Cognitive dysfunction is evident in a wide variety of neurological disorders from
schizophrenia to Alzheimer's disease (AD). Impaired attention has been recorded in
each of these patient groups and has been hypothesised to directly impact on their
general cognitive ability and symptomatology. To date there is a paucity of
treatment options for this impairment. Administration of nicotine, the prototypical
agonist of the nicotinic class of acetylcholine receptors (nAChR), improves attention
and the overall symptomatology of various CNS disorders. Its use as a possible
therapeutic agent is limited by its adverse side-effects profile which includes
addictiveness and nausea. Identification of the receptors/pathways through which
nicotine produces these beneficial effects is a prerequisite to the discovery of more
selective agonists with minimal side-effects. Current interest has focused on the
homopentameric alpha 7 (α7) receptor (nAChR) due to its proposed role in attention
and memory, and neuroprotection in AD and other neurodegenerative disorders. In
the thesis, the role of the α7 nAChR in modulating nicotine-induced cognitive
improvement has been studied using both pharmacological and genetic means.Assessment of sustained attention in rodents can be performed using the 5-choice
serial reaction-time (5-CSR) task; analogous to the continuous performance test used
in man. A protocol was established which allowed the demonstration of nicotine induced
improvements in sustained attention in mice. In this task α7 nAChR
knockout (KO) mice exhibited impaired acquisition and performance, providing
additional evidence that this receptor may be a valid therapeutic target for cognitive
enhancement. In order to investigate the role of nAChR manipulation on working
memory, the odour span task, a test of olfactory working memory capacity, was
established in mice. Nicotine administration did not improve performance of
C57B1/6J mice probably as a consequence of ceiling effects. Transgenic mice overexpressing
human caspase-3 (hc-3) displayed a robust impairment in the task that
was attenuated by nicotine administration. Moreover α7 nAChR KO mice exhibited
impaired acquisition and performance in the task but in a different pattern to that of
the hc-3 mice. This pattern may reflect an impaired ability to attend to the task as
opposed to a working memory deficit. These demonstrations provide further support
for a role of the α7 nAChR in cognition. Tg2576 mice represent the best well
characterised transgenic mouse model of AD, however there remains a dearth of
information on their attentional and olfactory capabilities. The mice exhibited a
deficit in sustained attention as measured by the 5-CSR task as well as an age-related
impairment in the odour span task.In conclusion the development of the 5-CSR task for mice was used to identify a
nicotine-induced improvement in normal mice and impaired performance in α7 KO
and Tg2576 mice. The establishment of the odour span task in mice allowed the
demonstration of impaired working memory performance in hc-3 mice (attenuated
by nicotine administration), α7 KO mice and Tg2576 mice (age-related). In
summary these data provide some evidence for a role of the α7 nAChR in nicotineinduced
improvement in cognition, and the tasks developed provide new tools for the
assessment of putative cognitive enhancing compounds
