Related Experiment Videos
Subchronic treatment with haloperidol and clozapine in rats with neonatal excitotoxic hippocampal damage
1Clinical Brain Disorders Branch, National Institute of Mental Health, NIH, Washington, DC 20032.
Insights
Neonatal hippocampal damage in rats models schizophrenia, showing abnormal dopamine behaviors. Antipsychotics haloperidol and clozapine differentially affected these behaviors, indicating drug-specific effects in this animal model.
Area of Science:
- Neuroscience
- Pharmacology
- Animal Models
Background:
- Neonatal excitotoxic hippocampal damage in rats leads to abnormal dopamine-related behaviors post-puberty.
- This phenomenon serves as a potential animal model for schizophrenia.
Purpose of the Study:
- To investigate the effects of subchronic haloperidol and clozapine treatment in rats with neonatal ventral hippocampus (VH) lesions.
- To assess the differential behavioral effects of these antipsychotics in lesioned versus sham-operated animals.
Main Methods:
- Ventral hippocampus lesions were induced in rat pups on postnatal day 7 (PD7).
- Starting at PD56, rats received 21-day treatments of vehicle, haloperidol, or clozapine.
- Locomotor activity, apomorphine-induced stereotypy, and locomotion were evaluated.
Main Results:
- VH-lesioned rats exhibited enhanced novelty- and apomorphine-induced hyperlocomotion and stereotypy compared to controls.
- Haloperidol and clozapine suppressed hyperlocomotion in lesioned rats, while only haloperidol suppressed it in sham-operated rats.
- Withdrawal supersensitivity to apomorphine was observed with haloperidol in lesioned rats but not clozapine-treated or sham-operated rats.
Conclusions:
- Haloperidol and clozapine demonstrate distinct behavioral effects in neurologically intact and hippocampally lesioned rats.
- These findings highlight drug-specific actions and support the utility of this model for studying antipsychotic efficacy in schizophrenia.
Abstract:
We have previously demonstrated that rats with neonatal excitotoxic hippocampal damage manifest abnormal dopamine (DA)-related behaviors after puberty, a phenomenon that has implications for an animal model of schizophrenia. In this study we investigated the effects of subchronic treatment with haloperidol and clozapine in these animals. The ventral hippocampus (VH) of rat pups was lesioned with ibotenic acid on postnatal day 7 (PD7). Starting at PD56, rats were treated for 21 days with either vehicle (VEH), haloperidol (HAL) (0.1 mg/kg, IP), or clozapine (CLOZ) (4 mg/kg, IP). Spontaneous locomotor activity was measured 0.5 hour after the last injection. Apomorphine (APO)-induced stereotypy and locomotion were evaluated five days later. The VH lesioned rats treated with VEH expressed enhanced novelty- and apomorphine-induced hyperlocomotion, as well as potentiated apomorphine-induced stereotypic behaviors as compared to sham-lesioned counterparts. Spontaneous locomotor activity was suppressed by haloperidol but not by clozapine in the sham-operated group, whereas both drugs were effective in suppressing hyperlocomotion in the VH lesioned rats. Withdrawal supersensitivity to apomorphine was seen in the haloperidol but not in the clozapine-treated lesioned rats, and none of the drugs produced significant supersensitivity in the sham-operated animals. These results indicate that the two neuroleptics exerted differential behavioral effects in neurologically intact and hippocampally lesioned animals, and that these effects were also drug-specific.