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 [(3)H]MK-801 and the expression of NR1 messenger RNA (mRNA) in the medial prefrontal cortex and nucleus accumbens. Adult rats received similar lesions and were tested 4 and 8 weeks after the lesion.


RESULTS
As juveniles, neonatally lesioned rats did not differ from control rats 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 [(3)H]MK-801 binding or expression of the NR1 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.
Clinical Brain Disorders Branch, Intramural Research Programs, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892, USA.
H A
HA
Al-Amin
C
C
Shannon Weickert
D R
DR
Weinberger
B K
BK
Lipska
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal / Q000187:drug effects*; D001667:Binding, Competitive / Q000502:physiology; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000009:adverse effects* / Q000493:pharmacokinetics; D004298:Dopamine / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000009:adverse effects* / Q000493:pharmacokinetics; D005260:Female; D006624:Hippocampus / Q000187:drug effects*; D006948:Hyperkinesis / Q000139:chemically induced*; D017403:In Situ Hybridization; D009714:Nucleus Accumbens / Q000378:metabolism; D017397:Prefrontal Cortex / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects; D011897:Random Allocation; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism
D018691:Excitatory Amino Acid Antagonists; C409466:NR1 NMDA receptor; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate; D004298:Dopamine