Risperidone pretreatment prevents elevated locomotor activity following neonatal hippocampal lesions

Abstract

Long-standing behavioral abnormalities emerge after puberty in rats following neonatal hippocampal lesion, providing a developmental model of abnormal rat behavior that may have predictive validity in identifying compounds effective in treating symptoms of schizophrenia. We sought to test the predictive validity of the neonatal hippocampal lesion model in identifying preventive treatment for first-episode psychosis. We determined the effect of risperidone, recently studied for prevention of first-episode psychosis, on the development of elevated locomotor activity following neonatal hippocampal lesions. Rat pups received hippocampal or sham lesions on postnatal day 7, followed by treatment with risperidone or vehicle from postnatal days 35 to 56. Locomotor activity in response to novelty, amphetamine, and nocturnal locomotion were determined on postnatal day 57. Low-dose risperidone (45 microg/kg) pretreatment prevented elevated locomotor activity in some, but not all, of the behavioral tasks following neonatal hippocampal lesions. In contrast, higher risperidone pretreatment was less effective in preventing elevated locomotor activity following neonatal hippocampal lesions. Because low risperidone dosages were also found to be effective in preventing first-episode psychosis in human studies, these data support the predictive validity of the hippocampal lesion model in identifying medications for prevention of first-episode psychosis. Additionally, these data support the use of low-dose risperidone in psychosis prevention, and suggest the possibility that higher risperidone doses could be less effective in this application.

Figure 1

Photomicrographs of representative NeuN-stained sections of adult control (a) and neonatal hippocampal-lesioned (b) rats. Note the neuronal loss in the dorsal CA1, CA3 and dentate gyrus (DG) granule cell layer, and associated ventricular dilation.

Figure 2

Schematic diagram of lesion boundaries following bilateral ibotenic acid infusion at P7. Lesion boundaries for individual animals were defined by neuronal loss, as determined immunocytochemically by NeuN staining. Shading denotes boundaries of the largest (gray) and smallest (black) lesions. Diagrams are from (Paxinos and Watson, 1986).

Figure 3

Effect of risperidone pretreatment on locomotor response to novelty. (a) Locomotor responses (crossovers/15 min interval) following introduction into a novel environment (RACs) on postnatal day (PD) 57 of lesioned and sham-lesioned rats treated on PD 35–56 with saline or risperidone (45 or 85 μg/kg). Data are expressed as mean crossovers; error bars are 95% confidence intervals. (b) Risperidone treatment effects (45 or 85 μg/kg) determined from [μ_{{Lesion/Risp x μg/kg}}−μ_{{Sham/Risp x μg/kg}}]−[μ_{{Lesion/Saline}}−μ_{{Sham/Saline}}]. Negative values indicate suppression of the hyperlocomotor effect of hippocampal lesions (0). Data are expressed as mean ± 95% confidence intervals. *P≤0.05, **P≤0.01, ***P≤0.001 vs lesion group.

Figure 4

Effect of risperidone pretreatment on amphetamine-stimulated locomotion. (a) Locomotor responses (crossovers per 15 min interval) following amphetamine (1.5 mg/kg) injection on PD 57 of lesioned and sham-lesioned rats treated on PD 35–56 with saline or risperidone (45 or 85 μg/kg). Data are expressed as mean crossovers; error bars are 95% confidence intervals. (b) Risperidone treatment effects (45 or 85 μg/kg) determined from [μ_{{Lesion/Risp x μg/kg}}−μ_{{Sham/Risp x μg/kg}}]−[μ_{{Lesion/Saline}}−μ_{{Sham/Saline}}]. Negative values indicate suppression of the hyperlocomotor effect of hippocampal lesions (0). Note that the protective effect of 45 μg/kg risperidone emerges over time, becoming statistically significant after 30 min. Data are expressed as mean ±95% confidence intervals. *P ≤0.05, **P≤0.01 vs lesion group.

Figure 5

Effect of risperidone pretreatment on locomotion following change between light and dark cycle. (a) Locomotor response (crossovers per 15 min interval) during the first 120 min of the ‘lights-out’ period in the RACs on PD 57 of lesioned and sham-lesioned animals following pretreatment with saline or risperidone (45 or 85 μg/kg) on PD 35–56. Data are expressed as mean crossovers; error bars are 95% confidence intervals. (b) Risperi-done treatment effects (45 or 85 μg/kg) determined from [μ_{{Lesion/Risp x μg/kg}}−μ_{{Sham/Risp x μg/kg}}]−[μ_{{Lesion/Saline}}−μ_{{Sham/Saline}}]. Negative values indicate suppression of the hyperlocomotor effect of hippocampal lesions (0). Data are expressed as mean ±95% confidence intervals. *P≤0.05, **P≤0.01, ***P≤0.001 vs lesion group.