Cognitive variables are associated with the development of the positive symptoms of schizophrenia. Specifically, persistent impairments in the ability to filter irrelevant stimuli and associations, and in related executive functions such as set switching, planning, and dual-task performance, have been hypothesized to impede the patient's efficacy in using and updating past experiences to interpret and properly respond to current inputs. The proposed research will test the general hypothesis that increases in dopaminergic transmission in the nucleus accumbens (NAC), now widely accepted as a neuronal hallmark of schizophrenia, contribute transynaptically to the increases in (re)activity of cortical cholinergic inputs, and that the increased cortical cholinergic transmission mediates attentional impairments. Preliminary data demonstrate that the repeated administration of amphetamine (AMPH), a procedure that sensitizes the mesolimbic dopaminergic system, results in augmented increases in cortical acetylcholine (ACh) efflux in naive animals. Furthermore, repeated AMPH exposure results in attentional impairments in rats tested in a sustained attention task. Partial loss of cortical cholinergic inputs attenuated the attentional consequences of repeated AMPH administration. Additional preliminary data support the hypotheses that cortical ACh efflux is modulated by the NAC, presumably via projections to the basal forebrain, and that cortical ACh efflux and attentional performance are regulated by basal forebrain GABAergic and glutamatergic mechanisms. The proposed experiments will test hypotheses about the effects of repeated AMPH on attentional performance-associated cortical ACh efflux, the necessity of cortical cholinergic inputs in the manifestation of repeated AMPH-induced attentional impairments, and about basal forebrain afferent neuronal circuits that mediate the effects of repeated AMPH on attentional performance and performance-associated cortical ACh efflux.
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