Original article| Volume 52, ISSUE 4, P362-370, August 15, 2002

Astrocytic basic fibroblast growth factor expression in dopaminergic regions after perinatal anoxia

  • Cecilia Flores
    Address reprint requests to Dr. Cecilia Flores, Department of Neurology and Neurosurgery, McGill University, Centre for Neuronal Survival Room F116, Montreal Neurological Institute, 3801 University Street, Montreal Quebec, H3A 2B4, Canada
    Center for Studies in Behavioral Neurobiology Department of Psychology (CF, JS, NS), Concordia University, Montreal, Quebec, Canada
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  • Jane Stewart
    Center for Studies in Behavioral Neurobiology Department of Psychology (CF, JS, NS), Concordia University, Montreal, Quebec, Canada
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  • Natalina Salmaso
    Center for Studies in Behavioral Neurobiology Department of Psychology (CF, JS, NS), Concordia University, Montreal, Quebec, Canada
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  • Ying Zhang
    Departments of Psychiatry and of Neurology and Neurosurgery (YZ, PB), McGill University, Douglas Hospital Research Centre, Verdun, Quebec, Canada
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  • Patricia Boksa
    Departments of Psychiatry and of Neurology and Neurosurgery (YZ, PB), McGill University, Douglas Hospital Research Centre, Verdun, Quebec, Canada
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      Background: Perinatal anoxia leads to persistent behavioral and neurochemical alterations suggestive of sensitized dopaminergic function. Because astrocytic basic fibroblast growth factor (bFGF) activity in the midbrain dopaminergic cell body region is required for the development of enduring changes in dopaminergic function induced by stimulant drugs, we investigated the effects of intrauterine anoxia on astrocytic bFGF expression in dopaminergic regions at 2 weeks of age and after a stress manipulation in adults.
      Methods: We examined bFGF immunoreactivity in dopaminergic regions of young and adult rats born by cesarean section, cesarean section + 15 min of intrauterine anoxia, or vaginally. bFGF immunoreactivity was also assessed before and after tail-pinch stress in adult animals exposed to the same perinatal interventions.
      Results: Perinatal anoxia produced persistent decreases in basal bFGF immunoreactivity in the ventral tegmental area (VTA), but enhanced the effect of stress on VTA bFGF immunoreactivity.
      Conclusions: Perinatal anoxia has enduring effects on VTA bFGF immunoreactivity and influences adult neuroadaptations to stress. The mechanisms whereby perinatal anoxia alters dopaminergic function may be similar to those responsible for the development of sensitization to stimulant drugs and may involve bFGF.


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        • Abi-Dargham A.
        • Gil R.
        • Krystal J.
        • et al.
        Increased striatal dopamine transmission in schizophrenia.
        Am J Psychiatry. 1998; 155: 761-767
        • Andersson K.
        • Blum M.
        • Chen Y.
        • et al.
        Perinatal asphyxia increases bFGF mRNA levels and DA cell body number in the mesencephalon of rats.
        NeuroReport. 1995; 6: 375-378
        • Berger N.
        • Vaillancourt C.
        • Boksa P.
        Genetic factors modulate effects of C-section birth on dopaminergic function in the rat.
        Neuroreport. 2000; 11: 639-643
        • Bjelke B.
        • Andersson K.
        • Ogren S.O.
        • Bolme P.
        Asphyctic lesion.
        Brain Res. 1991; 543: 1-9
        • Bouvier M.M.
        • Mytilineou C.
        Basic fibroblast growth factor increases division and delays differentiation of dopamine precursors in vitro.
        J Neurosci. 1995; 15: 7141-7149
        • Brady K.T.
        • Lydiard R.B.
        • Malcolm R.
        • Ballenger J.C.
        Cocaine-induced psychosis.
        J Clin Psychiatry. 1991; 52: 509-512
        • Brake W.G.
        • Boksa P.
        • Gratton A.
        Effects of perinatal anoxia on the acute locomotor response to repeated amphetamine administration in adult rats.
        Psychopharmacology (Berl). 1997; 133: 389-395
        • Brake W.G.
        • Noel M.B.
        • Boksa P.
        • Gratton A.
        Influence of perinatal factors on the nucleus accumbens dopamine response to repeated stress during adulthood.
        Neuroscience. 1997; 77: 1067-1076
        • Caday C.G.
        • Klagsbrun M.
        • Fanning P.J.
        • Mirzabegian A.
        • Finklestein S.P.
        Fibroblast growth factor (FGF) levels in the developing rat brain.
        Brain Res Dev Brain Res. 1990; 52: 241-246
        • Castner S.A.
        • al-Tikriti M.S.
        • Baldwin R.M.
        • Seibyl J.P.
        • Innis R.B.
        • Goldman-Rakic P.S.
        Behavioral changes and [123I]IBZM equilibrium SPECT measurement of amphetamine-induced dopamine release in rhesus monkeys exposed to subchronic amphetamine.
        Neuropsychopharmacology. 2000; 22: 4-13
        • Castner S.A.
        • Goldman-Rakic P.S.
        Long-lasting psychotomimetic consequences of repeated low-dose amphetamine exposure in rhesus monkeys.
        Neuropsychopharmacology. 1999; 20: 10-28
        • Chadi G.
        • Cao Y.
        • Pettersson R.F.
        • Fuxe K.
        Temporal and spatial increase of astroglial basic fibroblast growth factor synthesis after 6-hydroxydopamine-induced degeneration of the nigrostriatal dopamine neurons.
        Neuroscience. 1994; 61: 891-910
        • Chadi G.
        • Tinner B.
        • Agnati L.F.
        • Fuxe K.
        Basic fibroblast growth factor (bFGF, FGF-2) immunoreactivity exists in the noradrenaline, adrenaline and 5-HT nerve cells of the rat brain.
        Neurosci Lett. 1993; 160: 171-176
        • Chen Y.
        • Herrera-Marschitz M.
        • Bjelke B.
        • Blum M.
        • Gross J.
        • Andersson K.
        Perinatal asphyxia-induced changes in rat brain tyrosine hydroxylase-immunoreactive cell body number.
        Neurosci Lett. 1997; 221: 77-80
        • Dalman C.
        • Allebeck P.
        • Cullberg J.
        • Grunewald C.
        • Koster M.
        Obstetric complications and the risk of schizophrenia.
        Arch Gen Psychiatry. 1999; 56: 234-240
        • Dell’Anna E.
        • Chen Y.
        • Loidl F.
        • et al.
        Short-term effects of perinatal asphyxia studied with Fos-immunocytochemistry and in vivo microdialysis in the rat.
        Exp Neurol. 1995; 131: 279-287
        • Eckenstein F.P.
        • Andersson C.
        • Kuzis K.
        • Woodward W.R.
        Distribution of acidic and basic fibroblast growth factors in the mature, injured and developing rat nervous system.
        Prog Brain Res. 1994; 103: 55-64
        • El-Khodor B.F.
        • Boksa P.
        Long-term reciprocal changes in dopamine levels in prefrontal cortex versus nucleus accumbens in rats born by Caesarean section compared to vaginal birth.
        Exp Neurol. 1997; 145: 118-129
        • El-Khodor B.F.
        • Boksa P.
        Birth insult increases amphetamine-induced behavioral responses in the adult rat.
        Neuroscience. 1998; 87: 893-904
        • El-Khodor B.F.
        • Boksa P.
        Transient birth hypoxia increases behavioral responses to repeated stress in the adult rat.
        Behav Brain Res. 2000; 107: 171-175
        • El-Khodor B.
        • Boksa P.
        Caesarean section birth produces long term changes in dopamine d1 receptors and in stress-induced regulation of d3 and d4 receptors in the rat brain.
        Neuropsychopharmacology. 2001; 25: 423-439
        • Ellinwood Jr, E.H.
        Amphetamine psychosis. I. Descriptions of the individuals and process.
        J Nerv Ment Dis. 1967; 144: 273-283
        • Flores C.
        • Rodaros D.
        • Stewart J.
        Long-lasting induction of astrocytic basic fibroblast growth factor by repeated injections of amphetamine.
        J Neurosci. 1998; 18: 9547-9555
        • Flores C.
        • Salmaso N.
        • Cain S.
        • Rodaros D.
        • Stewart J.
        Ovariectomy of adult rats leads to increased expression of astrocytic basic fibroblast growth factor in the ventral tegmental area and in dopaminergic projection regions of the entorhinal and prefrontal cortex.
        J Neurosci. 1999; 19: 8665-8673
        • Flores C.
        • Samaha A.N.
        • Stewart J.
        Requirement of endogenous basic fibroblast growth factor for sensitization to amphetamine.
        J Neurosci. 2000; 20: RC55
        • Flores C.
        • Stewart J.
        Basic fibroblast growth factor as a mediator of the effects of glutamate in the development of long-lasting sensitization to stimulant drugs.
        Psychopharmacology (Berl). 2000; 151: 152-165
        • Geddes J.R.
        • Verdoux H.
        • Takei N.
        • et al.
        Schizophrenia and complications of pregnancy and labor.
        Schizophr Bull. 1999; 25: 413-423
        • Gross J.
        • Muller I.
        • Chen Y.
        • et al.
        Perinatal asphyxia induces region-specific long-term changes in mRNA levels of tyrosine hydroxylase and dopamine D(1) and D(2) receptors in rat brain.
        Brain Res Mol Brain Res. 2000; 79: 110-117
        • Hosli E.
        • Hosli L.
        Receptors for neurotransmitters on astrocytes in the mammalian central nervous system.
        Prog Neurobiol. 1993; 40: 477-506
        • Hosli E.
        • Hosli L.
        Colocalization of neurotransmitter receptors on astrocytes in explant cultures of rat CNS.
        Neurochem Int. 2000; 36: 301-311
        • Hou J.G.
        • Cohen G.
        • Mytilineou C.
        Basic fibroblast growth factor stimulation of glial cells protects dopamine neurons from 6-hydroxydopamine toxicity.
        J Neurochem. 1997; 69: 76-83
        • Hsu S.M.
        • Raine L.
        • Fanger H.
        Use of avidin-biotin-peroxidase complex (ABC) in immunoperoxidase techniques.
        J Histochem Cytochem. 1981; 29: 577-580
        • Jones P.B.
        • Rantakallio P.
        • Hartikainen A.L.
        • Isohanni M.
        • Sipila P.
        Schizophrenia as a long-term outcome of pregnancy, delivery, and perinatal complications.
        Am J Psychiatry. 1998; 155: 355-364
        • Kalivas P.W.
        • Stewart J.
        Dopamine transmission in the initiation and expression of drug- and stress-induced sensitization of motor activity.
        Brain Res Brain Res Rev. 1991; 16: 223-244
        • Kalivas P.W.
        • Weber B.
        Amphetamine injection into the A10 dopamine region sensitizes rats to peripheral amphetamine and cocaine.
        J Pharmacol Exp Ther. 1988; 245: 1095-1102
        • Kapur S.
        • Seeman P.
        Does fast dissociation from the dopamine d(2) receptor explain the action of atypical antipsychotics?.
        Am J Psychiatry. 2001; 158: 360-369
        • Kolb B.
        • Cioe J.
        Recovery from early cortical damage in rats, VIII. Earlier may be worse.
        Neuropharmacology. 2000; 39: 756-764
        • Kolb B.
        • Cioe J.
        • Whishaw I.Q.
        Is there an optimal age for recovery from motor cortex lesions? I. Behavioral and anatomical sequelae of bilateral motor cortex lesions in rats on postnatal days 1, 10, and in adulthood.
        Brain Res. 2000; 882: 62-74
        • Kolb B.
        • Cioe J.
        • Whishaw I.Q.
        Is there an optimal age for recovery from motor cortex lesions? II. Behavioural and anatomical consequences of unilateral motor cortex lesions in perinatal, infant, and adult rats.
        Restor Neurol Neurosci. 2000; 17: 61-70
        • Kramer J.C.
        • Fischman V.S.
        • Littlefield D.C.
        Amphetamine abuse. Pattern and effects of high doses taken intravenously.
        JAMA. 1967; 201: 305-309
        • Kuzis K.
        • Coffin J.D.
        • Eckenstein F.P.
        Time course and age dependence of motor neuron death following facial nerve crush injury.
        Exp Neurol. 1999; 157: 77-87
        • Kuzis K.
        • Reed S.
        • Cherry N.J.
        • Woodward W.R.
        • Eckenstein F.P.
        Developmental time course of acidic and basic fibroblast growth factors’ expression in distinct cellular populations of the rat central nervous system.
        J Comp Neurol. 1995; 358: 142-153
        • Laruelle M.
        The role of endogenous sensitization in the pathophysiology of schizophrenia.
        Brain Res Brain Res Rev. 2000; 31: 371-384
        • Laruelle M.
        • Abi-Dargham A.
        • Gil R.
        • Kegeles L.
        • Innis R.
        Increased dopamine transmission in schizophrenia.
        Biol Psychiatry. 1999; 46: 56-72
        • Lieberman J.A.
        • Kane J.M.
        • Alvir J.
        Provocative tests with psychostimulant drugs in schizophrenia.
        Psychopharmacology. 1987; 91: 415-433
        • Lieberman J.A.
        • Sheitman B.B.
        • Kinon B.J.
        Neurochemical sensitization in the pathophysiology of schizophrenia.
        Neuropsychopharmacology. 1997; 17: 205-229
        • Matsuzaki K.
        • Yoshitake Y.
        • Matuo Y.
        • Sasaki H.
        • Nishikawa K.
        Monoclonal antibodies against heparin-binding growth factor II/basic fibroblast growth factor that block its biological activity.
        Proc Natl Acad Sci USA. 1989; 86: 9911-9915
        • McNeil T.F.
        • Cantor-Graae E.
        • Ismail B.
        Obstetric complications and congenital malformation in schizophrenia.
        Brain Res Brain Res Rev. 2000; 31: 166-178
        • Neal-Beliveau B.S.
        • Joyce J.N.
        Neurotoxicol Teratol. 1999; 21: 129-140
        • Otto D.
        • Unsicker K.
        Basic FGF reverses chemical and morphological deficits in the nigrostriatal system of MPTP-treated mice.
        J Neurosci. 1990; 10: 1912-1921
        • Paxinos G.
        • Watson C.
        The rat brain in stereotaxic coordinates. Academic Press, New York1997
        • Reuss B.
        • Unsicker K.
        Survival and differentiation of dopaminergic mesencephalic neurons are promoted by dopamine-mediated induction of FGF-2 in striatal astroglial cells.
        Mol Cell Neurosci. 2000; 16: 781-792
        • Riva M.A.
        • Mocchetti I.
        Developmental expression of the basic fibroblast growth factor gene in rat brain.
        Brain Res Dev Brain Res. 1991; 62: 45-50
        • Robinson T.E.
        • Jurson P.A.
        • Bennett J.A.
        • Bentgen K.M.
        Persistent sensitization of dopamine neurotransmission in ventral striatum (nucleus accumbens) produced by prior experience with (+)- amphetamine.
        Brain Res. 1988; 462: 211-222
        • Rosso I.M.
        • Cannon T.D.
        • Huttunen T.
        • Huttunen M.O.
        • Lonnqvist J.
        • Gasperoni T.L.
        Obstetric risk factors for early-onset schizophrenia in a Finnish birth cohort.
        Am J Psychiatry. 2000; 157: 801-807
        • Sanyal S.
        • Van Tol H.H.
        Review the role of dopamine D4 receptors in schizophrenia and antipsychotic action.
        J Psychiatr Res. 1997; 31: 219-232
        • Satel S.L.
        • Southwick S.M.
        • Gawin F.H.
        Clinical features of cocaine-induced paranoia.
        Am J Psychiatry. 1991; 148: 495-498
        • Sato M.
        • Chen C.C.
        • Akiyama K.
        • Otsuki S.
        Acute exacerbation of paranoid psychotic state after long-term abstinence in patients with previous methamphetamine psychosis.
        Biol Psychiatry. 1983; 18: 429-440
        • Seeman P.
        • Kapur S.
        Proc Natl Acad Sci USA. 2000; 97: 7673-7675
        • Szele F.
        • Alexander C.
        • Chesselet M.-F.
        Expression of molecules associated with neuronal plasticity in the striatum after aspiration and thermocoagulatory lesions of the cerebral cortex in adult rats.
        J Neurosci. 1995; 15: 4429-4448
        • Takayama H.
        • Ray J.
        • Raymon H.K.
        • et al.
        Basic fibroblast growth factor increases dopaminergic graft survival and function in a rat model of Parkinson’s disease.
        Nat Med. 1995; 1: 53-58
        • Vanderschuren L.J.
        • Kalivas P.W.
        Alterations in dopaminergic and glutamatergic transmission in the induction and expression of behavioral sensitization.
        Psychopharmacology (Berl). 2000; 151: 99-120
        • Vezina P.
        Amphetamine injected into the ventral tegmental area sensitizes the nucleus accumbens dopaminergic response to systemic amphetamine.
        Brain Res. 1993; 605: 332-337
        • Vezina P.
        D1 dopamine receptor activation is necessary for the induction of sensitization by amphetamine in the ventral tegmental area.
        J Neurosci. 1996; 16: 2411-2420
        • Vezina P.
        • Stewart J.
        Amphetamine administered to the ventral tegmental area but not to the nucleus accumbens sensitizes rats to systemic morphine.
        Brain Res. 1990; 516: 99-106
        • Woodward W.R.
        • Nishi R.
        • Meshul C.K.
        • Williams T.E.
        • Coulombe M.M.
        • Eckenstein F.P.
        Nuclear and cytoplasmic localization of basic fibroblast growth factor in astrocytes and CA2 hippocampal neurons.
        J Neurosci. 1992; 12: 142-152
        • Yui K.
        • Goto K.
        • Ikemoto S.
        • et al.
        Neurobiological basis of relapse prediction in stimulant-induced psychosis and schizophrenia.
        Mol Psychiatry. 1999; 4: 512-523
        • Zilles K.
        The cortex of the rat. Springer-Verlag, New York1985
        • Zornberg G.L.
        • Buka S.L.
        • Tsuang M.T.
        Hypoxic-ischemia-related fetal/neonatal complications and risk of schizophrenia and other nonaffective psychoses.
        Am J Psychiatry. 2000; 157: 196-202