Postnatal Effects of Prenatal Exposure to Psychoactive Drugs
Publication Date:March 1991
Exposure to anxiolytic drugs during the third week of gestation in the rat leaves a lasting imprint on the organism. Functionally, animals exposed prenatally to diazepam (Valium) demonstrate alterations in arousal-attention and stress-related functions. Neural systems underlying these functions are also influenced by the early exposure. The effects of early diazepam exposure are related to the interaction of the drug in utero with specific binding sites in the fetal brain. The consequences of the early exposure, however, often do not become evident until after a period of normal development and become most apparent as the organism reaches young adulthood (late adolescence). These observations suggest that changes that take place in an organism during puberty are necessary for full expression of the effects of prenatal diazepam exposure. Furthermore, the results implicate perinatal insults at the molecular level in the etiology of behavioral disorders that emerge during adolescence.
Aaltonen, L., Erkkola, R. & Kanto, J. (1983). Benzodiazepine receptors in the human fetus. Biol. Neonate 44, 54-57.
Anholt, R.R.H., De Souza, E.B., Oster-Granite, M.L. & Snyder, S.H. (1985). Peripheral type benzodiazepine receptors: Autoradiographic localization in whole-body sections of neonatal rats. Journal of Pharmacology and Experimental Therapeutics 233, 517-526.
Anholt, R.R.H., Peterson, P.L. De Souza, E.B. & Snyder, S.H. (1986). The peripheral benzodiazepine receptor: Localization to mitochondrial membranes. Journal Biologic Chemistry 261, 576-583.
Belin, M.F., Gamrani, H., Agnera, M., Calas, A. & Pujol, J.F. (1980). Selective uptake of [^sup 3^H]gammaaminobutyrate by rat supra- and subependymal nerve fibers: Histologic and high resolution radioautographic studies. Neuroscience 5, 241-254.
Braestrup, C. & Nielsen, M. (1978). Ontogenetic development of benzodiazepine receptors in the brain. Brain Research 147, 170-173.
Brooksbank, B.W.L., Atkinson, D.J. & Balazs, R. (1982). Biochemical development of the human brain. III. Benzodiazepine receptors, free gamma-aminobutyrate (GABA) and other amino acids. J. Neurosci. Res. 8, 581-594.
Campbell, M. & Spencer, E.K. (1988). Psychopharmacology in child and adolescent psychiatry: A review of the past five years. Journal of American Academy of Child and Adolescent Psychiatry 27, 269-279.
Curran, T. & Morgan, J.I. (1985). Superinduction of C-fos by nerve growth factor in the presence of peripherally active benzodiazepines. Science 229, 1265-1268.
Dobbing, J. (1974). Prenatal nutrition and neurologic development. In J. Crovido, L. Hambraeus & B. Vahlquist (Eds.). Early Malnutrition and Mental Development (pp. 96-110). Stockholm: Almquist & Wiksel.
Doble, A., Malgouris, C, Daniel, M., Daniel, N., Imbault, F., Basbaum, A., Uzan, A., Gueremy, C. & Le Fur, G. (1987). Labelling of peripheral-type benzodiazepine binding sites in human brain with [^sup 3^H]PK11195: Anatomical and subcellular distribution. Brain Research Bulletin 18, 49-61.
File, S.F. (1985). Animal models for predicting clinical efficacy of anxiolytic drugs: Social behavior. Neuropsychology 13, 55-62.
Frieder, B. & Grimm, V.E. (1985). Some long-lasting neurochemical effects of prenatal or early postnatal exposure to diazepam. Journal of Neurochemistry 45, 37-43.
Frieder, B., Epstein, S. & Grimm, V.E. (1984). The effects of exposure to diazepam during various stages of gestation or during lactation on the development and behavior of rat pups. Psychopharmacology 83, 51-55.
Friedhoff, A.J. & Miller, J.C. (1983). Prenatal psychotropic drug exposure and the development of central dopaminergic and cholinergic neurotransmitter systems. Monographs in Neural Science 9, 91-98.
Gai, N. & Grimm, V.E. (1982). The effect of prenatal exposure to diazepam on aspects of postnatal development and behavior in rats. Psychopharmacology 78, 225-229.
Guillet, R. & Kellogg, C.K. (1988). Age-related effects of handling, diazepam exposure, and gonadectomy on corticosterone response to stress in the rat. Soc. Neurosci. Abstracts 14, 112.5.
Harlow, H.F., Dodsworth, R.O. & Harlow, M.K. (1965). Total social isolation in monkeys. Proceedings of the National Academy of Sciences 54, 90-97.
Hebebrand, J., Friedl, W. & Propping, P. (1988). The concept of isoreceptors: Application to the nicotenic acetylcholine receptor and the gamma-aminobutyric acid^sup A^/ benzodiazepine receptor complex. Journal Neural Transmission 71, 1-9.
Hoffman, H.S. & Searle, J.L. (1965). Acoustic variables in the modification of startle reaction in the rat. Journal of Comparative and Physiological Psychology 60, 53-58.
Hokfelt, T., Holets, V.R., Staines, W., Meister, B., Melander, T., Schalling, M., Schultzberg, M., Freedman, J., Bjorklund, H., Olson, L., Lindh, B., Elfvin, L-G., Lundberg, J.M., Lindren, J.A., Samuelson, B., Pernow, B., Terenius, L., Post, C, Everitt, B. & Goldstein, M. (1986). Coexistence of neuronal messengers. Progress in Brain Research 68, 33-70.
Hubel, D.H. & Wiesel, T.N. (1970). The period of susceptibility to the physiological effects of eye closure in kittens. Journal of Physiology 206, 419-436.
Ison, J.R. (1982). Temporal acuity in auditory function in the rat: Reflex inhibition by brief gaps in noise. Journal of Comparative and Physiological Psychology 96, 945-954.
Kellogg, C.K. (1988). Benzodiazepines: Influence on the developing brain. Progress in Brain Research 73, 207-228.
Kellogg, C.K. & Wennerstrom, G. (1974). An ontogenic study on the effect of catecholamine receptor-stimulating agents on the turnover of noradrenaline and dopamine in the brain. Brain Research 79, 451-464.
Kellogg, C.K. & Retell, T.M. (1986). Release of [^sup 3^H] norepinephrine: Alteration by early developmental exposure to diazepam. Brain Research 366, 137-144.
Kellogg, C.K. & Pleger, G.L. (1989). GABA-stimulated chloride uptake and enhancement by diazepam in synaptoneurosomes from rat brain during prenatal and postnatal development. Developmental Brain Research, 49, 87-95.
Kellogg, C., Ison, J.R. & Miller, R.K. (1983). Prenatal diazepam exposure: effects on auditory temporal resolution in rats. Psychopharmacology 79, 332-337.
Kellogg, C, Tervo, D., Ison, J., Parisi, T. & Miller, R.K. (1980). Prenatal exposure to diazepam alters behavioral development in rats. Science 297, 205-207.
Langley, J.N. (1906). On nerve-endings and on special excitable substances in cells. Proceedings of the Royal Society of London 78 (Series B), 170-194.
Levitt, M., Hutchings, D.E., Bodnarenko, S.R. & Leicach, L.L. (1982). Postnatal persistence of methadone following prenatal exposure in the rat. Neurobehavioral Toxicology and Teratology 4, 383-385.
Livezey, G.T., Radulovacki, M., Isaac, L. & Marczynski, J. (1985). Prenatal exposure to diazepam results in enduring reductions in brain receptors and slow wave sleep. Brain Research 334, 361-365.
Livezey, G.T., Marczynski, T.J. & Isaac, L. (1986). Enduring effects of prenatal diazepam on the behavior, EEG and brain receptors of the adult cat progeny. Neurotoxicology 7, 319-334.
Lohr, J.B. & Bacha, H.A. (1989). Can schizophrenia be related to prenatal exposure to alcohol? Some speculations. Schizophrenia Bulletin 15, 595-603.
Madtes, P. (1987). Ontogeny of the GABA receptor complex. In D. Redburn & A. Shousboe (Eds.). Neurotrophic Activity of GABA During Development (pp. 161-187). New York: Alan R. Liss, Inc.
McCrosky, R.L. & Kidder, H.C. (1980). Auditory fusion among learning disabled, reading disabled, and normal children. Journal of Learning Disabilities 13, 18-25.
Miller, R.K., Kellogg, C.K. & Saltzman, R.A. (1987). Reproductive and perinatal toxicology. In W.O. Berndt & W. Haley (Eds). Fundamentals of Toxicology (pp. 195-309). Washington, D.C.: Hemisphere Publishing Corporation.
Miranda, R., Wagner, J.P. & Kellogg, C.K. (1989). Early developmental exposure to benzodiazepine ligands alters brain levels of thiobarbituric acid-reactive products in young adult rats. Neurochemical Research 14, 1119-1127.
Miranda, R., Ceckler, T., Guillet, R. & Kellogg, C.K. (1990). Early developmental exposure to benzodiazepine ligands alters brain ^sup 31^P NMR spectra in young adult rats. Brain Research 506, 85-92.
Morgan, J.I., Johnson, M.D., Wang, J.K.T., Sonnenfeld, K.H. & Spector, S. (1985). Peripheral-type benzodiazepines influence ornithine decarboxylase levels and neurite outgrowth in PC12 cells. Proceedings of the National Academy of Sciences 82, 5223-5226.
Oppenheim, R.W. & Kaverkamp, L. (1986). Early development of behavior and the nervous system. In E.M. Blass (Ed.) Handbook of Behavioral Neurobiology (Vol. 8, pp. 1-33). New York: Plenum Press.
Owen, J., Trani, S.F. & Blair, A.W. (1972). Effect of diazepam administered to mothers during labour on temperature regulation of neonate. Archives of the Diseased Child 47, 107-100.
Pazos, A., Cymerman, U., Brobst, A. & Palacios, J.M. (1986). 'Peripheral' benzodiazepine binding sites in human brain and kidney: Autoradiographic studies. Neuroscience Letters 66, 147-152.
Primus, R.J. & Kellogg, C.K. (1989a). Pubertal-related changes influence the development of environment-related social interaction in the male rat. Developmental Psychobiology 22, 633-643.
Primus, R.J. & Kellogg, C.K. (1989b). Sexually dimorphic aspects of social interaction in adult rats are altered by prenatal exposure to diazepam. Society for Neuroscience Abstracts 15, 415 (no. 167.7).
Primus, R.J. & Kellogg, C.K. Developmental influence of gonadal function on the anxiolytic effect of diazepam on environment-related social interaction in the male rat. Behavioural Pharmacology (in press).
Rosenzweig, M.R., Bennett, E.L. & Diamond, M.C. (1972). Chemical and anatomical plasticity of brain: Replications and extensions. In J. Gaito (Ed.). Macromolecules and Behavior (pp. 205-277). New York: Appelton Century Crofts.
Schlumpf, M., Richards, J.G., Lichtensteiger, W. & Mohler, H. (1983). An autoradiographical study of the prenatal development of benzodiazepine binding sites in rat brain. Journal of Neuroscience 3, 1478-1487.
Schultzberg, M., Foster, G.A., Gage, F.H., Bjorklund, A. & Hokfelt, T. (1986). Coexistence during ontogeny and transplantation. Progress in Brain Research 68, 129-145.
Schwartz, R. (1988). The GABAa receptor-gated ion channel: Biochemical and pharmacological studies of structure and function. Biochemical Pharmacology 37, 3369-3375.
Selye, H. (1973). The evolution of the stress concept. American Scientist 61, 692-699.
Simmons, R.D., Miller, R.K. & Kellogg, C.K. (1983). Prenatal diazepam: Distribution and metabolism in perinatal rats. Teratology 28, 181-188.
Simmons, R.D., Kellogg, C.K. & Miller, R.K. (1984). Prenatal diazepam exposure in rats: Long-lasting, receptor-mediated effects on hypothalamic norepinephrine-containing neurons. Brain Research 293, 73-83.
Simmons, R.D., Miller, R.K. & Kellogg, C.K. (1984). Prenatal exposure to diazepam alters central and peripheral responses to stress in adult rat offspring. Brain Research 307, 39-46.
Sullivan, A.T. & Kellogg, C.K. (1985). Dose-related effects of diazepam on noise-induced potentiation of the acoustic startle reflex: Disclosure of several underlying mechanisms. Society for Neuroscience Abstracts 11, 1289.
Tallman, J.F. & Gallagher, D.W. (1985). The GABA-ergic system: A locus of benzodiazepine action. Annual Review of Neuroscience 8, 21-44.
Toran-Allerand, CD. (1986). Sexual differentiation of the brain. In W.T. Greenough & J.M. Juraska (Eds.). Developmental Neuropsychobiology (pp. 175-212). New York: Academic Press.
Trinder, E. (1979). Auditory fusion: A critical test with implications in differential diagnosis. British Journal of Audiology 13, 143-147.
Wang, J.K.T., Morgan, J.I. & Spector, S. (1984). Benzodiazepines that bind at peripheral sites inhibit cell proliferation. Proceedings of the National Academy of Sciences 81, 753-756.
Wolff, J.R. (1981). Evidence for a dual role of GABA as a synaptic transmitter and promoter of synaptogenesis. In F.V. Defeundis & P. Mandel (Eds.). Amino Acid Neurotransmitters (pp. 215-239). New York: Raven Press.
Carol K. Kellogg, Ph.D.
Carol Kellogg received the Ph.D. in Physiology-Neurobiology in 1970. She currently holds the position of Professor in Psychology and Associate Professor of Pharmacology at the University of Rochester, Rochester, NY. Her research is directed towards understanding neural development and related behavioral development. The author gratefully acknowledges the following individuals who participated in the studies reported: Daniel Bitran, Jane A. Chisholm, Ronnie Guillet, Norma Harary, James R. Ison, Rajesh Miranda, Richard K. Miller, Gloria Pleger, Renee Primus, Todd M. Retell, Steven M. Shamah, Roy D. Simmons, Alan T. Sullivan, Donna M. Tervo, and Joseph P. Wagner. Research reported in this paper was supported by PHS grant MH 31850 and by Research Scientist Development Award MH 00651, both from the National Institute of Mental Health. Diazepam and Ro 15-1788 were generously supplied by Dr. William Scott and Dr. Peter Sorter, Hoffmann-LaRoche, Nutley, New Jersey. Special thanks are extended to Prof. Dale McAdam for editorial assistance in the preparation of this manuscript. Address correspondence to the Department of Psychology, University of Rochester, Room 186 Meliora Hall, Rochester, NY 14627.