Delayed onset of enhanced MK-801-induced motor hyperactivity after neonatal lesions of the rat ventral hippocampus

Background: Abnormalities in the glutamatergic system, glutamate/dopamine/gamma -aminobutyric acid interactions, and cortical development are implicated in schizophrenia. Moreover, patients with schizophrenia show symptom exacerbation in response to N-methyl-D-aspartate (NMDA) antagonist drugs, Using an animal model of schizophrenia, we compared the impact of neonatal and adult hippocampal lesions on behavioral responses to MK-801, a noncompetitive NMDA antagonist, Methods: Neonatal rats were lesioned on postnatal day 7, Their motor activity in response to MK-801 was tested at a juvenile age, in adolescence, and in adulthood. We also measured binding of [H-3]MK-801 and the expression of NR1 messenger RNA (mRNA) in the medial prefrontal cortex and nucleus accumbens, Adult mts received similar lesions and were tested 4 and 8 weeks after the lesion. Results: As juveniles, neonatally lesioned rats did not differ from control mts in responsiveness to MK-801, whereas in adolescence and adulthood they showed more pronounced hyperactivity than control rats. The adult lesion did not alter behaviors elicited by MK-801. Neonatally lesioned rats showed no apparent changes in [H-3]MK-801 binding or expression of the NRI mRNA. Conclusions: These results suggest that an early lesion of the ventral hippocampus affects development of neural systems involved in MK-801 action without changes at the NMDA receptor level, and they show that the behavioral changes manifest first in early adulthood. Biol Psychiatry 2001;49:528-539 (C) 2001 Society of Biological Psychiatry.