005;58:437–446.
  136. Colvis CM, Pollock JD, Goodman RH, et al: Epigenetic mechanisms and gene networks in the nervous system. J Neurosci 2005;25:10379–10389.
  137. Oberlander TF, Weinberg J, Papsdorf M, Grunau R, Misri S, Devlin AM: Prenatal exposure to maternal depression, neonatal methylation of human glucocorticoid receptor gene (NR3C1) and infant cortisol stress responses. Epigenetics 2008;3:97–106.
  138. Kumar A, Choi K, Renthal W, et al: Chromatin remodeling is a key mechanism underlying cocaine-induced plasticity in striatum. Neuron 2005;48:303–314.
  139. Loeber R, Burke JD, Lahey BB, Winters A, Zera M: Oppositional defiant and conduct disorder: a review of the past 10 years, part I. J Am Acad Child Adolesc Psychiatry 2000;39:1468–1484.
  140. Hawkins JD, Graham JW, Maguin E, Abbott R, Hill KG, Catalano RF: Exploring the effects of age of alcohol use initiation and psychosocial risk factors on subsequent alcohol misuse. J Stud Alcohol 1997;58:280–290.
  141. Ellickson PL, Tucker JS, Klein DJ: High-risk behaviors associated with early smoking: results from a 5-year follow-up. J Adolesc Health 2001;28:465–473.
  142. Tarter R, Vanyukov M, Giancola P, et al: Etiology of early age onset substance use disorder: a maturational perspective. Dev Psychopathol 1999;11:657–683.
  143. Brook JS, Whiteman MM, Finch S: Childhood aggression, adolescent delinquency, and drug use: a longitudinal study. J Genet Psychol 1992;153:369–383.
  144. Blackson TC, Butler T, Belsky J, Ammerman RT, Shaw DS, Tarter RE: Individual traits and family contexts predict sons’ externalizing behavior and preliminary relative risk ratios for conduct disorder and substance use disorder outcomes. Drug Alcohol Depend 1999;56:115–131.
  145. Chassin L, Barrera MJ: Substance use escalation and substance use restraint among adolescent children of alcoholics. Psychol Addict Bahav 1993;7:3–20.

    External Resources

  146. Tarter RE, Blackson T, Brigham J, Moss H, Caprara GV: The association between childhood irritability and liability to substance use in early adolescence: a 2-year follow-up study of boys at risk for substance abuse. Drug Alcohol Depend 1995;39:253–261.
  147. Clark DB, Parker AM, Lynch KG: Psychopathology and substance-related problems during early adolescence: a survival analysis. J Clin Child Psychol 1999;28:333–341.
  148. Aytaclar S, Tarter RE, Kirisci L, Lu S: Association between hyperactivity and executive cognitive functioning in childhood and substance use in early adolescence. J Am Acad Child Adolesc Psychiatry 1999;38:172–178.
  149. Giancola P, Martin C, Tarter R, et al: Executive cognitive functioning and aggressive behavior in preadolescent boys at high risk for substance abuse. J Stud Alcohol 1996;57:352–359.
  150. Shoal G, Giancola P: Executive cognitive functioning, negative affectivity, and drug use in adolescent boys with and without a family history of a substance use disorder. J Child Adolesc Subst Abuse 2001;10:111–121.

    External Resources

  151. Tarter RE, Kirisci L, Mezzich A, et al: Neurobehavioral disinhibition in childhood predicts early age at onset of substance use disorder. Am J Psychiatry 2003;160:1078–1085.
  152. Volkow ND, Li TK: Drugs and alcohol: treating and preventing abuse, addiction and their medical consequences. Pharmacol Ther 2005;108:3–17.
  153. Sowell ER, Thompson PM, Toga AW: Mapping changes in the human cortex throughout the span of life. Neuroscientist 2004;10:372–392.
  154. Sowell ER, Thompson PM, Peterson BS, et al: Mapping cortical gray matter asymmetry patterns in adolescents with heavy prenatal alcohol exposure. Neuroimage 2002;17:1807–1819.
  155. Giedd J: Brain development. IX. Human brain growth. Am J Psychiatry 1999;156:4.
  156. Paus T, Zijdenbos A, Worsley K, et al: Structural maturation of neural pathways in children and adolescents: in vivo study. Science 1999;283:1908–1911.
  157. Gogtay N, Giedd JN, Lusk L, et al: Dynamic mapping of human cortical development during childhood through early adulthood. Proc Natl Acad Sci USA 2004;101:8174–8179.
  158. Bauer LO, Hesselbrock VM: P300 decrements in teenagers with conduct problems: implications for substance abuse risk and brain development. Biol Psychiatry 1999;46:263–272.
  159. Giancola P, Tarter R: Executive cognitive functioning and risk for substance abuse. Psychol Sci 1999;10:203–205.

    External Resources

  160. Schweinsburg AD, Paulus MP, Barlett VC, et al: An fMRI study of response inhibition in youths with a family history of alcoholism. Ann NY Acad Sci 2004;1021:391–394.
  161. Fuster JM: Executive frontal functions. Exp Brain Res 2000;133:66–70.
  162. Chambers RA, Taylor JR, Potenza MN: Developmental neurocircuitry of motivation in adolescence: a critical period of addiction vulnerability. Am J Psychiatry 2003;160:1041–1052.
  163. Spear L: Neurobehavioral changes in adolescence. Curr Dir Psychol Sci 2000;9:111–114.

    External Resources

  164. Romeo RD, McEwen BS: Stress and the adolescent brain. Ann NY Acad Sci 2006;1094:202–214.
  165. McEwen BS, De Kloet ER, Rostene W: Adrenal steroid receptors and actions in the nervous system. Physiol Rev 1986;66:1121–1188.
  166. Meaney MJ, Aitken DH: [3H]Dexamethasone binding in rat frontal cortex. Brain Res 1985;328:176–180.
  167. Diorio D, Viau V, Meaney MJ: The role of the medial prefrontal cortex (cingulate gyrus) in the regulation of hypothalamic-pituitary-adrenal responses to stress. J Neurosci 1993;13:3839–3847.
  168. Sanchez MM, Young LJ, Plotsky PM, Insel TR: Distribution of corticosteroid receptors in the rhesus brain: relative absence of glucocorticoid receptors in the hippocampal formation. J Neurosci 2000;20:4657–4668.
  169. Patel PD, Lopez JF, Lyons DM, Burke S, Wallace M, Schatzberg AF: Glucocorticoid and mineralocorticoid receptor mRNA expression in squirrel monkey brain. J Psychiatr Res 2000;34:383–392.
  170. Paule MG, Gillam MP, Allen RR, Chelonis JJ: Effects of chronic in utero exposure to cocaine on behavioral adaptability in rhesus monkey offspring when examined in adulthood. Ann NY Acad Sci 2000;914:412–417.
  171. Chelonis JJ, Gillam MP, Paule MG: The effects of prenatal cocaine exposure on reversal learning using a simple visual discrimination task in rhesus monkeys. Neurotox- icol Teratol 2003;25:437–446.
  172. McEwen BS: Glucocorticoids, depression, and mood disorders: structural remodeling in the brain. Metabolism 2005;54(suppl 1):20–23.

    External Resources

  173. Isgor C, Kabbaj M, Akil H, Watson SJ: Delayed effects of chronic variable stress during peripubertal-juvenile period on hippocampal morphology and on cognitive and stress axis functions in rats. Hippocampus 2004;14:636–648.
  174. Radley JJ, Rocher AB, Miller M, et al: Repeated stress induces dendritic spine loss in the rat medial prefrontal cortex. Cereb Cortex 2006;16:313–320.
  175. Gunnar M, Prudhomme-White B: Salivary cortisol measures in infant and child assessment; in Twarog-Singer L, Zeskind PS (eds): Biobehavioral Assessment of the Infant. New York, Guilford Press, 2001.
  176. Magnano CL, Gardner JM, Karmel BZ: Differences in salivary cortisol levels in cocaine-exposed and noncocaine-exposed NICU infants. Dev Psychobiol 1992;25:93–103.
  177. Jacobson SW, Bihun JT, Chiodo LM: Effects of prenatal alcohol and cocaine exposure on infant cortisol levels. Dev Psychopathol 1999;11:195–208.
  178. Scafidi FA, Field TM, Wheeden A, et al: Cocaine-exposed preterm neonates show behavioral and hormonal differences. Pediatrics 1996;97(part 1):851–855.
  179. Harvey JA: Cocaine effects on the developing brain: current status. Neurosci Biobehav Rev 2004;27:751–764.
  180. Mayes LC: Developing brain and in utero cocaine exposure: effects on neural ontogeny. Dev Psychopathol 1999;11:685–714.
  181. Lester BM, Tronick EZ, LaGasse L, et al: The maternal lifestyle study: effects of substance exposure during pregnancy on neurodevelopmental outcome in 1-month-old infants. Pediatrics 2002;110:1182–1192.
  182. Lester BM, Lagasse L, Seifer R, et al: The Maternal Lifestyle Study (MLS): effects of prenatal cocaine and/or opiate exposure on auditory brain response at one month. J Pediatr 2003;142:279–285.
  183. Miller-Loncar C, Lester BM, Seifer R, et al: Predictors of motor development in children prenatally exposed to cocaine. Neurotoxicol Teratol 2005;27:213–220.
  184. Sheinkopf S, Lester B, LaGasse L, et al: Neonatal irritability, prenatal substance exposure, and later parenting stress. J Pediatr Psychol 2005;31:27–40.
  185. Tronick EZ, Messinger DS, Weinberg MK, et al: Cocaine exposure is associated with subtle compromises of infants’ and mothers’ social-emotional behavior and dyadic features of their interaction in the face-to-face still-face paradigm. Dev Psychol 2005;41:711–722.
  186. Seifer R, LaGasse LL, Lester B, et al: Attachment status in children prenatally exposed to cocaine and other substances. Child Dev 2004;75:850–868.
  187. Bendersky M, Lewis M: Arousal modulation in cocaine-exposed infants. Dev Psychol 1998;34:555–564.
  188. DiPietro J, Suess P, Wheeler J, Smouse P, Newlin D: Reactivity and regulation in cocaine-exposed neonates. Infant Behav Dev 1995;18:407–414.

    External Resources

  189. Gingras JL, O’Donnell KJ, Hume RF: Maternal cocaine addiction and fetal behavioral state. I. A human model for the study of sudden infant death syndrome. Med Hypotheses 1990;33:227–230.
  190. Gingras JL, O’Donnell KJ: State control in the substance-exposed fetus. I. The fetal neurobehavioral profile: an assessment of fetal state, arousal, and regulation competency. Ann NY Acad Sci 1998;846:262–276.
  191. Mayes LC, Bornstein MH, Chawarska K, Granger RH: Information processing and developmental assessments in 3-month-old infants exposed prenatally to cocaine. Pediatrics 1995;95:539–545.
  192. Regalado M, Schechtman V, del Angel A, Bean X: Sleep disorganization in cocaine-exposed neonates. Infant Behav Dev 1995;18:319–327.

    External Resources

  193. Regalado MG, Schechtman VL, Del Angel AP, Bean XD: Cardiac and respiratory patterns during sleep in cocaine-exposed neonates. Early Hum Dev 1996;44:187–200.
  194. Susman EJ: Psychobiology of persistent antisocial behavior: stress, early vulnerabilities and the attenuation hypothesis. Neurosci Biobehav Rev 2006;30:376–389.
  195. Gold PW, Chrousos GP: Organization of the stress system and its dysregulation in melancholic and atypical depression: high vs. low CRH/NE states. Mol Psychiatry 2002;7:254–275.
  196. Richardson GA: Prenatal cocaine exposure: a longitudinal study of development. Ann NY Acad Sci 1998;846:144–152.
  197. Bennett DS, Bendersky M, Lewis M: Children’s intellectual and emotional-behavioral adjustment at 4 years as a function of cocaine exposure, maternal characteristics, and environmental risk. Dev Psychol 2002;38:648–658.
  198. Arendt RE, Short EJ, Singer LT, et al: Children prenatally exposed to cocaine: developmental outcomes and environmental risks at seven years of age. J Dev Behav Pediatr 2004;25:83–90.
  199. LaGasse L, Lester B, Seifer R, et al: Prenatal cocaine exposure and cognitive development at school age. Pediatr Res 2004;55:69.
  200. Lester BM, LaGasse LL, Seifer R: Cocaine exposure and children: the meaning of subtle effects. Science 1998;282:633–634.
  201. Singer LT, Minnes S, Short E, et al: Cognitive outcomes of preschool children with prenatal cocaine exposure. JAMA 2004;291:2448–2456.
  202. Mentis M: In utero cocaine exposure and language development. Semin Speech Lang 1998;19:147–164, quiz 165.
  203. Bandstra ES, Vogel AL, Morrow CE, Xue L, Anthony JC: Severity of prenatal cocaine exposure and child language functioning through age seven years: a longitudinal latent growth curve analysis. Subst Use Misuse 2004;39:25–59.
  204. Lewis BA, Singer LT, Short EJ, et al: Four-year language outcomes of children exposed to cocaine in utero. Neurotoxicol Teratol 2004;26:617–627.
  205. Bandstra ES, Morrow CE, Vogel AL, et al: Longitudinal influence of prenatal cocaine exposure on child language functioning. Neurotoxicol Teratol 2002;24:297–308.
  206. Morrow CE, Bandstra ES, Anthony JC, Ofir AY, Xue L, Reyes MB: Influence of prenatal cocaine exposure on early language development: longitudinal findings from four months to three years of age. J Dev Behav Pediatr 2003;24:39–50.
  207. Loebstein R, Koren G: Pregnancy outcome and neurodevelopment of children exposed in utero to psychoactive drugs: the Motherisk experience. J Psychiatry Neurosci 1997;22:192–196.
  208. Noland JS, Singer LT, Short EJ, et al: Prenatal drug exposure and selective attention in preschoolers. Neurotoxicol Teratol 2005;27:429–438.
  209. Schroder MD, Snyder PJ, Sielski I, Mayes L: Impaired performance of children exposed in utero to cocaine on a novel test of visuospatial working memory. Brain Cogn 2004;55:409–412.
  210. Bandstra ES, Morrow CE, Anthony JC, Accornero VH, Fried PA: Longitudinal investigation of task persistence and sustained attention in children with prenatal cocaine exposure. Neurotoxicol Teratol 2001;23:545–559.
  211. Delaney-Black V, Covington C, Templin T, Ager J, Martier S, Sokol R: Prenatal cocaine exposure and child behavior. Pediatrics 1998;102(part 1):945–950.
  212. Delaney-Black V, Covington C, Templin T, et al: Teacher-assessed behavior of children prenatally exposed to cocaine. Pediatrics 2000;106:782–791.
  213. Mayes L, Snyder PJ, Langlois E, Hunter N: Visuospatial working memory in school-aged children exposed in utero to cocaine. Child Neuropsychol 2007;13:205–218.
  214. Morrow CE, Culbertson JL, Accornero VH, Xue L, Anthony JC, Bandstra ES: Learning disabilities and intellectual functioning in school-aged children with prenatal cocaine exposure. Dev Neuropsychol 2006;30:905–931.
  215. Levine T, Liu J, Das A, et al: Effects of prenatal cocaine exposure on special education in school age children. Pediatrics 2008;122:e83–e91.
  216. Covington C, Nordstrom-Klee B, Delaney-Black V, Templin T, Ager J, Sokol RJ: Development of an instrument to assess problem behavior in first grade students prenatally exposed to cocaine. Part II. Validation. Subst Abus 2001;22:217–233.
  217. Linares TJ, Singer LT, Kirchner HL, et al: Mental health outcomes of cocaine-exposed children at 6 years of age. J Pediatr Psychol 2006;31:85–97.
  218. Accornero VH, Morrow CE, Bandstra ES, Johnson AL, Anthony JC: Behavioral outcome of preschoolers exposed prenatally to cocaine: role of maternal behavioral health. J Pediatr Psychol 2002;27:259–269.
  219. Bada HS, Das A, Bauer CR, et al: Impact of prenatal cocaine exposure on child behavior problems through school age. Pediatrics 2007;119:e348–e359.
  220. Savage J, Brodsky NL, Malmud E, Giannetta JM, Hurt H: Attentional functioning and impulse control in cocaine-exposed and control children at age ten years. J Dev Behav Pediatr 2005;26:42–47.
  221. Wasserman GA, Kline JK, Bateman DA, et al: Prenatal cocaine exposure and school-age intelligence. Drug Alcohol Depend 1998;50:203–210.
  222. Hurt H, Malmud E, Betancourt L, Brodsky NL, Giannetta J: A prospective evaluation of early language development in children with in utero cocaine exposure and in control subjects. J Pediatr 1997;130:310–312.
  223. Pulsifer MB, Radonovich K, Belcher HM, Butz AM: Intelligence and school readiness in preschool children with prenatal drug exposure. Child Neuropsychol 2004;10:89–101.
  224. Warner TD, Behnke M, Eyler FD, et al: Diffusion tensor imaging of frontal white matter and executive functioning in cocaine-exposed children. Pediatrics 2006;118:2014–2024.
  225. Dow-Edwards DL, Benveniste H, Behnke M, et al: Neuroimaging of prenatal drug exposure. Neurotoxicol Teratol 2006;28:386–402.
  226. Avants BB, Hurt H, Giannetta JM, et al: Effects of heavy in utero cocaine exposure on adolescent caudate morphology. Pediatr Neurol 2007;37:275–279.
  227. Neyzi N, Quinn B, Kekatpure D, et al: Automated Segmentation of Brain Structures in a Pediatric Population with Prenatal Cocaine Exposure. San Diego, Society for Neuroscience, 2007.
  228. Hurt H, Giannetta JM, Korczykowski M, et al: Functional magnetic resonance imaging and working memory in adolescents with gestational cocaine exposure. J Pediatr 2008;152:371–377.
  229. Sheinkopf S, Lester B, Sanes J, et al: Functional MRI and response inhibition in children exposed to cocaine in utero. Dev Neurosci, in press.
  230. Rao H, Wang J, Giannetta J, et al: Altered resting cerebral blood flow in adolescents with in utero cocaine exposure revealed by perfusion functional MRI. Pediatrics 2007;120:e1245–e1254.
  231. Smith LM, Chang L, Yonekura ML, et al: Brain proton magnetic resonance spectroscopy and imaging in children exposed to cocaine in utero. Pediatrics 2001;107:227–231.
  232. Wetherington C, Smeriglio V, Finnegan L: Behavioral Studies of Drug-Exposed Offspring: Methodological Issues in Human and Animal Research. NIDA Monograph Series 164. Rockville, National Institute on Drug Abuse, 1998.
  233. Frank DA, Augustyn M, Knight WG, Pell T, Zuckerman B: Growth, development, and behavior in early childhood following prenatal cocaine exposure: a systematic review. JAMA 2001;285:1613–1625.
  234. Lester BM, ElSohly M, Wright LL, et al: The Maternal Lifestyle Study: drug use by meconium toxicology and maternal self-report. Pediatrics 2001;107:309–317.
  235. Blum K, Cull J, Braverman E, Comings D: Reward deficiency syndrome. Am Sci 1996;84:132–145.

    External Resources

  236. Wang GJ, Volkow ND, Logan J, et al: Brain dopamine and obesity. Lancet 2001;357:354–357.
  237. Shankaran S, Das A, Bada H, et al: Prenatal cocaine exposure predicts blood pressure at 9 years of age. Presented at the Pediatric Academic Society Annual Meeting. May 16th, 2005; Washington , DC. http://www.abstracts2view.com/pasall/view.php? nu=PAS5L1_694