Immediate-early gene expression in structures outside the basal ganglia is associated to L-DOPA-induced dysldnesia

Long-term L-3,4-dihydroxyphenylalanine (L-DOPA) treatment in Parkinson's disease (PD) leads to L-DOPAinduced dyskinesia (LID), a condition thought to primarily involve the dopamine D1 receptor-expressing striatal medium spiny neurons. Activation of the D1 receptor results in increased expression of several molecular markers, in particular the members of the immediate-early gene (IEG) family, a class of genes rapidly transcribed in response to an external stimulus. However, several dopaminoceptive structures in the brain that are likely to be affected by the exogenously produced DA have received little attention although they might play a key role in mediating those L-DOPA-induced abnormal behaviours. AFosB, ARC, FRA2 and Zif268 IEGs expression patterns were thus characterised, using unbiased stereological methods, in the whole brain of dyskinetic and nondysldnetic rats to identify brain nuclei displaying a transcriptional response specifically related to LID. Within the basal ganglia, the striatum and the substantia nigra pars reticulata showed an increased expression of all four IEGs in dyskinetic compared to non-dyskinetic rats. Outside the basal ganglia, there was a striking increased expression of the four IEGs in the motor cortex, the bed nucleus of the stria terminalis, the dorsal hippocampus, the pontine nuclei, the cuneiform nucleus and the pedunculopontine nuclei. Moreover, the zona incerta and the lateral habenula displayed an overexpression of FosB, ARC and Zi1268. Among these structures, the IEG expression in the striatum, the bed nucleus of the stria terminalis, the lateral habenula, the pontine nuclei and the cuneiform nucleus correlate with LID severity. These results illustrate a global transcriptional response to a dysldnetic state in the whole brain suggesting the possible involvement of these structures in LID. (C) 2013 Elsevier Inc. All rights reserved.