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

Neonatal lesions of the ventral hippocampus in rats produce changes in spon taneous and pharmacologically induced dopamine-dependent behaviors that eme rge in early adulthood. Neural mechanisms underlying these changes may have implications for understanding the neurobiology of schizophrenia, putative ly a neurodevelopmental disorder. In this study, we evaluated the effects o f MK-801 (dizocilpine), on automated measures of distance traveled and ster eotypies 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 beha viors. The lesioned rats showed significantly greater increases in motor ac tivity after 0.05 and 0.1 mg/kg of MK-801 than did controls. Both haloperid ol (0.1 and 0.4 mg/kg) and clozapine (4 and 10 mg/kg) reduced hyperlocomoti on elicited by 0.2 mg/kg MK-801 in the ventral hippocampus (VH)-lesioned an d sham rats. Haloperidol was more potent than clozapine in decreasing MK-80 1-induced stereotypy, especially in the lesioned rats. Moreover, an AMPA an tagonist normalized exaggerated MK-801-induced hyperolocomotion in the lesi oned rats at doses that had no effect in controls. These results demonstrat e 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. (C) 2000 Lippincott Williams & Wilkins.