Optimisation and mechanistic insights of dyskinesia in rodent models of Parkinson’s disease

The work presented in herein focuses on the optimisation and use of established animal models to study behavioural, pharmacological, histological and molecular correlates of the debilitating motor side effects of current and future treatments for Parkinson’s disease, namely L-DOPA induced dyskinesia (LID) and graft induced dyskinesia (GID). Chapter 3 optimises the 6-OHDA lesion model in mice, from surgical approaches to behavioural assessment of motor function. The neurotoxin was injected at three different regions along the nigrostriatal tract to produce unique patterns of dopaminergic cell death in the midbrain. The resulting cell loss was correlated to behavioural deficits identified through an extensive battery of motor hand tests. Fully lesioned mice from each of the three models were chosen for chronic L-DOPA treatment, described in Chapter 4, where doses were increased every 1-2 weeks. Behaviour was assessed and correlated to deficits on motor hand tests prior to L-DOPA treatment, cell loss within sub regions of the midbrain, serotonergic density levels and upregulations in ΔFosB and striatal TH cell populations. Chapter 5 uses knowledge gained in previous chapters to use the most appropriate 6-OHDA mouse model of LID for the examination of changes in the Regulators of G-protein Signalling (RGS) following an acute and chronic L-DOPA treatment. RGS2 was the only one to increase significantly following either treatment regime. In Chapter 6 a well established rat model of GID (the induction of dyskinesia in the transplanted 6-OHDA lesioned rat through the administration of amphetamine) was used to assess the use of pharmacological agents known to reduce LID. Changes in locomotor function and abnormal inhibitory movements (AIMs) could be assessed giving an insight into the mechanism and receptors involved. To further the understanding of GID, Chapter 7 examines dopamine receptor levels, RGS transcript expression, and the proportions of dopamine and serotonin cells in the transplanted, 6-OHDA lesioned rodent brain. The aim was to determine any correlation between these parameters and amphetamine induced dyskinesia. Only the number of dopaminergic and serotonin cells could be correlated to dyskinesia and not the proportion of serotonin cells. As no previous mouse model of GID has been established, Chapter 8 demonstrates that transplantation of E12 ventral mesencephalon (VM) grafts can be optimised in the lesioned mouse of C57/Bl6 and CD1 strains to give functional recovery, and amphetamine induced dyskinesia. Both strains were also used to demonstrate that transplants were also able to reduce LID