Cognitive dysfunction and schizophrenia : Modelling attentional impairment with psychotomimetics. Investigating attentional impairment and structural brain abnormalities following phencyclidine administration: Enhancing translatability between preclinical and clinical tests of attention utilising the modified 5-choice task in rats - the 5-Choice Continuous Performance Test.

Abstract

This thesis consisted of experiments designed to explore the construct of attention and investigate the disruptive effects of psychotomimetics, with a specific focus on NMDA antagonists. Phencyclidine (PCP) was administered through a variety of treatment regimens in order to to determine the ability of inducing cognitive-specific disruptions in attentional functioning. The hypothesis that sub-chronic exposure to PCP would result in persistent attentional impairment was tested, using the 5-choice serial reaction time task (5-CSRTT). The 5-CSRTT assesses not only visuospatial attention, but also components of impulsivity, compulsivity, speed of processing and motivation. It was determined that an additional task-related intervention that increased the attentional load was required to elucidate attentional impairment following sub-chronic PCP treatment. The ability of rats to perform the modified version of the 5-CSRTT, known as the 5-choice continuous performance test (5C-CPT), was investigated. The 5C-CPT was implemented to provide a task that may have greater analogy to the human CPT, than the original 5-CSRTT. The consequence of dopaminergic D1 system activation was investigated. It was revealed that D1 partial agonism improved attentional performance in a baseline-dependent manner. Following successful acquisition of the task, it was shown that repeated PCP treatment induced cognitive disruption that was cognitive-specific, and not confounded by generalised response disruption. Furthermore, a partial attenuation of the PCP-induced performance disruption was achieved following administration of the D1 partial agonist, SKF 38393. Moreover, sub-chronic PCP treatment was shown to impair 5C-CPT performance in the drug-free state. However, an additional challenge that further increased the attentional load was needed to elucidate a performance deficit. This highlighted that sustained attention/vigilance is sensitive to persistent impairment following sub-chronic PCP administration in a manner consistent with deficits observed in schizophrenia patients. This prompted the investigation that tested the hypothesis that sub-chronic PCP treatment could induce enduring structural deficits in regions associated with attentional performance. Magnetic resonance imaging (MRI) was conducted, in conjunction with 5-CSRTT and pre-pulse inhibition (PPI). It was revealed that sub-chronic PCP treatment resulted in morphological brain abnormalities in brain regions associated with 5-CSRTT performance. This was coupled with deficits in sustained attentional performance following an increase in attentional load, yet PPI was unaffected. Taken together, these findings suggested sub-chronic PCP treatment impairs attentional functionality, an effect that dissociates between effortful and passive attentional processes.