We have previously demonstrated that neonatal (postnatal day 7, PD7) excitotoxic ventral hippocampal (VH) damage in the rat produces an array of behavioral changes that appear around puberty, suggest dopaminergic hyperactivity, and are reversed by antipsychotic drugs. We study this neonatal lesion as an animal model of schizophrenia. We have continued to explore the mechanisms underlying these behavioral abnormalities, investigated the effects of the lesion on cognitive function and social behaviors as possible models of negative symptoms of schizophrenia, characterized the behavioral pattern of neonatal hippocampal damage produced earlier (PD3) and later (PD14) than before, and investigated the effects of neuroleptics. We used in vivo microdialysis technique to measure extracellular dopamine release at baseline and after amphetamine and stress. Despite the evidence from behavioral studies for increased dopaminergic activity in the lesioned rats, we have found no significant changes at baseline, and attenuated extracellular dopamine release in response to amphetamine and stress in prefrontal cortex (mPFC) and nucleus accumbens (NAc). This is, in fact, in accordance with our earlier reports on reduced 3- methoxytyramine, another measure of dopamine release, in the lesioned rats under various conditions. We continue to look at other indices of dopamine function such as the expression of dopamine transporter and tyrosine hydroxylase. We also explored function of glutamatergic system in the lesioned rats by measuring binding of [3H]MK-801 to NMDA receptors. Despite behavioral hyperresponsiveness to glutamatergic stimulation, we found no changes in binding of MK-801 in various brain regions tested, including mPFC and NAc. We demonstrated that neonatally VH lesioned rats show deficits in social interactions that, in contrast to postpubertally appearing dopamine- related behavioral abnormalities, are seen early in development, continue into adulthood, and are not corrected with clozapine. Moreover, these rats show cognitive deficits as indicated by impaired performance in the delayed alternation task. We have also shown that the age at lesion predicts the pattern of behavioral abnormalities. Early neonatal VH damage (PD3 and PD7) results in potentiated apomorphine-induced stereotypic behaviors, and delayed postpubertal amphetamine-induced hyperlocomotion. Later-induced damage (PD14 and PD42) is characterized by attenuated stereotypies and no delay in appearance of amphetamine-induced hyperactivity. We studied the effects of typical and atypical antipsychotics on c-fos and neurotensin mRNA expression and showed that the lesioned rats respond with potentiated expression of neurotensin to chronic clozapine treatment.
