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 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.
Al-Amin
H A
HA
Clinical Brain Disorders Branch, Intramural Research Programs, National Institute of Mental Health, Bethesda 20892-1385, USA.
Weinberger
D R
DR
Lipska
B K
BK
D000818:Animals; D000831:Animals, Newborn; D014150:Antipsychotic Agents / Q000494:pharmacology; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D004298:Dopamine / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D018698:Glutamic Acid / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000254:growth & development / Q000473:pathology*; D008124:Locomotion / Q000187:drug effects*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012559:Schizophrenia / Q000503:physiopathology*
D014150:Antipsychotic Agents; D018691:Excitatory Amino Acid Antagonists; D018698:Glutamic Acid; D016291:Dizocilpine Maleate; D004298:Dopamine