Parkinson's disease is a progressive neurodegenerative disorder that is observed in approximately 1% of the population over 55 and consists of a syndrome including bradykinesia, rigidity, postural abnormalities and tremor. The principal pathological characteristic of PD is the progressive death of the pigmented neurons of the substantia nigra pars compacta (SNc) (Hassler, 1938
). The discovery, in 1960, that degeneration of the dopamine (DA) supplying neurons of the SNc causes parkinsonism (Ehringer and Hornykiewicz, 1960
) opened the way for the development of pharmaceutical therapies for PD that act to enhance synaptic DA transmission using the DA precursor L-3,4-dihydroxyphenylalanine (L-dopa) (Birkmayer and Hornykiewicz, 1961
; Carlsson et al., 1957
The initial exuberance surrounding the positive effects of L-dopa in PD soon gave way to the recognition that long-term levodopa therapy is confounded by the development of adverse events related to fluctuations in motor response. These motor fluctuations include on-off fluctuations, sudden, unpredictable changes in mobility, and the wearing-off phenomenon, a decrease in the duration of action of levodopa. However, the most debilitating class of motor fluctuation is involuntary movements known as L-dopa-induced dyskinesia (LID) (Duvoisin, 1974
). Dyskinesia can be broadly categorised into chorea (hyperkinetic, purposeless dancelike movements) and dystonia (sustained, abnormal muscle contractions). With increasing duration of treatment, there is an increase in both the frequency and the severity of dyskinesia (Marsden et al., 1982
). Ultimately, the majority of L-dopa-treated patients experience dyskinesia, with up to 80% of patients having dyskinesia within 5 years of treatment (Rascol et al., 2000
). It should be noted that treatment-related dyskinesia are not solely a problem of L-dopa and that DA receptor agonists are also capable of eliciting dyskinesia and within the context of this review, the commonly-used term, LID, will be used, as it is widely understood, to describe DAergic treatment–related dyskinesia generally.
The past few years have seen an unprecedented increase in understanding the neural mechanisms underlying LID manifestation in PD (Bezard et al., 2001
; Brotchie, 2005
; Cenci, 2007
), associating them with a sequence of events that include pulsatile stimulation of DA receptors, downstream changes in proteins and genes, and abnormalities in non-DAergic transmitter systems, all of which combine to produce alterations in the neuronal firing patterns that signal between the basal ganglia and the cortex.
This article, however, will NOT review those new findings but will, instead, specifically focus upon the very first molecular events thought to be responsible for the establishment of LID and generally grouped under the term of “priming”. Priming is classically defined as the process by which the brain becomes sensitized such that administration of DAergic therapy modifies the response to subsequent DAergic treatments (Brotchie, 2005
). In this way, over time, with repeated treatment, the chance of DAergic stimulation eliciting LID is increased and once LID has been established, the severity of dyskinesia increases.
In this review, we aim at strongly opposing the common view of priming. We propose, and hopefully will demonstrate, that priming does not exist per se but is the direct and intrinsic consequence of the loss of DA innervation of the striatum (and other target structures).