Psychopharmacology

, Volume 122, Issue 1, pp 35–43 | Cite as

Neonatal excitotoxic hippocampal damage in rats causes post-pubertal changes in prepulse inhibition of startle and its disruption by apomorphine

  • B. K. Lipska
  • D. R. Weinberger
  • N. R. Swerdlow
  • M. A. Geyer
  • D. L. Braff
  • G. E. Jaskiw
Original Investigation

Abstract

Neonatal excitotoxic hippocampal damage in the rat results in postpubertal onset of a variety of abnormal behaviors related to excessive dopaminergic transmission in the mesolimbic/nigrostriatal system, and thus may be considered an animal model of some aspects of schizophrenia. Because sensorimotor gating is impaired in adult patients with schizophrenia and in rats with experimentally induced mesolimbic dopamine hyperactivity, the present experiments investigated the effects of neonatal (postnatal day 7, PD7) ibotenic acid (3 µg) lesions of the ventral hippocampus (VH) on the amplitude and prepulse inhibition (PPI) of acoustic startle in prepubertal (PD35) and postpubertal (PD56) rats. Startle was elicited using 105 and 118-dB pulses alone or preceded by 4, 8, or 16 dB above-background prepulses in rats treated with vehicle or apomorphine (APO; 0.025 or 0.1 mg/kg SC). At PD35, PPI in VH-lesioned rats did not differ significantly from these measures in sham operated rats. Apomorphine significantly increased startle amplitude and reduced PPI in both sham operated and VH-lesioned rats at PD35. At PD56, startle amplitude in VH-lesioned rats was not significantly different from controls, but PPI was reduced significantly compared to controls. Ventral hippocampus lesioned rats also exhibited an exaggerated reduction in PPI after treatment with APO. These findings provide further evidence of postpubertal impairments that may be related to increased mesolimbic dopamine transmission and receptor sensitivity in rats with neonatal hippocampal damage, and provide further support for the fidelity of this animal model of schizophrenia.

Key words

Prepulse inhibition of startle Sensorimotor gating Neonatal lesion Hippocampus Ibotenic acid Apomorphine Startle 

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References

  1. Bickford-Wimer PC, Nagamoto H, Johnson R, Adler LE, Egan M, Rose GM, Freedman R (1990) Auditory sensory gating in hippocampal neurons: a model system in the rat. Biol Psychiatry 27:183–192Google Scholar
  2. Bolino F, Di Michele V, Di Cicco L, Manna V, Daneluzzo E, Casacchia M (1994) Sensorimotor gating and habituation evoked by electro-cutaneous stimulation in schizophrenia. Biol Psychiatry 36:670–679Google Scholar
  3. Braff DL (1993) Information processing and attention dysfunctions in schizophrenia. Schizophr Bull 19:233–259Google Scholar
  4. Braff DL, Stone C, Callaway E, Geyer MA, Glick ID, Bali L (1978) Prestimulus effects on human startle reflex in normals and schizophrenics. Psychophysiology 15:339–343Google Scholar
  5. Braff DL, Grillon C, Geyer MA (1992) Gating and habituation of the startle reflex in schizophrenic patients. Arch Gen Psychiatry 49:206–215Google Scholar
  6. Cadenhead KS, Geyer MA, Braff DL (1993) Impaired startle prepulse inhibition and habituation in schizotypal patients. Am J Psychiatry 150:1862–1867Google Scholar
  7. Caine SB, Geyer MA, Swerdlow NR (1991) Carbachol infusion into the dentate gyrus disrupts sensorimotor gating of startle in the rat. Psychopharmacology 105:347–354Google Scholar
  8. Davis M, Sollberger (1971) Twenty-four hour periodicity of the startle response in rats. Psychonom Sci 25:1Google Scholar
  9. Davis M, Mansbach RS, Swerdlow NR, Campeau S, Braff DL, Geyer MA (1990) Apomorphine disrupts the inhibition of acoustic startle induced by weak prepulses in rats. Psychopharmacology 102:1–4Google Scholar
  10. Geyer MA, Braff DL (1982) Habituation of the blink reflex in normals and schzophrenic patients. Psychophysiology 19:1–6Google Scholar
  11. Geyer MA, Swerdlow NR, Mansbach RS, Braff DL (1990) Startle response models of sensorimotor gating and habituation deficits in schizophrenia. Brain Res Bull 25:485–498Google Scholar
  12. Geyer MA, Wilkinson LS, Hunby T, Robbins TW (1993) Isolation rearing of rats produces a deficit in prepulse inhibition of acoustic startle similar to that in schizophrenia. Biol Psychiatry 34:361–372Google Scholar
  13. Goldberg TE, Gold JM, Braff DL (1991) Neuropsychological functioning and time-linked information processing in schizophrenia. In: Tasman A, Goldfinger SM (eds) Review of psychiatry, American psychiatric press, vol 10, pp 60–78Google Scholar
  14. Graham FK (1975) The more or less startling effects of weak prestimuli. Psychophysiology 12:238–248Google Scholar
  15. Grillon C, Ameli R, Charney DS, Krystal J, Braff DL (1992) Startle gating deficits occur across prepulse intensities in schizophrenic patients. Biol Psychiatry 32:939–943Google Scholar
  16. Holzman PS, Levy DL, Proctor LR (1976) Smooth pursuit eye movements, attention and schizophrenia. Arch Gen Psychiatry 33:1415–1420Google Scholar
  17. Ison JR, Hoffman HS (1983) Reflex modification in the domain of startle: II. The anomalous history of a robust and ubiquitous phenomenon. Psychol Bull 94:3–17Google Scholar
  18. Jaskiw GE, Weinberger DR (1992) Dopamine and schizophrenia - a cortically corrective perspective. Semin Neurosci 4:179–188Google Scholar
  19. Keith VA, Mansbach RS, Geyer MA (1991) Failure of haloperidol to block the effects of phencyclidine and dizolcipine on prepulse inhibition of startle. Biol Psychiatry 30:557–566Google Scholar
  20. Kraepelin E (1921) Clinical psychiatry: a textbook for students and physicians. Macmillan Publishing, New YorkGoogle Scholar
  21. Lipska BK, Weinberger DR (1993a): Cortical regulation of the mesolimbic dopamine system: implications for schizophrenia. In: Kalivas PW, Barnes CD (eds) Limbic circuits and neuropsychiatry. CRC Press, Boca Raton, pp 329–349Google Scholar
  22. Lipska BK, Weinberger DR (1993b) Delayed effects of neonatal hippocampal damage on haloperidol-induced catalepsy and apomorphine-induced stereotypic behaviors in the rat. Dev Brain Res 75:213–222Google Scholar
  23. Lipska BK, Weinberger DR (1994a) Gonadectomy does not prevent novelty or drug-induced motor hyperresponsiveness in rats with neonatal hippocampal damage. Dev Brain Res 78:253–258Google Scholar
  24. Lipska BK, Weinberger DR (1994b) Subchronic treatment with haloperidol and clozapine in rats with neonatal excitotoxic hippocampal damage. Neuropsychopharmacology 10:199–205Google Scholar
  25. Lipska BK, Jaskiw GE, Chrapusta S, Karoum F, Weinberger DR (1992) Ibotenic acid lesion of the ventral hippocampus differentially affects dopamine and its metabolites in the nucleus accumbens and prefrontal cortex in the rat. Brain Res 585:1–6Google Scholar
  26. Lipska BK, Jaskiw GE, Weinberger DR (1993) Postpubertal emergence of hyperresponsiveness to stress and to amphetamine after neonatal excitotoxic hippocampal damage: a potential animal model of schizophrenia. Neuropsychopharmacology 9:67–75Google Scholar
  27. Lipska BK, Jaskiw GE, Weinberger DR (1994) The effects of combined prefrontal cortical and hippocampal damage on dopamine-related behaviors in rats. Pharmacol Biochem Behav 48:1053–1057Google Scholar
  28. Mansbach RS, Geyer MA (1989) Effects of phencyclidine and phencyclidine biologs on sensorimotor gating in the rat. Neuropsychopharmacology 2:299–308Google Scholar
  29. Mansbach RS, Geyer MA, Braff DL (1988) Dopaminergic stimulation disrupts sensorimotor gating in the rat. Psychopharmacology 94:507–514Google Scholar
  30. McGhie A, Chapman J (1961) Disorders of attention and perception in early schizophrenia. Br J Med Psychol 34:103–116Google Scholar
  31. Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates. Academic Press AustraliaGoogle Scholar
  32. Rigdon GC (1990) Differential effects of apomorphine on prepulse inhibition of acoustic startle reflex in two rat strains. Psychopharmacology 102:419–421Google Scholar
  33. Schwarzkopf SB, Mitra T, Bruno JP (1992) Sensory gating in rats depleted of dopamine as neonates: potential relevance to findings in schizophrenic patients. Biol Psychiatry 31:759–773Google Scholar
  34. Siegel C, Waldo M, Mizner G, Adler LE, Freedman R (1984) Deficits in sensory gating in schizophrenic patients and their relatives: evidence obtained with auditory evoked responses. Arch Gen Psychiatry 41:607–612Google Scholar
  35. Swerdlow NR, Geyer MA (1993a) Clozapine and haloperidol in an animal model of sensorimotor gating deficits in schizophrenia. Pharmacol Biochem Behav 44:741–744Google Scholar
  36. Swerdlow NR, Geyer MA (1993b) Prepulse inhibition of acoustic startle in rats after lesions of the pedunculopontine nucleus. Behav Neurosci 107:104–117Google Scholar
  37. Swerdlow NR, Braff DL, Geyer MA, Koob GF (1986) Central dopamine hyperactivity in rats mimicks abnormal acoustic startle response in schizophrenics. Biol Psychiatry 21:23–33Google Scholar
  38. Swerdlow NR, Mansbach RS, Geyer MA, Pulvirenti L, Koob GF, Braff DL (1990a) Amphetamine disruption of prepulse inhibition of acoustic startle is reversed by depletion of mesolimbic dopamine. Psychopharmacology 100:413–416Google Scholar
  39. Swerdlow NR, Braff DL, Masten VL, Geyer MA (1990b) Schizophrenic-like sensorimotor gating abnormalities in rats following dopamine infusions into the nucleus accumbens. Psychopharmacology 101:414–420Google Scholar
  40. Swerdlow NR, Keith VA, Braff DL, Geyer MA (1991) Effects of spiperone, raclopride, SCH 23390 and clozapine on apomorphine inhibition of sensorimotor gating of the startle response in the rat. J Pharmacol Exp Ther 256:530–536Google Scholar
  41. Swerdlow NR, Caine BC, Geyer MA (1992a) Regionally selective effects of intracerebral dopamine infusion on sensorimotor gating of the startle reflex in rats. Psychopharmacology 108:189–195Google Scholar
  42. Swerdlow NR, Caine SB, Braff DL, Geyer MA (1992b) Neural substrates of sensorimotor gating of the startle reflex: preclinical findings and their implications. J Psychopharmacol 6:176–190Google Scholar
  43. Swerdlow NR, Braff DL, Taaid N, Geyer MA (1994) Assessing the validity of an animal model of deficient sensorimotor gating in schizophrenic patients. Arch Gen Psychiatry 51:139–154Google Scholar
  44. Swerdlow NR, Lipska BK, Weinberger DR, Braff DL, Jaskiw GE, Geyer MA (1995) Increased sensitivity to the sensorimotor gating-disruptive effects of apomorphine after lesions of medial prefrontal cortex or ventral hippocampus in adult rats. PsychopharmacologyGoogle Scholar
  45. Weinberger DR (1987) Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry 44:660–669Google Scholar
  46. Weinberger DR, Lipska BK (1995) Cortical maldevelopment, antipsychotic drugs, and schizophrenia: search for common groundsGoogle Scholar
  47. Wilkinson LS, Killcross AS, Hunby T, Hall FS, Torres EM, Geyer MA, Robbins TW (1994) Social isolation produces developmentally specific deficits in prepulse inhibition of the acoustic startle response but does not disrupt latent inhibition. Neuropsychopharmacology 10:61–72Google Scholar

Copyright information

© Springer-Verlag 1995

Authors and Affiliations

  • B. K. Lipska
    • 1
  • D. R. Weinberger
    • 1
  • N. R. Swerdlow
    • 2
  • M. A. Geyer
    • 2
  • D. L. Braff
    • 2
  • G. E. Jaskiw
    • 3
  1. 1.Clinical Brain Disorders Branch, Intramural Research ProgramNational Institute of Mental Health, NIH, Neuroscience Center at St ElizabethsWashington, DCUSA
  2. 2.Department of PsychiatryUCSD School of MedicineLa JollaUSA
  3. 3.Psychiatry Service 116A(B)Brecksville VAMCBrecksvilleUSA

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