Abstract
RATIONALE: The development and validation of animal models of the cognitive impairments of schizophrenia have remained challenging subjects. OBJECTIVE: We review evidence from a series of experiments concerning an animal model that dissociates between the disruption of attentional capacities during acute illness periods and the cognitive load-dependent impairments that characterize periods of remission. The model focuses on the long-term attentional consequences of an escalating-dosing pretreatment regimen with amphetamine (AMPH). RESULTS: Acute illness periods are modeled by the administration of AMPH challenges. Such challenges result in extensive impairments in attentional performance and the "freezing" of performance-associated cortical acetylcholine (ACh) release at pretask levels. During periods of remission (in the absence of AMPH challenges), AMPH-pretreated animals' attentional performance is associated with abnormally high levels of performance-associated cortical ACh release, indicative of the elevated attentional effort required to maintain performance. Furthermore, and corresponding with clinical evidence, attentional performance during remission periods is exquisitely vulnerable to distractors, reflecting impaired top-down control and abnormalities in fronto-mesolimbic-basal forebrain circuitry. Finally, this animal model detects the moderately beneficial cognitive effects of low-dose treatment with haloperidol and clozapine that were observed in clinical studies. CONCLUSIONS: The usefulness and limitations of this model for research on the neuronal mechanisms underlying the cognitive impairments in schizophrenia and for drug-finding efforts are discussed.