Striatal Overexpression of ΔFosB Reproduces Chronic Levodopa-Induced Involuntary Movements

Abstract

Long-term dopamine replacement therapy in Parkinson's disease leads to the development of disabling involuntary movements named dyskinesias that are related to adaptive changes in striatal signaling pathways. The chronic transcription factor ⌬FosB, which is overexpressed in striatal neurons after chronic dopaminergic drug exposure, is suspected to mediate these adaptive changes. Here, we sought to demonstrate the ability of ⌬FosB to lead directly to the abnormal motor responses associated with chronic dopaminergic therapy. Using rAAV (recombinant adenoassociated virus) viral vectors, high levels of ⌬FosB expression were induced in the striatum of dopaminedenervated rats naive of chronic drug administration. Transgenic ⌬FosB overexpression reproduced the entire spectrum of altered motor behaviors in response to acute levodopa tests, including different types of abnormal involuntary movements and hypersensitivity of rotational responses that are typically associated with chronic levodopa treatment. JunD, the usual protein partner of ⌬FosB binding to AP-1 (activator protein-1) sites of genes, remained unchanged in rats with high ⌬FosB expression induced by viral vectors. These findings demonstrate that the increase of striatal ⌬FosB in the evolution of chronically treated Parkinson's disease may be a trigger for the development of abnormal responsiveness to dopamine and the emergence of involuntary movements.

The Pharmacology of l-DOPA-Induced Dyskinesia in Parkinson’s Disease

“…Moreover, dyskinetic, chronically L-DOPA-treated mice exhibited higher DFosB levels than nondyskinetic mice chronically treated with L-DOPA (Pavon et al, 2006). Furthermore, and this is perhaps the most convincing evidence in favor of a direct etiological role of DFosB in LID, striatal overexpression of DFosB induced by viral vector led to the development of a dyskinetic phenotype similar to LI-AIMs, in the absence of L-DOPA administration, in the 6-OHDA-lesioned rat (Cao et al, 2010). In addition, in a study performed in the MPTP-lesioned macaque, a linear relationship was demonstrated between striatal DFosB levels and dyskinesia severity (Berton et al, 2009).…”

Striatal tyrosine hydroxylase-positive neurons are associated with l-DOPA-induced dyskinesia in hemiparkinsonian mice

“…However, the cited studies did not distinguish between occurrence and absence of dyskinesia and the observed average increase may be predominantly due to dyskinetic animals, as seen in our results. Furthermore, there is convincing evidence that above a critical threshold DFosB is causally linked to LID, as its striatal overexpression in rats induced by viral vectors provoked dyskinesia even without L-DOPA administration (Cao et al, 2010) and as molecular interventions reducing DFosB activity attenuated the severity of already established LID in different animal models of PD (Berton et al, 2009;Engeln et al, 2014).…”

α6β2* and α4β2* Nicotinic Acetylcholine Receptors As Drug Targets for Parkinson's Disease

“…In fact, research is in progress in numerous laboratories to investigate the antidyskinetic potential of drugs directed to various molecular targets linked to the nigrostriatal system, including the glutamatergic, GABAergic, adenosine, cannabinoid, noradrenergic, and other systems (Carta et al, 2008a;Fox et al, 2008;Jenner, 2008a,b;Cao et al, 2010;Lebel et al, 2010;Morin et al, 2010). Work is also being done to investigate the antidyskinetic potential of nicotine and nAChR-directed ligands in view of the extensive nicotinic cholinergic innervation in the nigrostriatal system (Quik et al, 2009).…”