Exaggerated MK-801-induced motor hyperactivity in rats with the neonatal lesion of the ventral hippocampus

Abstract

Neonatal lesions of the ventral hippocampus in rats produce changes in spontaneous and pharmacologically induced dopamine-dependent behaviors that emerge in early adulthood. Neural mechanisms underlying these changes may have implications for understanding the neurobiology of schizophrenia, putatively a neurodevelopmental disorder. In this study, we evaluated the effects of MK-801 (dizocilpine), on automated measures of distance traveled and stereotypies in adult rats with neonatal (postnatal day 7) lesions, and tested the effects of haloperidol, clozapine and an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA) antagonist LY293558 on the MK-801-induced behaviors. The lesioned rats showed significantly greater increases in motor activity after 0.05 and O.1 mg/kg of MK-801 than did controls. Both haloperidol (0.1 and 0.4 mg/kg) and clozapine (4 and 10 mg/kg) reduced hyperlocomotion elicited by 0.2 mg/kg MK-801 in the ventral hippocampus (VH)-lesioned and sham rats. Haloperidol was more potent than clozapine in decreasing MK-801-induced stereotypy, especially in the lesioned rats. Moreover, an AMPA antagonist normalized exaggerated MK-801-induced hyperolocomotion in the lesioned rats at doses that had no effect in controls. These results demonstrate that the lesioned rats are more sensitive to MK-801 during adulthood than control rats, and that antidopaminergic drugs as well as AMPA antagonists antagonize the MK-801-induced behaviors. The neonatal lesion rat model may be useful to further our understanding of the interactions between dopamine and glutamate and their role in the pathophysiology of schizophrenia.