Skip to main content
SpringerLink
Log in

Effects of prenatal exposure to cocaine on the developing brain: Anatomical, chemical, physiological and behavioral consequences

  • Published:
Neurotoxicity Research Aims and scope Submit manuscript

Abstract

Earlier studies of human infants and studies employing animal models had indicated that prenatal exposure to cocaine produced developmental changes in the behavior of the offspring. The present paper reports on the results obtained in a rabbit model ofin utero exposure to cocaine using intravenous injections (4 mg/kg, twice daily) that mimic the pharmacokinetics of crack cocaine in humans. At this dose, cocaine had no effect on the body weight gain of dams, time to delivery, litter size and body weight or other physical characteristics of the offspring. In spite of an otherwise normal appearance, cocaine-exposed neonates displayed a permanent impairment in signal transduction via the D1 dopamine receptor in caudate nucleus, frontal cortex and cingulate cortex due to an uncoupling of the receptor from its associated Gs protein. This uncoupling in the caudate nucleus was shown to have behavioral consequences in that young or adult rabbits, exposed to cocainein utero, failed to demonstrate amphetamine-elicited motor responses normally seen after activation of D1 receptors in the caudate. The cocaine progeny also demonstrated permanent morphological abnormalities in the anterior cingulate cortex due to uncoupling of the D1 receptor and the consequent inability of dopamine to regulate neurite outgrowth during neuronal development. Consistent with the known functions of the anterior cingulate cortex, adult cocaine progeny demonstrated deficits in attentional processes. This was reflected by impairment in discrimination learning during classical conditioning that was due to an inability to ignore salient stimuli even when these were not relevant to the task. The impairment in discrimination learning also occurred in an instrumental avoidance task and could be shown to be due to an impairment of cingulothalamic learning-related neuronal coding. It was proposed that the selective loss of D1-related neurotransmission in the anterior cingulate cortex prevented an appropriate activation of GABA neurons and thus a loss of inhibitory regulation that is necessary for processes involved in associative attention. Taken together, these findings suggest that the uncoupling of the D1 receptor from its G protein may be the fundamental source of the anatomic, cognitive and motor disturbances seen in rabbits exposed to cocainein utero. Moreover, the long-term cognitive and motor deficits observed in the rabbit model are in agreement with recent reports indicating that persistent attentional and other behavioral deficits may be evident in cocaine-exposed children as they grow older and are challenged to master more complex cognitive tasks.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Aloyo, V.J., Ruffin, J.S., Pazdalski, P.S., Kirifides, A.L. and Harvey, J.A. (1995) [3H]WIN 35, 428 binding in the caudate nucleus of the rabbit: evidence for a single site on the dopamine transporter.J. Pharmacol. Exp. Ther. 273, 435–444.

    PubMed  CAS  Google Scholar 

  • Anday, E.K., Cohen, M.E., Kelley, N.E. and Leitner, D.S. (1989) Effect ofin utero cocaine exposure on startle and its modification.Dev. Pharmacol. Ther. 12, 137–145.

    PubMed  CAS  Google Scholar 

  • Anderson-Brown, T., Slotkin, T.A. and Seidler, F.J. (1990) Cocaine acutely inhibits DNA synthesis in developing rat brain regions: evidence for direct actions.Brain Res. 537, 197–202.

    Article  PubMed  CAS  Google Scholar 

  • Atlas, S.J. and Wallach, E.E. (1991) Effects of intravenous cocaine on reproductive function in the mated rabbit.Am. J. Obstet. Gynecol. 165, 1785–1790.

    PubMed  CAS  Google Scholar 

  • Azuma, S.D. and Chasnoff, I.J. (1993) Outcome of children prenatally exposed to cocaine and other drugs: a path analysis of three-year data.Pediatr. 92, 396–402.

    CAS  Google Scholar 

  • Barron, S. and Irvine, J. (1994) Behavioral effects of neonatal cocaine exposure using a rodent model.Pharmacol. Biochem. Behav. 50, 107–114.

    Article  Google Scholar 

  • Benes, F.M., Vincent, S.L. and Molloy, R. (1993) Dopamine-immunoreactive axon varicosities form nonrandom contacts with GABA-immunoreactive neurons in rat medial prefrontal cortex.Synapse 15, 285–295.

    Article  PubMed  CAS  Google Scholar 

  • Benes, EM, Vincent, S.L., Molloy, R. and Khan, Y. (1996) Increased interaction of dopamine-immunoreactive varicosities with GABA neurons of rat medial prefrontal cortex occurs during the postweanling period.Synapse 23, 237–245.

    Article  PubMed  CAS  Google Scholar 

  • Berger, B. and Verney, C. (1984) Development of the catecholamine innervation in rat neocortex. Morphological features. In:Monoamine Innervation of Cerebral Cortex. Descarries, L., Reader, T.R. and Jasper, H.H. (Eds.), pp. 95–121. AlanR. Liss. New York, NY.

    Google Scholar 

  • Besson, M.J., Graybiel, A.M. and Nastuk, M.A. (1988) [3H]SCH 23390 binding to Dl dopamine receptors in the basal ganglia of the cat and primate: delineation of strioso-mal compartments and pallidal and nigral subdivisions.Neuroscience 26:101–119.

    Article  PubMed  CAS  Google Scholar 

  • Bracha, V. and Bloedel, J.R. (1996) The multiple-pathway model of circuits subserving the classical conditioning of withdrawal reflexes. In:The Acquisition of Motor Behavior in Vertebrates. Bloedel, J.R., Ebner, T.J. and Wise, S.P. (Eds.), pp. 175-204.

  • Brogden, W.J. and Culler, F.A. (1936) A device for motor conditioning of small animals.Science 83, 269.

    Article  PubMed  Google Scholar 

  • Buchanan, S.L. and Powell, D.A. (1982) Cingulate cortex: its role in Pavlovian conditioning.J. Comp. Physiol. Psychol. 96, 755–774.

    Article  PubMed  CAS  Google Scholar 

  • Burchfield, D.J. and Abrams, R.M. (1993) Cocaine depresses cerebral glucose utilization in fetal sheep.Dev. Brain Res. 73, 283–288.

    Article  CAS  Google Scholar 

  • Butcher, S.P, Fairbrother, I.S., Kelly, J.S. and Arbuthnott, G.W. (1988) Amphetamine-induced dopamine release in rat striatum: anin vivo microdialysis study.J. Neurochem. 50, 346–355.

    Article  PubMed  CAS  Google Scholar 

  • Butkerait, P., Wang, H.Y. and Friedman, E. (1993) Increases in guanine nucleotide binding to striatal G proteins is associated with dopamine receptor supersensitivity.J. Pharmacol. Exp. Ther. 271, 422–428.

    Google Scholar 

  • Carlson, K.E., Brass, L.F. and Manning, D.R. (1989) Thrombin and phorbol esters cause the selective phosphorylation of a G protein other than Gi in human platelets.J. Biol. Chem. 264, 13298–13305.

    PubMed  CAS  Google Scholar 

  • Chilcoat, H.D. and Johanson, C.E. (1998) Vulnerability to cocaine abuse. In:Cocaine Abuse: Behavior, Pharmacology and Clinical Applications. Higgins, S.T. and Katz, J.L. (Eds.), pp. 313–341. San Diego, CA: Academic Press.

    Google Scholar 

  • Chiriboga, C.A., Bateman, D.A., Brust, J.C.M. and Hauser, W.A. (1993) Neurologic findings in cocaine-exposed infants.Ped. Neurol. 9, 115–119.

    Article  CAS  Google Scholar 

  • Church, M.W. and Overbeck, G.W. (1990) Prenatal cocaine exposure in the long-evans rat: II. Dose-dependent effects on offspring behavior.Neurotox. Teratol. 12, 335–343.

    Article  CAS  Google Scholar 

  • Clark, C.V., Gorman, D. and Vernadakis, A. (1970) Effects of prenatal administration of psychotropic drugs on behavior of developing rats.Dev. Psychobiol. 3, 225–235.

    Article  PubMed  CAS  Google Scholar 

  • Corbetta, M., Miezin, F.M., Dobmeyer, S., Shulman, G.L. and Petersen, S.E. (1991) Selective and divided attention during visual discriminations of shape, color and speed: functional anatomy by positron emission tomography.J. Neurosci. 11, 2383–2402.

    PubMed  CAS  Google Scholar 

  • Cutler, A.R., Wilkerson, A.E., Gingras, J.L. and Levin, E.D. (1996) Prenatal cocaine and/or nicotine exposure in rats: preliminary findings on long-term cognitive outcome and genital development at birth.Neurotoxicol. Teratol. 18, 635–643.

    Article  PubMed  CAS  Google Scholar 

  • Denenberg, V.H., Zeidner, L.P, Thoman, E.B., Kramer, P., Rowe, J.C., Philipps, A.F. and Raye, J.R. (1982) Effects of theophylline on behavioral state development in newborn rabbit.J. Pharmacol. Exp. Ther. 221, 604–608.

    PubMed  CAS  Google Scholar 

  • Dos Santos Rodrigues, P. and Dowling, J.E. (1990) Dopamine induces neurite retraction in retinal horizontal cells via diacylglycerol and protein kinase C.Proc. Natl. Acad. Sci. 87, 9693–9697.

    Article  CAS  Google Scholar 

  • Dow-Edwards, D.L. (1991) Cocaine effects on fetal development: a comparison of clinical and animal research findings.Neurotoxicol. Teratol. 13, 347–352.

    Article  PubMed  CAS  Google Scholar 

  • Du, W., Aloyo, V.J., Pazdelski, P.S. and Harvey, J.A. (1999) Effects of prenatal cocaine exposure on amphetamine-induced dopamine release in the caudate nucleus of the adult rabbit.Brain Res. 836, 194–198.

    Article  PubMed  CAS  Google Scholar 

  • Foss, J.A. and Riley, P. (1991a) Elicitation and Modification of the acoustic startle reflex in animals prenatally exposed to cocaine.Neurotoxicol. Teratol. 13, 541–546.

    Article  PubMed  CAS  Google Scholar 

  • Foss, J.A. and Riley, E.P. (1991b) Failure of acute cocaine administration to differentially affect acoustic startle and activity in rats prenatally exposed to cocaine.Neurotoxicol. Teratol. 13, 547–551.

    Article  PubMed  CAS  Google Scholar 

  • Friedman, E., Yadin, E. and Wang, H.-Y. (1996) Effect of prenatal cocaine on dopamine receptor-G protein coupling in meso-cortical regions of the rabbit brain.Neuroscience 70, 739–747.

    Article  PubMed  CAS  Google Scholar 

  • Friedman, E., Jin, L.-Q., Cai, G.-P, Hollon, T.R., Drago, J., Sibley, D.R. and Wang, H.-Y. (1997) Dj-like dopaminergic activation of phosphoinositide hydrolysis is independent of D1A dopamine receptors: evidence from D1A knockout mice.Mol. Pharmacol. 51, 6–11.

    PubMed  CAS  Google Scholar 

  • Gabriel, M. (1990) Functions of anterior and posterior cingulate cortex during avoidance learning in rabbits. In:Progress in Brain Research, Vol. 85, pp. 467–483. Elsevier Science Publishers B.V., New York.

    Google Scholar 

  • Gabriel, M. (1993) Discriminative avoidance learning: a model system. In:Neurobiology of Cingulate Cortex and Limbic Thalamus: A Comprehensive Handbook. Vogt, B. and Gabriel, M. (Eds.), pp. 478–523. Birkhauser. Boston, MA.

    Google Scholar 

  • Gabriel, M. and Taylor, C. (1998) Prenatal exposure to cocaine impairs neuronal coding of attention and discriminative learning. In:Cocaine: Effects on the Developing Brain. Harvey, J.A. and Kosofsky, B.E. (Eds.) Ann. N.Y. Acad. Sci.846, 194–212.

    CAS  Google Scholar 

  • Gabriel, M., Foster, K., Orona, E., Saltwick, S.E. and Stanton, M. (1980) Neuronal activity of cingulate cortex, anteroventral thalamus and hippocampal formation in discriminative conditioning: encoding and extraction of the significance of conditional stimuli. In:Progress in Psychobiology and Physiological Psychology. Vol. 9, pp. 125–231. Academic Press, New York.

    Google Scholar 

  • Gabriel, M., Kubota, Y, Sparenborg, S., Straube, K. and Vogt, B.A. (1991) Effects of cingulate cortical lesions on avoidance learning and training-induced unit activity in rabbits.Exp. Brain. Res.86, 585–600.

    Article  PubMed  CAS  Google Scholar 

  • Gibbs, CM. and Powell, D.A. (1991) Single-unit activity in the dorsomedial prefrontal cortex during the expression of discriminative bradycardia in rabbits.Behav. Brain Res. 43, 79–92.

    Article  PubMed  CAS  Google Scholar 

  • Gingras, J.L., Weese-Mayer, D.E., Hume Jr., R.F. and O’Donnell, K.J. (1992) Cocaine and development: mechanisms of fetal toxicity and neonatal consequences of prenatal cocaine exposure.Early Human Dev. 31, 1–24.

    Article  CAS  Google Scholar 

  • Goeders, N.E. and Smith, J.E. (1983) Central dopaminergic involvement in cocaine reinforcement.Science 221, 773–775.

    Article  PubMed  CAS  Google Scholar 

  • Golub, M. and Kornetsky, C. (1975) Modification of the behavioral response to drugs in rats exposed prenatally to chlorpromazine.Psychopharmacol. J. 43, 289–291.

    Article  CAS  Google Scholar 

  • Graybiel, A.M., Moratalla, R.H. and Robertson, H. (1990) Amphetamine and cocaine induce drug-specific activation of the c-fos gene in striosome-matrix compartments and limbic subdivisions of the striatum.Proc. Natl. Acad. Sci. USA 87, 6912–6916.

    Article  PubMed  CAS  Google Scholar 

  • Grayson, D.R., Wu, Y, Book, A.A. and Murphy, E.H. (1996) Alterations in GABAA receptor/32 mRNA levels in the anterior cingulate cortex of rabbits exposed prenatally to cocaine.Soc. Neurosci. Abstr. 22, No. 762.9, 1941.

    Google Scholar 

  • Hartman, H.A. (1974) The fetus in experimental teratology. In:The Biology of the Laboratory Rabbit. Flatt, R.E. and Kraus, A.L. (Eds.) pp. 92–144 New York. Academic Press.

    Google Scholar 

  • Harel, S., Watanabe, K., Linke, I. and Schain, R.J. (1972) Growth and development of the rabbit brain.Biol. Neonate 21, 381–399.

    Article  PubMed  CAS  Google Scholar 

  • Harvey, J.A. (1987) Effect of drugs on associative learning. In:Psychopharmacology, The Third Generation of Progress. Meltzer, H. (Ed.) pp. 1485–1491. New York, Raven Press.

    Google Scholar 

  • Harvey, J.A. and Kosofsky, B.E. (1998)Cocaine: Effects on the Developing Brain. Ann. N.Y. Acad. Sci. 846.

  • Henderson, M.G. and McMillan, B.A. (1990) Effects of prenatal exposure to cocaine or related drugs on rat developmental and neurological indices.Brain Res. Bull. 24, 207–212.

    Article  PubMed  CAS  Google Scholar 

  • Henderson, M.G., McConnaughey, M.M. and McMillen, B.A. (1991) Long-term consequences of prenatal exposure to cocaine or related drugs: effects on rat brain monoaminergic receptors,Brain Res. Bull.26, 941–945.

    CAS  Google Scholar 

  • Heyser, C.J., Spear, N.E. and Spear, L.P. (1992) Effects of prenatal exposure to cocaine on conditional discrimination learning in adult rats.Behav. Neurosci. 106, 837–845.

    Article  PubMed  CAS  Google Scholar 

  • Heyser, C.J., Spear, N.E. and Spear, L.P. (1995) Effects of prenatal exposure to cocaine on Morris water maze performance in adult rats.Behav. Neurosci. 109, 734–743.

    Article  PubMed  CAS  Google Scholar 

  • Heyser, C.J., Chen, W.-J., Miller, J., Spear, N.E. and Spear, L.P. (1990) Prenatal cocaine exposure induces deficits in Pavlo-vian conditioning and sensory preconditioning among infant rat pups.Behav. Neurosci. 104, 955–963.

    Article  PubMed  CAS  Google Scholar 

  • Hill, R.M., Desmond, M.M. and Kay, J.L. (1966) Extrapyramidal dysfunction in an infant of a schizophrenic mother.J. Pediatr. 69, 589–595.

    Article  PubMed  CAS  Google Scholar 

  • Hudson, R. and Distel, H. (1986) The potential of the newborn rabbit for behavioral teratological research.Neurobehav. Toxicol. Teratol. 8, 209–212.

    PubMed  CAS  Google Scholar 

  • Hughes, H.E., Donohue, L.M. and Dow-Edwards, D.L. (1996) Prenatal cocaine exposure affects the acoustic startle response in adult rats.Behav. Brain Res.75, 83–90.

    Article  PubMed  CAS  Google Scholar 

  • Hutchings, D.E. (1993) The puzzle of cocaine’s effects following maternal use during pregnancy: are there reconcilable differences?Neurotoxicol. Teratol.15, 281–286.

    CAS  Google Scholar 

  • Hutchings, D.E., Fico, T.A. and Dow-Edwards, D.L. (1989) Prenatal cocaine: maternal toxicity, fetal effects and locomotor activity in rat offspring.Neurotoxicol. Teratol. 11, 65–69.

    Article  PubMed  CAS  Google Scholar 

  • Irle, E. and Markowitsch, H.J. (1982) Single and combined lesions of the cat’s thalamic mediodorsal nucleus and the mammillary bodies lead to severe deficits in the acquisition of an alternation task.Behav. Brain Res. 6, 147–165.

    Article  PubMed  CAS  Google Scholar 

  • Johns, J.M., Means, M.J., Anderson, D.R., Means, L.W. and McMillen, B.A. (1992) Prenatal exposure to cocaine. II: Effects on open-field activity and cognitive behavior in Sprague-Dawley rats.Neurotoxicol. Teratol. 14, 343–349.

    Article  PubMed  CAS  Google Scholar 

  • Jones, R.T. (1990) The pharmacology of cocaine smoking in humans. In: Chiang, C.N. and Hawks, R.L. (Eds.)Research Findings on Smoking of Abused Substances, National Institute on Drug Abuse Research Monograph 99. U.S. Government Printing Office.

  • Jones, L., Fischer, I. and Levitt, P. (1996) Nonuniform alteration of dendritic development in the cerebral cortex following prenatal cocaine exposure.Cereb. Cortex 6, 431–445.

    Article  PubMed  CAS  Google Scholar 

  • Joyce, J.N., Sapp, D.W. and Marshall, J.F. (1986) Human striatal dopamine receptors are organized in compartments.Proc. Natl. Acad. Sciences USA 83, 8002–8006.

    Article  CAS  Google Scholar 

  • Kadata, T., Gilman, A.G., Watanabe, Y., Bauer, S. and Jacobs, K.H. (1985) Protein kinase C phosphorylates the inhibitory guanine nucleotide-binding regulatory component and apparently suppresses its function in hormonal inhibition of adenylate cyclase.Eur. J. Biochem. 151: 431–437.

    Article  Google Scholar 

  • Kamal, L.A., Arbilla, S. and Langer, S.Z. (1981) Presynaptic modulation of the release of dopamine from the rabbit caudate nucleus: differences between electrical stimulation, amphetamine and tyramine,J. Pharmacol. Exp. Ther.216, 592–598.

    CAS  Google Scholar 

  • Kasirsky, G. and Tansy, M.F. (1971) Teratogenic effects of methamphetamine in mice and rabbits.J. Amer. Osteopath. Assoc. 70, 1119–1120.

    CAS  Google Scholar 

  • Kaufmann, R.A., Savoy-Moore, R.T., Sacco, A.G. and Subramanian, M.G. (1990) The effect of cocaine on oocyte development and the follicular microenvironment in the rabbit.Fertil. Steril. 54, 921–926.

    PubMed  CAS  Google Scholar 

  • Kebabian, J.W., Petzold, G.L. and Greengard, P. (1972) Dopa-mine-sensitive adenylate cyclase in caudate nucleus of rat brain and its similarity to the “dopamine receptor.”Proc. Natl. Acad. Sci. USA69, 2145–2149.

    Article  CAS  Google Scholar 

  • Keller, Jr., R.W., Marsonneuve, I.M., Nuccio, D.M., Carlson, J.N. and Click, S.D. (1994) Effects of prenatal cocaine exposure on the nigrostriatal dopamine system: anin vivo microdialysis study in the rat.Brain Res. 634, 266–274.

    Article  PubMed  Google Scholar 

  • Koegler, S.M., Seidler, F.J., Spencer, J.R. and Slotkin, T.A. (1991) Ischemia contributes to adverse effects of cocaine on brain development: suppression of ornithine decarboxylase activity in neonatal rats.Brain Res. Bull. 27, 829–834.

    Article  PubMed  CAS  Google Scholar 

  • Kolb, B. (1990) Animal models for human PFC-related disorders. In:Progress in Brain Research. Vol. 85, pp. 501–519. Elsevier Science Publishers B.V., New York.

    Google Scholar 

  • Kosofsky, B.E. and Friedman, E. (2000) Unpublished data.

  • Kosofsky, B.E. and Wilkins, A.S. (1998) Structural and functional correlates of cocaine induced brain maldevelopment. In:Cocaine: Effects on the Developing Brain. Harvey, J.A. and Kosofsky, B.E. (Eds.)Ann. N.Y. Acad. Sci. 846, 248–261.

    CAS  Google Scholar 

  • Kosofsky, B.E., Wilkins, A.S., Gressens, P. and Evrard, P. (1994) Transplacental cocaine exposure — A mouse model demonstrating neuroanatomic and behavioral abnormalities.J. Child Neurol. 9, 234–241.

    Article  PubMed  CAS  Google Scholar 

  • Kozell, N.J. and Adams, E.H. (1986) Epidemiology of drug abuse: an overview.Science (Washington)234, 970–974.

    Article  Google Scholar 

  • Kunko, P.M., Moyer, D. and Robinson, S.E. (1993) Intravenous gestational cocaine in rats: effects on offspring development and weanling behavior.Neurotoxicol. Teratol. 15, 335–344.

    Article  PubMed  CAS  Google Scholar 

  • Leslie, C.A., Robertson, M.W., Jung, A.B., Liebermann, J. and Bennett Jr., J.R. (1994) Effects of prenatal cocaine exposure upon postnatal development of neostriatal dopaminergic function.Synapse 17, 210–215.

    Article  PubMed  CAS  Google Scholar 

  • Levin, E.D. and Seidler, F.J. (1993) Sex-related spatial learning differences after prenatal cocaine exposure in the young adult rat.Neurotoxicol. Teratol. 14, 23–28.

    CAS  Google Scholar 

  • Levitt, P., Harvey, J.A., Friedman, E., Simansky, K. and Murphy, E.H. (1997) New evidence for neurotransmitter influences on brain development.Trends Neurosci. 20, 269–274.

    Article  PubMed  CAS  Google Scholar 

  • Levy, W. and Wisniewski, K. (1974) Chlorpromazine causing extrapyramidal dysfunction in newborn infant of psychotic mother.N.Y. St. J. Med. 74, 684–685.

    CAS  Google Scholar 

  • Leysen, J.E. (1992) 5HT2-receptors: Location, pharmacological, pathological and physiological role. In:Serotonin Receptor Subtypes: Pharmacological Significance and Clinical Implications. Int. Acad. Biomed. Drug Res. Langer, S.Z., Brunello, N., Racagni, G. and Mendlewicz, J. (Eds.), Vol. 1, pp. 31–43. Karger, Basel.

    Google Scholar 

  • Lidow, M.S. (1998) Nonhuman primate model of the effect of prenatal cocaine exposure on cerebral cortical development. In:Cocaine: Effects on the Developing Brain. Harvey, J.A. and Kosofsky, B.E. (Eds.)Ann. N.Y. Acad. Sci. 846, 182–193.

    CAS  Google Scholar 

  • Linder, M.E., Middleton, P., Hepler, J.R., Taussig, R., Gilman, A. and Mumby, S.M. (1993) Lipid modifications of G proteins:a subunits are palmitoylated.Proc. Natl. Acad. Sci. USA 90, 3675–3679.

    Article  PubMed  CAS  Google Scholar 

  • Little, J.Z. and Teyler, T.J. (1996)In utero exposure decreases dopamine Dj receptor modulation of hippocampal long-term potentiation in the rabbit.Neurosci. Letters 215, 157–160.

    CAS  Google Scholar 

  • Lundborg, P. (1972) Abnormal ontogeny in young rabbit after chronic administration of haloperidol to the nursing mothers.Brain Res.44, 684–687.

    Article  PubMed  CAS  Google Scholar 

  • Mackintosh, N.J. (1975) A theory of attention: variations in the associability of stimuli with reinforcement.Psychol. Rev. 82, 276–298.

    Article  Google Scholar 

  • Malchiodi-Albedi, F, Petrucci, T.C., Picconi, B., Iosi, F and Falchi, M. (1997) Protein phosphatase inhibitors induce modification of synapse structure and tau hyperphosphor-ylation in cultured rat hippocampal neurons.J. Neurosci. Res. 48, 425–438.

    Article  PubMed  CAS  Google Scholar 

  • Mayes, L.C., Bornstein, M.H., Chawarska, K. and Granger, R.H. (1995) Information processing and developmental assessments in 3-month-old infants exposed pre-natally to cocaine.Pediatrics 95, 539–545.

    PubMed  CAS  Google Scholar 

  • Mayes, L.C., Granger, R.H., Frank, M.A., Schottenfeld, R. and Bornstein, M.H. (1993) Neurobehavioral profiles of neonates exposed to cocaine prenatally.Pediatrics 91, 778–783.

    PubMed  CAS  Google Scholar 

  • Mayes, L.C, Grillon, C, Granger, R. and Schottenfeld, R. (1998) Regulation of arousal and attention in preschool children exposed to cocaine prenatally. In:Cocaine: Effects on the Developing Brain. Harvey, J.A. and Kosofsky, B.E. (Eds.)Ann. N.Y. Acad. Sci. 846, 126–143.

    CAS  Google Scholar 

  • Mayfield, R.D., Larson, G. and Zahniser, N.R. (1992) Cocaine-induced behavioral sensitization and Di dopamine receptor function in rat nucleus accumbens and striatum.Brain Res. 573, 331–335.

    Article  PubMed  CAS  Google Scholar 

  • McCreary, A.C. and Marsden, C.A. (1993) Cocaine-induced behavior: dopamine DJ receptor antagonism by SCH 23390 prevents expression of conditioned sensitisation following repeated administration of cocaine.Neuropharmacology 32, 387–391.

    Article  PubMed  CAS  Google Scholar 

  • McMillen, B.A., German, D.C. and Shore, P.A. (1980) Functional and pharmacological significance of brain dopamine and norepinephrine storage pools.Biochem. Pharmacol. 29, 3045–3050.

    Article  PubMed  CAS  Google Scholar 

  • Mesulam, M.M. and Geschwind, N. (1978) On the possible role of neocortex and its limbic connections in the process of attention and schizophrenia: clinical cases of inattention in man and experimental anatomy in monkey.J. Psychiat. Res. 14, 249–259.

    Article  PubMed  CAS  Google Scholar 

  • Meyer, J., Shearman, L.P., Collins, M. and Maguire, R.L. (1993) Cocaine binding sites in fetal rat brain: implications for prenatal cocaine action.Psychopharmacology 112, 445–451.

    Article  PubMed  CAS  Google Scholar 

  • Miller, J.C. and Friedhoff, A.J. (1988) Prenatal neurotransmitter programming of postnatal receptor function.Prog. Brain-Res. 73, 509–522.

    Article  PubMed  CAS  Google Scholar 

  • Minabe, Y., Ashby Jr., C.R., Heyser, C, Spear, L.P. and Wang, R.Y. (1992) The effects of prenatal cocaine exposure on spontaneously active midbrain dopamine neurons in adult male offspring: an electrophysiological study.Brain Res.586, 152–156.

    Article  PubMed  CAS  Google Scholar 

  • Miserendino, M.J.D. and Nestler, E.J. (1995) Behavioral sensitization to cocaine: modulation by the cyclic AMP system in the nucleus accumbens.Brain Res. 674, 299–306.

    Article  PubMed  CAS  Google Scholar 

  • Monsma Jr., F.J., Mahan, L.C., McVittie, L.D., Gerfen, C.R. and Sibley, D.R. (1990) Molecular cloning and expression of a Dj dopamine receptor linked to adenylyl cyclase activation.Proc. Natl. Acad. Sci. USA 87, 6723–6727.

    Article  PubMed  CAS  Google Scholar 

  • Moody, C.A., Frambes, N.A. and Spear, L.P. (1992) Psycho-pharmacological responsiveness to the dopamine agonist quinpirole in normal weanlings and in weanling offspring exposed gestationally to cocaine.Psychopharmacology 108, 256–262.

    Article  PubMed  CAS  Google Scholar 

  • Murphy, E.H., Hammer, J.G., Schumann, M.D., Groce, M.Y., Wang, X.-H., Jones, L., Romano, A.G. and Harvey, J.A. (1995) The rabbit as a model for studies of cocaine exposurein utero. Lab. Animal Sci.45, 94–101.

    Google Scholar 

  • National Pregnancy and Health Survey (1995).

  • Nestler, E.J., Terwilliger, R.Z., Walker, J.R., Sevarino, K.A. and Duman, R.S. (1990) Chronic cocaine treatment decreases levels of the G protein subunits Gi alpha and Go alpha in discrete regions of rat brain.J. Neurochem. 55, 1079–1082.

    Article  PubMed  CAS  Google Scholar 

  • Ng, J.P., Hubert, G.W. and Justice, J.B. (1991) Increased stimulated release and uptake of dopamine in nucleus accumbens after repeated cocaine administration as measured byin vivo voltammetry.J. Neurochem. 56, 1485–1492.

    Article  PubMed  CAS  Google Scholar 

  • Ng, G.Y.K., Mouillac, B., George, S.R., Caron, M.G., Dennis, M., Bouvier, M. and O’Dowd, B.F. (1994) Desensitization, phosphorylation and palmitoylation of the human dopamine D! receptor.Eur. J. Pharmacol. 267, 7–19.

    Article  PubMed  CAS  Google Scholar 

  • Olson, L. and Seiger, A. (1972) Early prenatal ontogeny of central monoamine neurons in the rat:fluorescent histo-chemical observations.Anat. Ent.-Gesh. 137, 301–316.

    Article  CAS  Google Scholar 

  • Olson, L., Blreus, L.O. and Seiger, A. (1973) Histochemical demonstration and mapping of 5-hydroxytryptamine and catecholamine containing neuron systems in the human fetal brain.Anat. Ent.-Gesh. 139, 259–282.

    Article  CAS  Google Scholar 

  • Ongini, E. and Caporali, M.G. (1987) Differential effects of dopamine D-l and D-2 receptor agonists on EEG activity and behaviour in the rabbit.Neuropharmacology lis, 355-360.

  • Ostrea Jr., E.M., Brady, M., Cause, S., Raymundo, A.L. and Stevens, M. (1992) Drug screening of newborns by meconium analysis: A large-scale, prospective, epidemiologic study.Pedoatrocs 89, 107–113.

    Google Scholar 

  • Pardo, J.V., Pardo, P.J., Janer, K.W. and Raichle, M.E. (1990) The anterior cingulate cortex mediates processing selection in the Stroop attentional conflict paradigm.Proc. Natl. Acad. Sci. USA 87, 256–259.

    Article  PubMed  CAS  Google Scholar 

  • Parenti, M., Vigano, M.A., Newman, C.M.H., Milligan, G. and Magee, A.I. (1993) A novel N-terminal motif for palmitoylation of G-proteina subunits.Biochem. J. 291, 349–353.

    PubMed  CAS  Google Scholar 

  • Petersen, S.E., Fox, P.E., Posner, M.I., Mintum, M. and Raichle, M.E. (1988) Positron emission tomographic studies of the cortical anatomy of single-word processing.Nature 331, 585–589.

    Article  PubMed  CAS  Google Scholar 

  • Petry, N., Furmidge, L., Tong, Z.-Y, Martin, C. and Clark, D. (1993) Time sampling observation procedure for studying drug effects: interaction between rf-amphetamine and selective dopamine receptor antagonists in the rat.Pharmacol. Biochem. Behav. 44, 167–180.

    Article  PubMed  CAS  Google Scholar 

  • Reader, T.A. and Dewar, K.M. (1989) Endogenous homovanil-lic acid levels differ between rat and rabbit caudate, hippocampus and cortical regions.Neurochem. Res. 14, 1137–1141.

    Article  PubMed  CAS  Google Scholar 

  • Reinoso, B.S., Undie, A.S. and Levitt, P. (1996) Dopamine receptors mediated differential morphological effects on cerebral cortical neuronsin vitro. J. Neurosci. Res.43, 439–453.

    Article  PubMed  CAS  Google Scholar 

  • Richardson, G.A., Conroy, M.L. and Day, N.L. (1996) Prenatal cocaine exposure: effects on the development of school-age children.Neurotox. Teratol. 18, 627–634.

    Article  CAS  Google Scholar 

  • Ritz, M.C., Cone, E.J. and Kuhar, M.J. (1990) Cocaine inhibition of ligand binding at dopamine, norepinephrine and serotonin transporters: a structure-activity study.Life Sci. 46, 635–645.

    Article  PubMed  CAS  Google Scholar 

  • Ritz, M.C., Lamb, R.J., Goldberg, S.R. and Kuhar, M.J. (1987) Cocaine receptors on dopamine transporter are related to self administration of cocaine.Science 237, 1219–1223.

    Article  PubMed  CAS  Google Scholar 

  • Roberts, D.C.S., Corcoran, M.E. and Fibiger, H.C. (1977) On the role of ascending catecholaminergic systems in intravenous self-administration of cocaine.Pharmacol. Biochem. Behav. 6, 615–620.

    Article  PubMed  CAS  Google Scholar 

  • Romano, A.G. and Harvey, J.A. (1992) Drug effects on sensorimotor integration in a model system. In:Drugs of Abuse and Neurobiology. Watson, R.R. (Ed.), pp. 23–37. CRC Press, Boca Raton, FL.

    Google Scholar 

  • Romano, A.G. and Harvey, J.A. (1996a) Prenatal exposure to cocaine disrupts discrimination learning in adult rabbits.Pharmacol. Biochem. Behav. 53, 617–621.

    Article  PubMed  CAS  Google Scholar 

  • Romano, A.G. and Harvey, J.A. (1996b) Elicitation and modification of the rabbit’s nictitating membrane reflex following prenatal exposure to cocaine.Pharmacol. Biochem. Behav. 53, 857–862.

    Article  PubMed  CAS  Google Scholar 

  • Romano, A.G. and Harvey, J.A. (1998) Prenatal cocaine exposure: long-term deficits in learning and motor performance. In:Cocaine: Effects on the Developing Brain. Harvey, J.A. and Kosofsky B.E. (Eds.)Ann. N.Y. Acad. Sci. 846, 89–108.

    CAS  Google Scholar 

  • Romano, A.G., Kachelries, W.J., Simansky, K.J. and Harvey, J.A. (1995) Intrauterine exposure to cocaine produces a modality specific acceleration of classical conditioning in adult rabbits.Pharmacol. Biochem. Behav. 52, 415–420.

    Article  PubMed  CAS  Google Scholar 

  • Rosa-Kenig, A., Puotz, J.K. and Rebec, G.V. (1993) The involvement of Di and D2 dopamine receptors in amphetamine-induced changes in striatal unit activity in behaving rats.Brain Res. 619, 347–351.

    Article  PubMed  CAS  Google Scholar 

  • Rosengarten, H., Friedman, E. and Friedhoff, A.J. (1983) Sensitive periods for the effect of haloperidol on development of striatal dopamine receptors.Birth Defects: Original Article Series 19, 511–513.

    CAS  Google Scholar 

  • Salamy, A., Eldredge, L., Anderson, J. and Bull, D. (1990) Brainstem transmission time in infants exposed to cocainein utero. f. Pediatr.117, 627–629.

    Article  CAS  Google Scholar 

  • Scalzo, F.M., Ali, S.R, Frambes, N.A. and Spear, L.P. (1990) Weanling rats exposed prenatally to cocaine exhibit an increase in striatal D2 dopamine binding associated with an increase in ligand affinity.Pharmacol. Biochem. Behav. 37, 371–373.

    Article  PubMed  CAS  Google Scholar 

  • Schindler, C.W. and Harvey, J.A. (1990) The use of classical conditioning procedures in behavioral pharmacology. In:Contemporary Research In Behavioral Pharmacology,

  • Dworkin, S.I., Higgins, S.T. and Bickel, W.K. (Eds.). Drug Development Research, 20, 169-187.

  • Schneider, J.W. and Chasnoff, I.J. (1992) Motor assessment of cocaine/polydrug exposed infants at age 4 months.Neuro-tox.Teratol. 14, 97–101.

    Article  CAS  Google Scholar 

  • Seidler, F.J. and Slotkin, T.A. (1992) Fetal cocaine exposure causes persistent noradrenergic hyperactivity in rat brain regions: Effects on neurotransmitter turnover and receptors.J. Pharmacol. Exp. Ther. 263, 413–421.

    PubMed  CAS  Google Scholar 

  • Senogles, S.E., Spiegel, A.M., Padrell, E., Iyengar, R. and Caron, M.G. (1990) Specificity of receptor-G protein interactions: discrimination of Gi subtypes by the D2 dopamine receptor in a reconstituted system.J. Biol Chem. 265, 4507–4514.

    PubMed  CAS  Google Scholar 

  • Sim, A.T. (1991) The regulation and function of protein phosphatases in the brain.Mol. Neurobiol. 5, 229–246.

    Article  PubMed  CAS  Google Scholar 

  • Simansky, K.J. and Kachelries, WJ. (1996) Prenatal exposure to cocaine selectively disrupts motor responding to d-amphet-amine in young and mature rabbits.Neuropharmacology 35, 71–78.

    Article  PubMed  CAS  Google Scholar 

  • Simansky, K.J., Baker, G., Kachelries, W.J., Hood, H., Romano, A.G. and Harvey, J.A. (1998) Prenatal exposure to cocaine reduces dopaminergic Drmediated motor function but spares the enhancement of learning by amphetamine in rabbits. In:Cocaine: Effects on the Developing Brain. Harvey, J.A. and Kosofsky, B.E. (Eds.)Ann. N.Y. Acad. Sci. 846, 375–378.

    CAS  Google Scholar 

  • Smith, R.F., Mattran, K.M., Kurkjian, M.F. and Kurtz, S.L. (1989) Alterations in offspring behavior induced by chronic prenatal cocaine dosing.Neurotoxicol. Teratol. 11, 35–38.

    Article  PubMed  CAS  Google Scholar 

  • Sparenborg, S. and Gabriel, M. (1990) Neuronal encoding of conditional stimulus duration in the cingulate cortex and the limbic thalamus of rabbits.Behav. Neurosci. 104, 919–933.

    Article  PubMed  CAS  Google Scholar 

  • Spear, L.P. (1996) Neurobehavioral consequences of gestational cocaine exposure: Studies using a rodent model. In:Prenatal Cocaine Exposure, Konkol, R.J. and Olsen, G.D. (Eds.) pp. 169–181. CRC Press, Boca Raton, FL.

    Google Scholar 

  • Spear, L., Kirstein, C.L., Bell, J., Yoottanasumpun, V, Greenbaum, R., O’Shea, J., Hoffman, H. and Spear, N.E. (1989) Effects of prenatal cocaine exposure on behavior during the early postnatal period.Neurotoxicol. Teratol. 11, 57–63.

    Article  PubMed  CAS  Google Scholar 

  • Steinmetz, J.E. (1996) The brain substrates of classical eyeblink conditioning in rabbits. In:The Acquisition of Motor Behavior in Vertebrates. Bloedel, J.R., Ebner, T.J. and Wise, S.R (Eds.), pp. 89-114.

  • Surmeier, D.J., Bargas, J., Hemmings Jr., H.C., Nairn, A.C. and Greengard, P. (1995) Modulation of calcium currents by a D! dopaminergic protein kinase/phosphatase cascade in rat neostriatal neurons.Neuron 14, 385–397.

    Article  PubMed  CAS  Google Scholar 

  • Taylor, C., Freeman Jr., J.H., Holt, W. and Gabriel, M. (1999) Impairment of Cingulothalamic learning-related neuronal coding in rabbits exposed to cocainein utero: general and sex-specific effects.Behav. Neurosci. 113, 62–77.

    Article  PubMed  CAS  Google Scholar 

  • Tennyson, V.M., Barrett, R.E., Cohen, G., Cote, L., Heikkila, R. and Mytilineou, C. (1972) The developing neostriatum of the rabbit: correlation of fluorescence histochemistry, electron microscopy, endogenous dopamine levels and 3H-dopamine uptake.Brain Res.46, 251–285.

    Article  PubMed  CAS  Google Scholar 

  • Tennyson, V.M., Mytilineou, C. and Barrett, R.E. (1973) Fluorescence and electron microscopic studies of the early development of the substantia nigra and area ventralis tegmenti in the fetal rabbit.J. Comp. Neurol. 149, 233–257.

    Article  PubMed  CAS  Google Scholar 

  • Terwilliger, R.Z., Beitner-Johnson, D., Sevarino, K., Crain, S.M. and Nestler, E.J. (1991) A general role for adaptations in G-proteins and the cyclic AMP system in mediating the chronic actions of morphine and cocaine on neuronal function.Brain Res. 548, 100–110.

    Article  PubMed  CAS  Google Scholar 

  • Tilakaratne, N., Cai, G.P. and Friedman, E. (1998) Cocaine-induced activation ofc-fos gene expression is attenuated in prenatal cocaine-exposed rabbits. In:Cocaine: Effects on the Developing Brain. Harvey, J.A. and Kosofsky, B.E. (Eds.)Ann. N.Y. Acad. Sci. 846, 368–370.

    CAS  Google Scholar 

  • Tong, G., Shepherd, D. and Hahr, C.E. (1995) Synaptic desensitization of NMDA receptors by calcineurin.Science 267, 1510–1512.

    Article  PubMed  CAS  Google Scholar 

  • Tronick, E.Z., Frank, D.A., Cabral, H., Mirochnick, M. and Zuckerman, B. (1996) Late dose-response effects of prenatal cocaine exposure on newborn neurobehavioral performance.Pediatrics 98, 76–83.

    PubMed  CAS  Google Scholar 

  • Vogt, B.A. and Gabriel, M. (1993)Neurobiology of Cingulate Cortex and Limbic Thalamus: A Comprehensive Handbook. Birkhauser. Boston, MA.

    Google Scholar 

  • Voorhees, C.V., Reed, T.M., Acuff-Smith, K.D., Schilling, M.A., Cappon, G.D., Fisher, J.E. and Cunfeng, P. (1995) Long-term learning deficits and changes in unlearned behaviors followingin utero exposure to multiple daily doses of cocaine during different exposure periods and maternal plasma cocaine concentrations.Neurotox. Teratol. 17, 253–264.

    Article  Google Scholar 

  • Wang, J.H. and Kelly, P.T. (1997) Postsynaptic calcineurin activity downregulates synaptic transmission by weakening intracellular Ca+ signaling mechanisms in hippocampal CAI neurons. J.Neurosci. 17, 4600–4611.

    PubMed  CAS  Google Scholar 

  • Wang, L. and Pitts, D.K. (1994) Perinatal cocaine exposure decreases the number of spontaneously active midbrain dopamine neurons in neonatal rats.Synapse 17, 275–277.

    Article  PubMed  CAS  Google Scholar 

  • Wang, H.-Y, Undie, A. and Friedman, E. (1995a) Evidence for the coupling of Gq protein to Drlike dopamine sites in rat striatum: possible role in dopamine-mediated inositol phosphates formation.Mol. Pharmacol. 48, 988–994.

    PubMed  CAS  Google Scholar 

  • Wang, H.Y., Yeung, J.M. and Friedman, E. (1995b) Prenatal cocaine exposure selectively reduces mesocortical dopamine release.J. Pharmacol. Exp. Ther. 273, 1211–1215.

    PubMed  CAS  Google Scholar 

  • Wang, H.-Y, Runyan, S., Yadin, E. and Friedman, E. (1995c) Prenatal exposure to cocaine selectively reduces D, dopamine receptor-mediated activation of striatal Gs proteins.J. Pharmacol. Exp. Ther. 273, 492–498.

    PubMed  CAS  Google Scholar 

  • Wang, X.-H., Jenkins, A.O., Choi, L. and Murphy, E.H. (1997a) Altered neuronal distribution of parvalbumin in anterior cingulate cortex of rabbits exposedin utero to cocaine.Exp. Brain Res. 112, 359–371.

    Google Scholar 

  • Wang, X.-H., Levitt, P., Grayson, D.R. and Murphy, E.H. (1995d) Intrauterine cocaine exposure of rabbits: persistent elevation of GABA immunoreactive neurons in anterior cingulate cortex but not visual cortex.Brain Res. 689, 32–46.

    Article  PubMed  CAS  Google Scholar 

  • Wang, X.-H., Levitt, P., O’Brien, J.A. and Murphy, E.H. (1997b) Normal development of tyrosine hydroxylase and serotonin immunoreactive fibers innervating anterior cingulate cortex and visual cortex in rabbits exposed prenatally to cocaine.Brain Res. 715, 221–224.

    Article  Google Scholar 

  • Wilkins, A.S., Genova, L.M., Posten, W. and Kosofsky, B.E. (1998) Transplacental cocaine exposure 1: A rodent model.Neurotoxicol. Teratol. 20, 1–11.

    Article  Google Scholar 

  • Wilkins, A.S., Kosofsky, B.E., Romano, A.G. and Harvey, J.A. (1996) Transplacental cocaine exposure: Behavioral consequences. In:Prenatal Cocaine Exposure. Konkol, R.J. and Msen, G. (Eds.), pp. 149–165. CRC Press Inc., Boca Raton, FL.

    Google Scholar 

  • Wolske, M., Pederson, C. and West, M.O. (1993) The effects of cocaine on single units correlated with vertical head movement in the lateral striatum of rats during performance of a vertical head movement operant task.Abstr. Soc. Neurosci. 19, 1855.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology and Physiology, MCP Hahnemann University, 3200 Henry Avenue, 19129, Philadelphia, PA, USA

    John A. Harvey, Anthony G. Romano, Kenny J. Simansky, Wei Du, Vincent J. Aloyo & Eitan Friedman

  2. Department of Psychology, the Beckman Institute, University of Illinois, 61801, Urbana, IL, USA

    Michael Gabriel

Authors
  1. John A. Harvey
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anthony G. Romano
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michael Gabriel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kenny J. Simansky
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wei Du
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Vincent J. Aloyo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Eitan Friedman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to John A. Harvey.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Harvey, J.A., Romano, A.G., Gabriel, M. et al. Effects of prenatal exposure to cocaine on the developing brain: Anatomical, chemical, physiological and behavioral consequences. neurotox res 3, 117–143 (2001). https://doi.org/10.1007/BF03033234

Download citation

  • Received:

  • Revised:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03033234

Keywords

Search

Navigation