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Title: The effect of pharmacotherapy on cognitive function and diabetes in a transgenic mouse model of Huntington's disease
Author: Hunt, M. J.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2002
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The R6/2 transgenic mice used in this study carry exon 1 of the human Huntington's disease mutation. They develop a progressive motor dysfunction and die prematurely at around 16 weeks of age. The experiments carried out in this thesis have examined the cognitive function of R6/2 mice and identified novel learning impairments in T-maze tasks, and sustained impairments in Morris water maze tasks. The inability to solve these tasks was associated with an increase in perseveration and thigmotaxis in the T-maze and Morris water maze, respectively. The cause of these learning deficits is at present unclear, but cannot be attributed to diabetes, since R6/2 mice remained normoglycaemic at fasting and following a glucose challenge until the mid-stage of phenotype, well before the onset of cognitive dysfunction. In an attempt to treat the cognitive dysfunction, R6/2 mice were treated chronically, from 5 weeks of age, with a combination of drugs aimed at boosting global neurotransmitter levels and energy availability. Tacrine (an acetylcholine esterase inhibitor), moclobemide (a monoamine oxidase inhibitor) and creatine (a drug that increases oxidative phosphorylation) administered as a triple treatment produced a long-lasting improvement in tasks sensitive to spatial navigation (T-maze alteration and the spatial version of the Morris water maze). However, the triple treatment did not improve nonspatial or reversal learning. No effect was found following treatment with these drugs individually. Remarkably, the onset of glycosuria was significantly delayed following triple treatment, but not by conventional antidiabetic drugs (glibenclamide and rosiglitazone). Importantly, no adverse effects were found following drug treatment. The experiments described in this thesis have identified novel learning deficits in R6/2 mice, and a combination of treatments that alleviate the cognitive dysfunction. The cognitive dysfunctions that were improved in R6/2 mice have human correlates that are found in Huntington's disease. The findings from this thesis suggest that treatments directed at elevating global neurotransmitter levels, combined with drugs which increase energetic availability are likely to provide optimal treatment for the cognitive deficits in Huntington's disease.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available