Young D, Howe WM, Martinez V, Bruno JP, Sarter M (2007) Neuronal mechanisms underlying the cognitive symptoms in a model of schizophrenia: prefrontal cholinergic inputs are necessary for attentional performance following repeated exposure to amphetamine. Neuroscience 2007 Abstracts 606.9/GG1. Society for Neuroscience, San Diego, CA.
Summary: The neuronal and cognitive effects of repeated exposure to amphetamine (AMPH) model important aspects of schizophrenia. Our prior results indicated that the attentional performance of AMPH-pretreated animals was maintained by abnormally high levels of prefrontal acetylcholine (ACh) release, and that the disruption of attentional performance by AMPH challenges was associated with a failure of the prefrontal cholinergic input system to respond to task onset (Kozak et al. 2007). The present experiment was designed to demonstrate that prefrontal cholinergic inputs are necessary for the (residual) attentional performance following repeated AMPH exposure. As removal of cortical cholinergic inputs per se disrupts attentional performance, we tested the hypothesis that limited prefrontal cholinergic deafferentation, which does not affect baseline attentional performance, prevents the establishment of normal performance following AMPH pretreatment. Rats were trained to perform a sustained attention task requiring the detection of visual signals and the discrimination between signal and non-signal events. Bilateral infusions of small concentrations and volumes of the immunotoxin 192 IgG-saporin into the medial prefrontal cortex did not affect the animals’ baseline performance. After re-establishing stable baseline performance, animals were pretreated with either saline or AMPH in accordance with an established, non-neurotoxic, escalating dosing regimen (1-10 mg/kg, twice daily over 40 days; Robinson et al. 1988). Animals were tested daily throughout the experiment. Following completion of the pretreatment regimen, the attentional performance of sham-lesioned controls recovered slowly over three weeks of continued training/testing. In contrast, performance recovery of deafferented, AMPH-pretreated animals was robustly attenuated and failed to reach pre-treatment levels. Collectively, these results indicate the necessary role of the prefrontal cholinergic input system in mediating the residual attentional performance of repeated AMPH. Therefore, pro-cholinergic treatments are predicted to benefit the attentional performance of schizophrenics. Repeated AMPH serves as a useful model to investigate the neuronal mechanisms underlying the cognitive symptoms of schizophrenia.
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