| Cognitive impairments, including deficits in attention processing, represent major and central elements of schizophrenic symptoms. First- and second-generation antipsychotic drugs can effectively mitigate the florid symptoms of psychosis. However, treating schizophrenia's cognitive deficits remains problematic and has met with limited success. Evidence indicates that the basal forebrain cholinergic system (BFCS) is an essential component of the neuronal circuitry involved in mediating attention processing - an important aspect of cognition. This thesis is based on the core hypothesis that cholinergic dysregulation contributes to the cognitive impairments associated with schizophrenia. Using a repeated-amphetamine (AMPH) rat model of schizophrenia, the following main hypotheses are tested: (1) Repeated, escalating AMPH administration, followed by 'AMPH-challenges' at previously innocuous doses, results in performance impairments on a task that measures sustained attention. (2) The consequences of repeated-AMPH administration and subsequent challenge dosing in task-performing animals include dysregulated cortical cholinergic transmission. (3) In AMPH-pretreated animals performing a sustained attention task; sub-chronic, low-dose administration of antipsychotic drugs will attenuate performance impairments.;The present findings provide evidence for aberrant regulation of the BFCS and impaired sustained attention processing in a repeated-AMPH model of schizophrenia. Specifically, pretreatment with AMPH resulted in attenuated performance associated cortical cholinergic transmission, This effect was evident only under conditions of task performance, and was not apparent in passive, non-performing animals. Cholinergic abnormalities were found to actually precede task onset, indicating that they contributed to rather than resulted from impaired performance. Furthermore, low doses of commonly prescribed first- and second-generation antipsychotic drugs were found to attenuate these attentional impairments, although the effects on cortical cholinergic transmission in task-performing animals remain speculative. Theses data are consistent with the hypothesis that the basal forebrain cholinergic system represents a principle component in the neuronal dysregulation mediating schizophrenia's cognitive impairments. Expanding this hypothesis, these data elucidate the dynamic nature of this dysregulation in response to different stimulus environments. Collectively, these experiments demonstrate the potential usefulness of this procedure for modeling aspects of impaired cognition in schizophrenia and may serve as a starting point for pre-clinical efforts aimed at discovering and developing novel, pro-cognitive drugs to improve the cognitive deficits of schizophrenia. |
