Prefrontal lesion reverses abnormal mesoaccumbens response in an animal model of schizophrenia

  • Yukiori Goto
    Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, New York, USA
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  • Patricio O'Donnell
    Address reprint requests to Patricio O'Donnell, M.D., Ph.D., Albany Medical College (MC-136), Center for Neuropharmacology and Neuroscience, 47 New Scotland Avenue, Albany NY 12208, USA.
    Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, New York, USA
    Search for articles by this author



      A neonatal hippocampal lesion induces postpubertal behavioral alterations resembling phenomena observed in schizophrenia. We have recently reported that nucleus accumbens neurons exhibit altered response to ventral tegmental area activation, but only when animals with this lesion reach adulthood. Because a prefrontal cortical lesion eliminates postpubertal abnormal behaviors in these animals, we investigated whether altered accumbens responses were reversed with this manipulation.


      In vivo intracellular recordings were conducted in accumbens neurons in rats that had received neonatal hippocampal lesions combined with either adult prefrontal cortical lesion or sham treatment. Accumbens response to mesolimbic pathway activation was recorded in these animals.


      Accumbens neurons from animals with a neonatal hippocampal lesion and an adult prefrontal sham operation still showed altered accumbens response to mesolimbic stimulation. On the other hand, most animals with combined neonatal hippocampal and adult prefrontal lesions exhibited responses similar to those of naïve animals.


      This result suggests that abnormal behaviors in these animals might be related to excessive prefrontal drive of accumbens neurons upon dopamine activation.


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        • Abi-Dargham A.
        • Mawlawi O.
        • Lombardo I.
        • Gil R.
        • Martinez D.
        • Huang Y.
        • et al.
        Prefrontal dopamine D1 receptors and working memory in schizophrenia.
        J Neurosci. 2002; 22: 3708-3719
        • Al-Amin H.A.
        • Weinberger D.R.
        • Lipska B.K.
        Exaggerated MK-801-induced motor hyperactivity in rats with the neonatal lesion of the ventral hippocampus.
        Behav Pharmacol. 2000; 11: 269-278
        • Au-Young S.M.W.
        • Shen H.
        • Yang C.R.
        Medial prefrontal cortical output neurons to the ventral tegmental area (VTA) and their responses to burst-patterned stimulation of the VTA.
        Synapse. 1999; 34: 245-255
        • Beasley C.L.
        • Reynolds G.P.
        Parvalbumin-immunoreactive neurons are reduced in the prefrontal cortex of schizophrenics.
        Schizophr Res. 1997; 24: 349-355
        • Becker A.
        • Grecksch G.
        • Bernstein H.G.
        • Höllt V.
        • Bogerts B.
        Social behaviour in rats lesioned with ibotenic acid in the hippocampus.
        Psychopharmacol (Berl). 1999; 144: 333-338
        • Berendse H.W.
        • Galis-de Graaf Y.
        • Groenewegen H.J.
        Topographical organization and relationship with ventral striatal compartments of prefrontal corticostriatal projections in the rat.
        J Comp Neurol. 1992; 316: 314-347
        • Callicott J.H.
        • Bertolino A.
        • Mattay V.S.
        • Langheim F.J.
        • Duyn J.
        • Coppola R.
        • et al.
        Physiological dysfunction of the dorsolateral prefrontal cortex in schizophrenia revisited.
        Cereb Cortex. 2000; 10: 1078-1092
        • Carlsson M.
        • Carlsson A.
        Schizophr Bull. 1990; 16: 425-432
        • Chang H.T.
        • Kitai S.T.
        Projection neurons of the nucleus accumbens.
        Brain Res. 1985; 347: 112-116
        • Flores G.
        • Barbeau D.
        • Quirion R.
        • Srivastava L.K.
        Decreased binding of dopamine D3 receptors in limbic subregions after neonatal bilateral lesion of rat hippocampus.
        J Neurosci. 1996; 16: 2020-2026
        • Goto Y.
        • O'Donnell P.
        Network synchrony in the nucleus accumbens in vivo.
        J Neurosci. 2001; 21: 4498-4504
      1. Goto Y, O'Donnell P (2001b): Synchronous activity in the hippocampus and nucleus accumbens in vivo. J Neurosci 21:R:C131

        • Goto Y.
        • O'Donnell P.
        Delayed mesolimbic system alteration in a developmental animal model of schizophrenia.
        J Neurosci. 2002; 22: 9070-9077
        • Grecksch G.
        • Bernstein H.G.
        • Becker A.
        • Höllt V.
        • Bogert B.
        Disruption of latent inhibition in rats with postnatal hippocampal lesions.
        Neuropsychopharmacology. 1999; 20: 525-532
      2. Gurden H, Takita M, Jay TM (2000): Essential role of D1 but not D2 receptors in the NMDA receptor-dependent long-term potentiation at hippocampal-prefrontal cortex synapses in vivo. J Neurosci 20:R:C106

        • Gurden H.
        • Tassin J.-P.
        • Jay T.M.
        Integrity of the mesocortical dopaminergic system is necessary for complete expression of in vivo hippocampal-prefrontal cortex long-term potentiation.
        Neurosci. 1999; 94: 1019-1027
        • Karkanias N.B.
        • Papke R.L.
        Subtype-specific effects of lithium on glutamate receptor function.
        J Neurophysiol. 1999; 81: 1506-1512
        • Kelley A.E.
        • Domesick V.B.
        The distribution of the projection from the hippocampal formation to the nucleus accumbens in the rat.
        Neuroscience. 1982; 7: 2321-2335
        • Khan Z.U.
        • Koulen P.
        • Rubinstein M.
        • Grandy D.K.
        • Goldman-Rakic P.S.
        An astroglia-linked dopamine D2-receptor action in prefrontal cortex.
        Proc Natl Acad Sci U S A. 2001; 98: 1964-1969
        • Laruelle M.
        The role of endogenous sensitization in the pathophysiology of schizophrenia.
        Brain Res Brain Res Rev. 2000; 31: 371-384
        • Lewis B.L.
        • O'Donnell P.
        Ventral tegmental area afferents to the prefrontal cortex maintain membrane potential ‘up’ states in pyramidal neurons via D1 dopamine receptors.
        Cereb Cortex. 2000; 10: 1168-1175
        • Lillrank S.M.
        • Lipska B.K.
        • Kolachana B.S.
        • Weinberger D.R.
        Attenuated extracellular dopamine levels after stress and amphetamine in the nucleus accumbens of rats with neonatal ventral hippocampal damage.
        J Neural Transm. 1999; 106: 183-196
        • Lipska B.K.
        • Al-Amin H.A.
        • Weinberger D.R.
        Excitotoxic lesions of the rat medial prefrontal cortex. Effects on abnormal behaviors associated with neonatal hippocampal damage.
        Neuropsychopharmacology. 1998; 19: 451-464
        • Lipska B.K.
        • Aultman J.M.
        • Verma A.
        • Weinberger D.R.
        • Moghaddam B.
        Neonatal damage of the ventral hippocampus impairs working memory in the rat.
        Neuropsychopharmacology. 2002; 27: 47-54
        • Lipska B.K.
        • Jaskiw G.E.
        • Weinberger D.R.
        Postpubertal emergence of hyperresponsiveness to stress and to amphetamine after neonatal excitotoxic hippocampal damage.
        Neuropsychopharmacology. 1993; 9: 67-75
        • Lipska B.K.
        • Weinberger D.R.
        Subchronic treatment with haloperidol and clozapine in rats with neonatal excitotoxic hippocampal damage.
        Neuropsychopharmacology. 1994; 10: 199-205
        • Lipska B.K.
        • Weinberger D.R.
        To model a psychiatric disorder in animals.
        Neuropsychopharmacology. 2000; 23: 223-239
        • Manoach D.S.
        Prefrontal cortex dysfunction during working memory performance in schizophrenia.
        Schizophr Res. 2003; 60: 285-298
        • Moniz E.
        Prefrontal leucotomy in the treatment of mental disorders.
        Am J Psychiatry. 1937; 93: 1379-1385
        • O'Donnell P.
        • Grace A.A.
        Synaptic interactions among excitatory afferents to nucleus accumbens neurons.
        J Neurosci. 1995; 15: 3622-3639
        • O'Donnell P.
        • Lewis B.L.
        • Weinberger D.R.
        • Lipska B.K.
        Neonatal hippocampal damage alters electrophysiological properties of prefrontal cortical neurons in adult rats.
        Cereb Cortex. 2002; 12: 975-982
        • Paxinos G.
        • Watson C.
        The rat brain in stereotaxic coordinates.
        Academic Press, San Diego1998
        • Pierri J.N.
        • Chaudry A.S.
        • Woo T.U.
        • Lewis D.A.
        Alterations in chandelier neuron axon terminals in the prefrontal cortex of schizophrenic subjects.
        Am J Psychiatry. 1999; 156: 1709-1719
        • Robbins T.W.
        The case of frontostriatal dysfunction in schizophrenia.
        Schizophr Bull. 1990; 16: 391-402
      3. Sesack SR, Bressler CN, Lewis DA (1995): Ultrastructural associations between dopamine terminals and local circuit neurons in the monkey prefrontal cortex: A study of calretinin-immunoreactive cells. Neurosci Lett 9–12

        • Stine C.D.
        • Lu W.
        • Wolf M.E.
        Expression of AMPA receptor flip and flop mRNAs in the nucleus accumbens and prefrontal cortex after neonatal ventral hippocampal lesions.
        Neuropsychopharmacology. 2001; 24: 253-266
        • Volk D.W.
        • Austin M.C.
        • Pierri J.N.
        • Sampson A.R.
        • Lewis D.A.
        Decreased glutamic acid decarboxylase67 messenger RNA expression in a subset of prefrontal cortical gamma-aminobutyric acid neurons in subjects with schizophrenia.
        Arch Gen Psychiatry. 2000; 57: 237-245
        • Wang J.
        • O'Donnell P.
        D1 dopamine receptors potentiate NMDA-mediated excitability increase in layer V prefrontal cortical pyramidal neurons.
        Cereb Cortex. 2001; 11: 452-462