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.
Al-Amin
H A
HA
Clinical Brain Disorders Branch, Intramural Research Programs, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892, USA.
Shannon Weickert
C
C
Weinberger
D R
DR
Lipska
B K
BK
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