Abstract
Impairments in attentional functions and capacities represent core aspects of the cognitive symptoms of schizophrenia. Attentional performance has been demonstrated to depend on the integrity and activity of cortical cholinergic inputs. The neurobiological, behavioral, and cognitive effects of repeated exposure to psychostimulants model important aspects of schizophrenia. In the present experiment, prefrontal acetylcholine (ACh) release was measured in attentional task-performing and non-performing rats pretreated with an escalating dosing regimen of amphetamine (AMPH) and following challenges with AMPH. In non-performing rats, pretreatment with AMPH did not affect the increases in ACh release produced by AMPH-challenges. In contrast, attentional task performance-associated increases in ACh release were attenuated in AMPH-pretreated and AMPH-challenged rats. This effect of repeated AMPH exposure on ACh release was already present before task-onset, suggesting that the loss of cognitive control that characterized these animals' performance was a result of cholinergic dysregulation. The findings indicate that the demonstration of repeated AMPH-induced dysregulation of the prefrontal cholinergic input system depends on interactions between the effects of repeated AMPH exposure and cognitive performance-associated recruitment of this neuronal system. Repeated AMPH-induced disruption of prefrontal cholinergic activity and attentional performance represents a useful model to investigate the cholinergic mechanisms contributing to the cognitive impairments of schizophrenia.
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Acknowledgements
Rouba Kozak is now at Pfizer Pharmaceuticals (Ann Arbor), and Holden Brown is at the University of Illinois (Chicago). The authors' research was supported by PHS Grants MH 063114, NS37026 (MS, JPB), MH057436 (JPB, MS) and KO2 MH01072 (MS). Damon Young was supported by a Predoctoral Fellowship from the Ford Foundation and Vicente Martinez by an Interdisciplinary Research Training Grant in Substance Abuse (T32 DA007267-12; University of Michigan Substance Abuse Research Center; UMSARC).
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Kozak, R., Martinez, V., Young, D. et al. Toward a Neuro-Cognitive Animal Model of the Cognitive Symptoms of Schizophrenia: Disruption of Cortical Cholinergic Neurotransmission Following Repeated Amphetamine Exposure in Attentional Task-Performing, but Not Non-Performing, Rats. Neuropsychopharmacol 32, 2074–2086 (2007). https://doi.org/10.1038/sj.npp.1301352
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