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Neonatal excitotoxic hippocampal damage in rats causes post-pubertal changes in prepulse inhibition of startle and
B K Lipska1, N R Swerdlow, M A Geyer
1Clinical Brain Disorders Branch, National Institute of Mental Health, NIH, Washington, DC 20032, USA.
Insights
Neonatal hippocampal damage in rats impairs sensorimotor gating in adulthood, mimicking schizophrenia. This damage affects dopamine system function, supporting its use as a schizophrenia animal model.
Area of Science:
- Neuroscience
- Behavioral Neuroscience
- Psychiatry
Background:
- Neonatal excitotoxic hippocampal damage in rats leads to abnormal behaviors linked to dopamine system hyperactivity.
- Sensorimotor gating deficits are observed in schizophrenia patients and animal models with dopamine hyperactivity.
Purpose of the Study:
- To investigate the impact of neonatal ventral hippocampus (VH) lesions on acoustic startle and prepulse inhibition (PPI) in prepubertal and postpubertal rats.
- To assess the role of dopaminergic transmission in these deficits using apomorphine (APO).
Main Methods:
- Neonatal (PD7) ibotenic acid lesions of the VH in rats.
- Assessment of acoustic startle amplitude and PPI at PD35 and PD56.
- Administration of apomorphine (APO) to evaluate its effects on startle and PPI.
Main Results:
- At PD35, VH-lesioned rats showed no significant difference in PPI compared to controls.
- At PD56, VH-lesioned rats exhibited significantly reduced PPI.
- APO administration caused a more pronounced PPI reduction in VH-lesioned rats than in controls at PD56.
Conclusions:
- Neonatal hippocampal damage results in postpubertal sensorimotor gating impairments.
- These impairments are associated with increased mesolimbic dopamine transmission and receptor sensitivity.
- This supports the validity of this rat model for studying schizophrenia.
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 micrograms) 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.