PhDDiseases which affect the central nervous system present a huge burden to sufferers
and caregivers. In tandem with longevity, prevalences of age-related
neurodegenerative diseases are increasing. However, despite the evident necessity
for pharmaceutical interventions, there has been a distinct lack of drug
development to combat these disorders. This is largely attributed to high financial
costs of using rodent models. Thus the validation of a more cost-effective in vivo
system would facilitate pharmaceutical screening. The work presented in this
thesis addresses this issue by assessing the utility of zebra fish in two costly areas of
translational neurobiology { lead identi cation and safety pharmacology.
An aversive classical conditioning assay was developed and automated as a
behavioural screening method. This robust assay allows fast assessment of
cognition and cognitive decline. The effect of neurotoxin treatment on aversive
learning was then assessed using this assay, demonstrating its efficacy as a
screening tool for neurodegeneration research.
Subsequently, a transgenic zebra fish line - expressing a mutated form of the
Alzheimer's-associated human amyloid precursor protein - was assessed,
demonstrating an age-related cognitive impairment. Additionally new genetic
zebra fish lines were generated, which over-express genes (both endogenous and
transgenic) related to Alzheimer's-like pathologies. Whilst these were not assessed
within this thesis, they present promising tools for possible future investigations.
Regarding safety pharmacology, regulatory bodies require all CNS-penetrant
drugs be assessed for abuse potential. Zebra fish display reward responses to several
common drugs of abuse (e.g. amphetamine, cocaine, morphine). Thus, the latter
sections of this thesis evaluated the utility of zebra fish for assessing human abuse
potential. A CPP paradigm was utilised to test a range of drugs, with the
sensitivity and specificity of zebra fish compared to previous reports using rodent.
Additionally, the development of a zebra fish drug discrimination assay was
attempted. However the paradigms utilised failed to develop an efficacious assay.EPSRC and P zer Inc., grant number
EP/K50290X/