Detection of the Moderately Beneficial Cognitive Effects of Low-Dose Treatment with Haloperidol or Clozapine in an Animal Model of the Attentional Impairments of Schizophrenia

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Abstract
The absence of effective cognition enhancers for the treatment of patients with schizophrenia limits the validation of animal models and behavioral tests used for drug finding and characterization. However, low doses of haloperidol and clozapine were documented to produce moderately beneficial effects in patients. Therefore, this experiment was designed to determine the attentional effects of such treatments in a repeated-amphetamine (AMPH) animal model. Animals were trained in an operant-sustained attention task and underwent a 40-day pretreatment period with saline or increasing doses (1–10 mg per kg) of AMPH. After regaining baseline performance following 10 days of saline treatment, animals were treated with haloperidol (0.025 mg per kg), clozapine (2.5 mg per kg), or vehicle for 10 days. Furthermore, the effects of AMPH challenges (1.0 mg per kg) were assessed. In AMPH-pretreated animals, the administration of AMPH challenges resulted in the disruption of attentional performance. Treatment with haloperidol and clozapine attenuated the detrimental performance effects of these challenges, with clozapine exhibiting more robust attenuation. Furthermore, clozapine, but not haloperidol, impaired the performance of control animals. In contrast, the performance of AMPH-pretreated animals remained unaffected by clozapine. As this animal model detects the moderately beneficial cognitive effects of haloperidol and clozapine, it may be useful for preclinical research designed to detect and characterize treatments for the cognitive symptoms of schizophrenia.

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