Effects of aripiprazole, olanzapine, and haloperidol in a model of cognitive deficit of schizophrenia in rats: relationship with glutamate release in the medial prefrontal cortex.
BACKGROUND
Disruption in cognition is characteristic of psychiatric illnesses such as schizophrenia. Studies of drugs that improve cognition might provide a better insight into the mechanisms underlying cognitive deficits.


OBJECTIVE
We compared the effects of the antipsychotic drugs aripiprazole, olanzapine, and haloperidol on performance deficit in a test of divided and sustained visual attention, the five-choice serial reaction time task (5-CSRTT), which provides information on attentional functioning (accuracy of visual discrimination), response control (measured by anticipatory and perseverative responses) and speed.


METHODS
The cognitive deficit was induced by infusion of the competitive NMDA receptor antagonist 3-(R)-2-carboxypiperazin-4-propyl-1-phosphonic acid (CPP) in the rat medial prefrontal cortex (mPFC). In vivo microdialysis was used to compare the effects of aripiprazole, olanzapine and haloperidol on CPP-induced glutamate (GLU) and serotonin (5-HT) release in the mPFC of conscious rats.


RESULTS
Oral aripiprazole (1.0 and 3.0 mg/kg) and olanzapine (0.3 and 1.0 mg/kg), but not haloperidol (0.1 mg/kg), abolished the CPP-induced accuracy deficit and GLU release. Haloperidol and aripiprazole, but not olanzapine, reduced perseverative over-responding, while anticipatory responding was best controlled by olanzapine. However, these effects were not associated with changes in GLU release. No association was found between the effects of these antipsychotics on CPP-induced attentional performance deficits in the 5-CSRTT and 5-HT efflux.


CONCLUSIONS
The data confirm that excessive GLU release in the mPFC is associated with attentional deficits. Thus, suppression of GLU release may be a target for the development of novel antipsychotic drugs with greater effect on some aspects of cognitive deficits.
Laboratory of Neurochemistry and Behavior, Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri, Via G. La Masa 19, 20156, Milan, Italy.
Mirjana
M
Carli
Eleonora
E
Calcagno
Pierangela
P
Mainolfi
Ester
E
Mainini
Roberto W
RW
Invernizzi
D000704:Analysis of Variance; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000068180:Aripiprazole; D001522:Behavior, Animal; D001569:Benzodiazepines / Q000494:pharmacology; D002755:Choice Behavior / Q000187:drug effects; D003072:Cognition Disorders / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000633:toxicity; D018698:Glutamic Acid / Q000378:metabolism*; D006220:Haloperidol / Q000494:pharmacology; D007175:Impulsive Behavior / Q000188:drug therapy; D008297:Male; D017551:Microdialysis / Q000379:methods; D009483:Neuropsychological Tests; D000077152:Olanzapine; D010879:Piperazines / Q000494:pharmacology / Q000633:toxicity; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D015363:Quinolones / Q000494:pharmacology; D051381:Rats; D011930:Reaction Time / Q000187:drug effects; D012559:Schizophrenia / Q000139:chemically induced / Q000150:complications*; D012701:Serotonin / Q000378:metabolism; D013997:Time Factors
D014150:Antipsychotic Agents; D018691:Excitatory Amino Acid Antagonists; D010879:Piperazines; D015363:Quinolones; D001569:Benzodiazepines; D012701:Serotonin; D018698:Glutamic Acid; D000068180:Aripiprazole; C050592:3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid; D006220:Haloperidol; D000077152:Olanzapine