Effects of acute and chronic dopaminergic treatment on motor and non-motor function in the hemi-Parkinsonian rat

Murphy, Ellen M. 2014. Effects of acute and chronic dopaminergic treatment on motor and non-motor function in the hemi-Parkinsonian rat. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Parkinson’s disease (PD) is commonly treated with L-DOPA. Long-term treatment is associated with the development of motor side effects such as L-DOPA induced dyskinesia (LID), and pathological changes in the striatal circuitry. However, while this circuitry is implicated in both motor and non-motor behaviour, little is known about the effects of long-term L-DOPA treatment on non-motor function. This thesis used a rat model of PD and LID to test the hypothesis that long-term L-DOPA treatment also affects non-motor behaviour. Pharmacological studies typically utilise albino rats, while pigmented rats are preferred for operant studies. To guide later methodological decisions, Experiment 1 compared pigmented Listed Hooded and albino Sprague Dawley rats’ motor, dyskinetic, or operant response to L-DOPA. As there were no gross strain differences, and Lister Hooded rats are preferred in operant studies, they were used in later experiments measuring both LID and operant behaviour. Experiment 2 aimed to identify appropriate lesion screening tests. Success of unilateral 6-OHDA lesions is commonly measured using amphetamine-induced rotations. However, amphetamine interferes with goal-directed behaviour. The ability of amphetamine-induced rotations and four non-pharmacological motor tests to accurately identify lesion rats was therefore compared. The non-pharmacological spontaneous rotations and cylinder tests were identified as robust screening tests and used in later experiments. L-DOPA competes with dietary amino acids for transport across the blood-brain barrier, and chronic L-DOPA treatment sensitises dopamine receptors. It was therefore hypothesised that food restriction and chronic L-DOPA would both decrease the L-DOPA dose required to alleviate motor symptoms in the rat 6-OHDA model. Chapter 4 describes two dose response curves testing the effect of food restriction and chronic L-DOPA on the motor response to acute L-DOPA in rats with intra-striatal or MFB lesions. Chronic L-DOPA increased the motor response to acute L-DOPA in the MFB, but not intra-striatal, lesion model. Conversely, food restriction increased the motor response to acute L-DOPA in the intra-striatal, but not MFB, lesion model. Chapter 5 used microdialysis to test the hypothesis that the increased motor response following food restriction was caused by an increased influx of L-DOPA to the striatum. The data did not support the hypothesis but suggested that food restriction affects baseline neurotransmitter levels in the 6-OHDA lesion rat. Chapter 6 tested the hypothesis that LID onset, by disrupting cortico-striatal synaptic plasticity which is implicated in motor skill learning, impairs acquisition of novel motor skills by measuring rats’ performance on the staircase task. While an initial experiment suggested that chronic LID onset impaired lesion rats’ acquisition of the task, the phenomenon could not be replicated. Chapters 7 and 8 further explored the effect of chronic L-DOPA on non-motor function using a lateralized choice reaction time task reliant on the striatal system. Chronic L-DOPA exacerbated a lesion induced accuracy deficit that has been hypothesised to reflect extinction. This deficit was linked to LID onset, rather than L-DOPA exposure per se. The data therefore expand on current knowledge by suggesting that the effects of chronic L-DOPA extends beyond inducing motor side effects to also affect non-motor function.

Item Type:	Thesis (PhD)
Status:	Unpublished
Schools:	Biosciences
Subjects:	R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
Funders:	Biotechnology and Biological Sciences Research Council, Eli Lilly & Company
Date of First Compliant Deposit:	30 March 2016
Last Modified:	09 Jan 2024 16:00
URI:	https://orca.cardiff.ac.uk/id/eprint/59308

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