Olanzapine and risperidone block a high dose of methamphetamine-induced schizophrenia-like behavioral abnormalities and accompanied apoptosis in the medial prefrontal cortex.
This study aims to propose a comprehensive new model for schizophrenia, which shows PPI disruption at baseline state as an endophenotype, the development of cross-sensitization to an NMDA receptor antagonist, MK-801 as a clinical phenotype of the progression into treatment-resistance, and accompanied induction of apoptosis in the medial prefrontal cortex as a critical possibility during the progression. Repeated administration of a high dose of methamphetamine (METH) (2.5 mg/kg), which could increase glutamate levels in the medial prefrontal cortex (mPFC), induced TUNEL-positive cells in this region, accompanied development of behavioral cross-sensitization to MK-801 in response to a challenge injection of MK-801, and PPI disruption at baseline state without a challenge injection. Olanzapine (OLZ) (1.0 mg/kg) and risperidone (RIS) (0.1 mg/kg), which inhibited and remarkably attenuated METH (2.5 mg/kg)-induced increases in glutamate levels, respectively, blocked not only the induction of TUNEL-positive cells in the mPFC but also the accompanied development of above behavioral abnormalities. These findings suggest that repeating the METH-induced glutamate release produces behavioral abnormalities as a clinical phenotype of schizophrenia, accompanied apoptosis as a critical possibility during the progression, and suggest that sufficient dose of olanzapine and risperidone can block the development of these behavioral abnormalities and accompanied apoptosis during the progression.
Abekawa
Tomohiro
T
Hokkaido University, Graduate School of Medicine, Department of Psychiatry, Kita 15, Nishi 7, 060-8638, Sapporo, Japan. tabekawa@med.hokudai.ac.jp
Ito
Koki
K
Nakagawa
Shin
S
Nakato
Yasuya
Y
Koyama
Tsukasa
T
D000818:Animals; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D001522:Behavior, Animal / Q000187:drug effects; D001569:Benzodiazepines / Q000627:therapeutic use*; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000008:administration & dosage; D004298:Dopamine / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018698:Glutamic Acid / Q000378:metabolism; D020287:In Situ Nick-End Labeling / Q000379:methods; D008297:Male; D008694:Methamphetamine / Q000633:toxicity; D009043:Motor Activity / Q000187:drug effects; D009433:Neural Inhibition / Q000187:drug effects; D018696:Neuroprotective Agents / Q000008:administration & dosage; D000077152:Olanzapine; D017397:Prefrontal Cortex / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018967:Risperidone / Q000627:therapeutic use*; D012559:Schizophrenia / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology*; D013997:Time Factors
D014150:Antipsychotic Agents; D018765:Dopamine Uptake Inhibitors; D018696:Neuroprotective Agents; D001569:Benzodiazepines; D018698:Glutamic Acid; D008694:Methamphetamine; D016291:Dizocilpine Maleate; D018967:Risperidone; D000077152:Olanzapine; D004298:Dopamine