Noradrenergic Mechanisms in Parkinson’s Disease and L-DOPA-Induced Dyskinesia: Hypothesis and Evidences from Behavioural and Biochemical Studies

The key pathological characteristic of Parkinson’s disease PD is the degeneration of dopaminergic neurons in the substantia nigra pars compacta SNc that project to the striatum (Barolin and Horykiewicz 1967). The depletion of dopamine leads to abnormalities of the transmission in striatal projections to the lateral or medial segments of the globus pallidus, or to the substantia nigra reticulata SNr (Brotchie et al, 1993; Albin et al., 1989). It is well known, however, that in PD, besides dopaminergic degeneration, a considerable loss of noradrenergic neurons, as well as, a decrease of noradrenaline levels in several brain regions occurs (Hornykiewicz & Kish 1987). Interestingly, the neural loss in PD in Locus coreleus is greater than that of dopamine in the substantia nigra (Zarow et al., 2003). The influence of noradrenergic neurotransmission on dopamine-mediated behaviour has been the focus of several studies over the last four decades, and has confirmed the importance of the relationship between dopaminergic and noradrenergic pathways in the control of locomotor activity. The progressive neurodegeneration of the main noradrenergic nucleus – the locus coeruleus LC – might influence not only the progression of Parkinson's disease but also the response to dopaminergic replacement. Furthermore, additional evidences support the notion that noradrenaline deficit might be relevant for the pathogenesis of long-term complications of L-DOPA treatment such as the wearing-off phenomenon and dyskinesias (Bezard et al., 2001; Obeso et al., 2000; Marsden and Parkes, 1976). However, in spite of the bulk of data on the influence of the alterations of noradrenergic transmission on locomotor behaviour, much of these data is conflicting and not conclusive. Therefore, definitive conclusions, as to the specific role of the noradrenergic system in the generation of symptoms of Parkinson’s disease and L-DOPA-induced dyskinesia LID, cannot yet be drawn.