Modelling parkinsonian akinesia and dyskinesia in dopamine depleted rodents

Abstract: Animal models of Parkinson’s disease and L-DOPA-induced dyskinesia are essential to explore pathophysiological hypotheses and to test new treatment options. There are many different animal models of Parkinson's disease, which differ greatly with respect to species, mechanisms of nigral cell death, and extent of dopamine-dependent motor deficits. My work has been performed in rats and mice with unilateral 6-hydroxydopamine (6-OHDA) lesions, as this model is cost-effective and is well characterized. The animals show the main motor symptoms of Parkinsons disease such as akinesia, bradykinesia and postural instability. Previously work have shown that chronic L-DOPA treatment induces abnormal involuntary movements (AIMs) in unilaterally 6-OHDA lesioned rats. It has been one of the main aims with this thesis to investigate wheter these movements are the rat equivalent of L-DOPA induced dyskinesia. Additionally I have developed and validated a new model of L-DOPA induced (AIMs) in mice. In yet another study the levels of L-DOPA was measured in the brain and blod in dyskinetic and non-dyskinetic animals after an i.p. injection of L-DOPA. In the validation studies, the effects of antiparkinsonian agents that are associated with low incidence of dyskinesia in patients were evaluated using sensitive behavioural test of motor function and the animals AIMs were monitored using the rodent AIMs rating scale. In a later stage, agents with documented antidyskinetic properties in patients, were tested for their ability to reduce the severity of rodent AIMs. The results from both the rat and the mouse studies shows that dopamine-depleted rodents develop AIMs with chronic L-DOPA treatment. The severity of the rodent AIM scores increased with continuing L-DOPA treatment, which conforms to the situation described in treated PD patients. The fact that rodent AIMs were induced by L-DOPA but not by dopamine agonists (such as ropinirole and bromocriptine) implies that the mechanisms underlying rodent abnormal involuntary movements are similar to those underlying L-DOPA induced dyskinesia in PD patients and non-human primate models. This is further corroborated by the fact that several non-dopaminergic drugs known to possess antidyskinetic properties in PD patients also reduced rodent AIM scores. The measurements of central and peripheral L-DOPA levels showed that even though the L-DOPA concetration in the blood did not differ between dyskinetic and non-dyskinetic animals, the extracellular striatal levels of L-DOPA were significantly higher in the dyskinetic animals. These results indicate that a different bioavailability of L-DOPA in the striatal extracellular fluid may provide a clue as to why certain rats develop dyskinesia during chronic L-DOPA treatment and other rats appear resistant. It can be concluded from the results in this thesis that the rodent models are well suited for being used in screening studies for novel antiakinetic and antidyskinetic treatments that will benefit patients with these symptoms as new and more efficient drugs and treatments.