Haloperidol and clozapine have dissociable effects in a model of attentional performance deficits induced by blockade of NMDA receptors in the mPFC.
BACKGROUND
Cognitive impairment in schizophrenia is particularly evident in the domains of attention and executive functions. Atypical antipsychotics are somewhat more effective than conventional antipsychotics in improving cognitive functioning in these patients.


OBJECTIVE
The aim of this study was to compare the effects of conventional and atypical antipsychotics in a model of attentional performance deficit of schizophrenia induced by blockade of N-methyl-D: -aspartate (NMDA) receptors in the medial prefrontal cortex.


METHODS
Attentional performance was assessed using the five-choice serial reaction time task. The task provides indices of attentional functioning (% correct responses), executive control (measured by anticipatory and perseverative responding), decision time (measured by correct response latency), and omissions. Haloperidol and clozapine were given intraperitoneally (IP) to animals that had received vehicle or a competitive NMDA receptor antagonist, 3-(R)-2-carboxypiperazin-4-propyl-1-phosphonic acid (CPP), directly into the medial prefrontal cortex.


RESULTS
Fifty nanograms/side of CPP reduced accuracy (% correct responses) and increased anticipatory and perseverative responding. Haloperidol (0.03 mg/kg IP) reduced the CPP-induced anticipatory and perseverative overresponding but not the impairment in accuracy. In contrast, clozapine (2.5 mg/kg IP) reversed the decrease in accuracy and impulsivity (anticipatory responding) but not perseverative overresponding. CPP increased decision time and omissions, but these effects were not affected by either haloperidol or clozapine.


CONCLUSIONS
The effects on "impulsivity" and "compulsive perseveration" in a rat model of attentional and executive deficit of schizophrenia might differentiate conventional and atypical antipsychotics. Antagonistic activity at 5-HT(2A) receptors may best explain the facilitatory effects of clozapine on cognition.
Baviera
Marta
M
Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri, via La Masa 19, 20156 Milan, Italy.
Invernizzi
Roberto W
RW
Carli
Mirjana
M
D000704:Analysis of Variance; D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000494:pharmacology; D001288:Attention / Q000187:drug effects*; D001522:Behavior, Animal / Q000187:drug effects; D003024:Clozapine / Q000008:administration & dosage / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006220:Haloperidol / Q000008:administration & dosage / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D008297:Male; D008845:Microinjections; D010879:Piperazines / Q000008:administration & dosage / Q000633:toxicity; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D011930:Reaction Time / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D012559:Schizophrenia / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D012691:Serial Learning / Q000187:drug effects; D012702:Serotonin Antagonists / Q000008:administration & dosage / Q000494:pharmacology
D014150:Antipsychotic Agents; D018492:Dopamine Antagonists; D010879:Piperazines; D016194:Receptors, N-Methyl-D-Aspartate; D012702:Serotonin Antagonists; C050592:3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid; D003024:Clozapine; D006220:Haloperidol