Clozapine administration reverses behavioral, neuronal, and nitric oxide disturbances in the neonatal ventral hippocampus rat.
Clozapine is widely used in the treatment of schizophrenia; however its complete mechanism of action is not fully established. The neonatal ventral hippocampal lesion (nVHL) has emerged as a model of schizophrenia-related behavior. Our group has previously shown hyperresponsiveness to novel environment, neuronal atrophy in prefrontal cortex (PFC) and nucleus accumbens (NAcc) neurons as well as abnormal levels of nitric oxide (NO) in the PFC of the nVHL rat. In the present study, we aimed to investigate the role of repeated clozapine administration (2 mg/kg/day for 21 days) in a novel environment, neuronal rearrangement in PFC, NAcc and basolateral amygdala (BLA) as well as NO levels in this model. Clozapine administration reversed the hyperlocomotion observed in a novel environment in the nVHL rat with no effect on locomotion in sham animals. Quantitative morphological analysis demonstrated a retracted neuronal arborization and decreased spinogenesis in the NAcc, PFC and BLA in nVHL rat. Interestingly, clozapine administration also rescued neuronal atrophy in these brain regions. The nVHL also displayed increased NO levels in PFC, striatum and occipital cortex. Clozapine administration selectively reversed these abnormal levels of NO in striatum in nVHL rat while NO levels were increased in the PFC of sham animals. Our results further extend the usefulness of the nVHL as a model of schizophrenia-related behavior and suggest that clozapine reverses behavioral deficits in these animals by modulating neuronal reorganization and NO levels in the brain.
Laboratorio de Neuropsiquiatría, Instituto de Fisiología, Universidad Autónoma de Puebla, Puebla, Mexico.
Maria Elena
ME
Bringas
Julio César
JC
Morales-Medina
Yaredi
Y
Flores-Vivaldo
Jose Vicente
JV
Negrete-Diaz
Patricia
P
Aguilar-Alonso
Bertha Alicia
BA
León-Chávez
Zayda
Z
Lazcano-Ortiz
Elibeth
E
Monroy
Antonio
A
Rodríguez-Moreno
Rémi
R
Quirion
Gonzalo
G
Flores
D000679:Amygdala / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D003024:Clozapine / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects*; D009569:Nitric Oxide / Q000378:metabolism*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D014150:Antipsychotic Agents; D009569:Nitric Oxide; D003024:Clozapine