Abstract
Opioid drugs such as methadone or buprenorphine are often used in the management of pregnant addicts. These drugs are generally thought of as nonteratogenic and preferable to repeated cycles of withdrawal in utero. However, evidence exists that perinatal exposure to these opioids delays and disrupts cholinergic development, particularly in the striatum. Acetylcholine (ACh) content and the expression of choline acetyltransferase protein and mRNA are reduced in the early postnatal period by prenatal opioid exposure in the rat. Although these indicators of the cholinergic phenotype return to normal levels over time, the activity of the cholinergic neurons remains disrupted, with a large increase in ACh turnover rate. The mechanism of these effects is unknown, but may involve changes in the expression of nerve growth factor, which is reduced by opioid exposure.
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Chasnoff IJ, Hatcher R, Burns WJ. Polydrug- and methadone-addicted infants: A continuum of impairment? Pediatrics 70:210–213;1982.
Chasnoff IJ, Burns KA, Burns WJ, Schnoll SH. Prenatal drug exposure: Effects on neonatal and infant growth and development. Neurobehav Toxicol Teratol 8:357–362;1986.
Coyle JT, Yamamura HI. Neurochemical aspects of the ontogenesis of cholinergic neurons in the rat brain. Brain Res 118:429–440;1976.
Davis DD, Templer DI. Neurobehavioral functioning in children exposed to narcotics in utero. Addict Behav 13:275–283;1988.
De Cubas MM, Field T. Children of methadone-dependent women: Developmental outcomes. Am J Orthopsychiatry 63:266–276;1993.
Dinges DF, Davis MM, Glass P. Fetal exposure to narcotics: Neonatal sleep as a measure of nervous system disturbances. Science 209:619–621;1980.
Ebstein RP, Bennett ER, Sokoloff M, Shoham S. The effect of nerve growth factor on cholinergic cells in primary fetal striatal cultures: Characterization by in situ hybridization. Dev Brain Res 73:165–172;1993.
Enters EK, Guo H, Pandey U, Ko D, Robinson SE. The effect of prenatal methadone exposure on development and nociception during the early postnatal period of the rat. Neurotoxicol Teratol 13:161–166;1991.
Forander P, Soderstrom S, Humpel C, Stromberg I. Chronic infusion of nerve growth factor into rat striatum increases cholinergic markers in inhibits striatal discharge rate. Eur J Neurosci 8:1822–1832;1996.
Gould E, Woolf NJ, Butcher LL. Postnatal development of cholinergic neurons in the rat. I. Forebrain. Brain Res Bull 27:767–789;1991.
Guo H, Enters EK, McDowell KP, Robinson SE. The effect of prenatal exposure to methadone on neurotransmitters in neonatal rats. Dev Brain Res 57:296–298;1990.
Hammer RP, Hauser KF. Consequences of early exposure to opioids on cell proliferation and neuronal morphogenesis. In: Miller MW, ed. Development of the Nervous System: Effects of Alcohol and Opiates. New York, Wiley-Liss, 319–339;1992.
Hartikka J, Hefti F. Comparison of nerve growth factor's effects on development of septum, striatum, and nucleus basalis cholinergic neurons in vitro. J Neurosci Res 21:352–364;1988.
Hutchings DE, Towey JP, Gorinson HS, Hunt HF: Methadone during pregnancy: Assessment of behavioral effects in the rat offspring. J Pharmacol Exp Ther 208:106–112;1979.
Hutchings DE, Towey JP, Bodnarenko SR. Effects of prenatal methadone on the activity level in the pre-weanling rat. Neurobehav Toxicol 2:331–335;1980.
Hutchings DE. Behavioral teratology: A new frontier in neurobehavioral research. In: Johnson EM, Kochhar DM, eds. Handbook of Experimental Pharmacology. Berlin, Springer, 65:207–235;1983.
Jarvis MAE, Schnoll SH. Methadone treatment during pregnancy. J Psychoactive Drugs 26:155–161;1994.
Johnston MV, Rutkowski JL, Wainer BH, Long JB, Mobley WC. NGF effects on developing forebrain cholinergic neurons are regionally specific. Neurochem Res 12:985–994;1987.
Koh S, Higgins GA. Differential regulation of the low-affinity nerve growth factor receptor during postnatal development of the rat brain. J Comp Neurol 313:494–508;1991.
Kunko PM, Smith JA, Wallace MJ, Maher JR, Saady JJ, Robinson SE. Perinatal methadone exposure produces physical dependence and altered behavioral development in the rat. J Pharmacol Exp Ther 277:1344–1351;1996.
Marcus J, Hand SL, Jeremy RJ. Differential motor and state functioning in newborns of women on methadone. Neurobehav Toxicol Teratol 4:459–462;1982.
Martínez HJ, Dreyfus CF, Jonakait GM, Black IB. Nerve growth factor promotes cholinergic development in striatal cultures. Proc Natl Acad Sci USA 82:7777–7781;1985.
McGeer EG, Fibiger HC, Wickson V. Differential development of caudate enzymes in the neonatal rat. Brain Res 32:433–440;1971.
Mitsuo K, Schwartz JP. Chronic treatment of newborn rats with naltrexone alters astrocyte production of nerve growth factor. J Mol Neurosci 4:21–28;1993.
Mobley WC, Rutkowski JL, Tennekoon GI, Buchanan K, Johnston MV. Choline acetyltransferase activity in striatum of neonatal rats increased by nerve growth factor. Science 229:284–287;1985.
Mobley WC, Woo JE, Edwards RH, Longo FM, Weskamp G, Otten U, Valletta JS, Johnston MV. Developmental regulation of nerve growth factor and its receptor in the rat caudate-putamen. Neuron 3:655–664;1989.
Robinson SE, Guo H, Enters EK, McDowell KP, Pascua JR. Prenatal exposure to methadone affects central cholinergic neuronal activity in the weanling rat. Dev Brain Res 64:183–188;1991.
Robinson SE, Guo H, Spencer RF. Prenatal exposure to methadone delays the development of striatal cholinergic neurons. Dev Brain Res 76:239–248;1993.
Robinson SE, Mo Q, Wallace MJ, Maher JR, Otey DT, Kunko PM. Perinatal opioid exposure affects cholinergic development in the rat. Soc Neurosci Abstr 21:2017;1995.
Robinson SE, Guo H, Maher JR, McDowell KP, Kunko PM. Postnatal methadone exposure does not prevent prenatal methadone-induced changes in striatal cholinergic neurons. Dev Brain Res 95:118–121;1996.
Robinson SE, Mo Q, Guo H, Maher JR, Wallace MJ, Kunko PM. Perinatal exposure to methadone affects central cholinergic activity in the weanling rat. Drug Alcohol Depend 41:116–126;1996.
Robinson SE, Wu VW, Mo Q, Schwartz JP. Perinatal opioids reduce nerve growth factor (NGF). Proceedings of the 60th Annual Scientific Meeting of the College on Problems of Drug Dependence, NIDA Res Monogr 179:131;1999.
Robinson SE, Halfon LM. Effect of perinatal opioid exposure on neurotrophin mRNAs in rat striatum. Proceedings of the 61st Annual Scientific Meeting of the College on Problems of Drug Dependence. In press.
Ruzicka BB, Fox CA, Thompson RC, Meng F, Watson SJ, Akil H. Primary astroglial cultures derived from several rat brain regions differentially express mu, delta, and kappa opioid receptor mRNA. Mol Brain Res 34:209–220;1995.
Schwartz JP, Nishiyama N. Neurotrophic factor gene expression in astrocytes during development and following injury. Brain Res Bull 35:403–407;1994.
Schwartz JP, Nishiyama N, Wilson D, Taniwaki T. Receptor-mediated regulation of neuropeptide gene expression in atrocytes. Glia 11:185–190;1994.
Semba K, Fibiger HC. Time of origin of cholinergic neurons in the rat basal forebrain. J Comp Neurol 269:87–95;1988.
Semba K, Vincent SR, Fibiger HC. Different times of origin of choline acetyltransferase- and somatostatin-immunoreactive neurons in the rat striatum. J Neurosci 8:3937–3944;1988.
Slotkin TA. Perinatal exposure to methadone: How do early biochemical alterations cause neurofunctional disturbances? In: Boer GJ, Feenstra MGP, Mirmiran M, Swaab DF, Van Haaren F, eds. Progress in Brain Research. Amsterdam, Elsevier, 73:265–279;1988.
Sobrian SK. Prenatal morphine alters behavioral development in the rat. Pharmacol Biochem Behav 7:285–288;1977.
Steine-Martin A, Zhou R, Hauser KF. Regional, developmental, and cell cycle-dependent differences in μ, δ, and κ-opioid receptor expression among cultured mouse astrocytes. Glia 22:249–259;1998.
Strauss ME, Lessen-Finestone JK, Chavez CJ, Stryker JC. Children of methadone-treated women at five years of age. Protracted effects of perinatal drug dependence. Pharmacol Biochem Behav 11(suppl):3–6;1979.
Van Baar AL, Fleury P, Soepatmi S, Ultee CA, Wesselman PJM. Neonatal behaviour after drug dependent pregnancy. Arch Dis Child 64:235–240;1989.
Vantini G, Schiavo N, Di Martino A, Polato P, Triban C, Callegaro L, Toffano G, Leon A. Evidence for a physiological role of nerve growth factor in the central nervous system of neonatal rats. Neuron 3:267–273;1989.
Whittemore SR, Seiger Å. The expression, localization and functional significance of β-nerve growth factor in the central nervous system. Brain Res Rev 12:439–464;1987.
Zagon IM, McLaughlin PJ. The effects of different schedules of methadone treatment on rat brain development. Exp Neurol 56:538–552;1977.
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Robinson, S.E. Effect of prenatal opioid exposure on cholinergic development. J Biomed Sci 7, 253–257 (2000). https://doi.org/10.1007/BF02255474
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DOI: https://doi.org/10.1007/BF02255474