Effects of aripiprazole and haloperidol on progression to schizophrenia-like behavioural abnormalities and apoptosis in rodents.
Aripiprazole (APZ) is considered a first-line medication for treating first and multiple episodes of schizophrenia, but its effect on preventing the progressive pathophysiology of schizophrenia remains unclear. This study examined the hypothesis that APZ blocks enhanced glutamate release in the medial prefrontal cortex (mPFC) during psychotic episodes of schizophrenia, thereby preventing progression of the pathophysiology. We examined effects of APZ on methamphetamine (METH)-induced increases in glutamate levels in the mPFC, and on repeatedly administered METH-induced progression to schizophrenia-like behavioural abnormalities involving cross-sensitization to the N-methyl-d-aspartate (NMDA) receptor antagonist, MK-801, deficit of prepulse inhibition (PPI), and expression of TUNEL-positive cells. Additionally, we compared the preventive effects of APZ to those of a conventional antipsychotic: haloperidol (HPD). Results show that APZ (1.0 and 3.0 mg/kg) and HPD (0.1 mg/kg) each blocked METH (2.5 mg/kg)-induced increases in glutamate levels in the mPFC. Furthermore, APZ (3.0 mg/kg) and HPD (0.1 mg/kg), when co-administered repeatedly with METH, each prevented progression to schizophrenia-like behavioural and neuropathological abnormalities. Repeated co-administration of APZ (3.0 mg/kg) with saline did not induce apoptosis, although HPD (0.1 mg/kg) with saline did induce apoptosis. These results indicate that APZ and HPD prevented progressive pathophysiology, which is related to increased glutamate levels, and indicate that repeated administration of HPD, but not APZ, induced apoptosis under conditions without increased glutamate levels. These findings suggest the importance of using APZ and HPD in the appropriate stages of the glutamate-related pathophysiology of schizophrenia.
Abekawa
Tomohiro
T
Kotoku-kai Aiko Hospital, Department of Psychiatry, Matsue 2-7-1, 243-0005, Kanagawa, Japan. spg35k69@opal.ocn.ne.jp
Ito
Koki
K
Nakagawa
Shin
S
Nakato
Yasuya
Y
Koyama
Tsukasa
T
D000161:Acoustic Stimulation / Q000009:adverse effects; D000704:Analysis of Variance; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D000068180:Aripiprazole; D001526:Behavioral Symptoms / Q000209:etiology*; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology / Q000627:therapeutic use; D006220:Haloperidol / Q000494:pharmacology / Q000627:therapeutic use*; D020287:In Situ Nick-End Labeling; D007266:Inhibition, Psychological; D008297:Male; D008694:Methamphetamine / Q000009:adverse effects / Q000494:pharmacology; D017551:Microdialysis / Q000379:methods; D009043:Motor Activity / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D015363:Quinolones / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013216:Reflex, Startle / Q000187:drug effects; D012559:Schizophrenia / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy / Q000473:pathology
D014150:Antipsychotic Agents; D018696:Neuroprotective Agents; D010879:Piperazines; D015363:Quinolones; D008694:Methamphetamine; D016291:Dizocilpine Maleate; D000068180:Aripiprazole; D006220:Haloperidol