5 research outputs found
Zebra fish as a model for translational neurobiology: Implications for drug discovery and development
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/
Atomoxetine reduces anticipatory responding in a 5-choice serial reaction time task for adult zebrafish
Alzheimer's Disease GWAS Risk Factor BIN1 Regulates Presynaptic Neurotransmitter Release and Memory Consolidation
Developmental role of acetylcholinesterase in impulse control in zebrafish
Cellular and molecular processes that mediate individual variability in impulsivity, a key behavioural component of many neuropsychiatric disorders, are poorly understood. Zebrafish heterozygous for a nonsense mutation in Ache (achesb55/+) showed lower levels of impulsivity in a 5-choice serial reaction time task (5-CSRTT) than wild type and ache+/+. Assessment of expression of cholinergic (nAChR), serotonergic (5-HT) and dopamine (DR) receptor mRNA in both adult and larval (9dpf) achesb55/+ revealed significant downregulation of Chrna2, Chrna5 and Drd2 mRNA in achesb55/+ larvae, but no differences in adults. Acute exposure to cholinergic agonist/antagonists had no effect on impulsivity, supporting the hypothesis that behavioural effects observed in adults were due to lasting impact of developmental alterations in cholinergic and dopaminergic signalling. This shows the cross-species role of cholinergic signalling during brain development in impulsivity, and suggests zebrafish may be a useful model for the role of cholinergic pathways as a target for therapeutic advances in addiction medicine