We have previously shown that dopamine (DA) denervation and repeated L-DOPA treatment modulate the pattern of Nur77 mRNA expression in the striatum. However, the exact role of this nuclear receptor in L-DOPA-induced molecular and behavioural adaptations observed in animal models of Parkinson's disease is still unknown. In the present study, we investigated the effects of Nur77 gene deletion on the development of behavioural sensitization and on changes in the regulation of neuropeptides and DA D3 receptor expression following DA denervation and repeated L-DOPA treatment in Nur77+/+ and Nur77−/− hemiparkinsonian mice. One week postsurgery, hemiparkinsonian mice were treated with L-DOPA (10 mg/kg) plus benserazide (3 mg/kg) once a day for 7 days. Despite similar extents of nigrostriatal denervation, L-DOPA-induced rotational response was exacerbated in Nur77−/− mice compared to Nur77+/+ ones. However, the rate of increase of the rotational behaviour after repeated L-DOPA injections was similar in the two mouse strains. Lesioning the nigrostriatal pathway increased enkephalin (ENK) and neurotensin (NT) mRNA levels in both mouse strains. However, the up-regulation of these neuropeptides was significantly reduced in Nur77−/− mice. There was no difference in the modulation of D3 receptor density and dynorphin (DYN) mRNA expression between the two mouse strains. The present results suggest that Nur77 is involved in setting the threshold level for L-DOPA-induced rotational behaviour, rather than controlling the development of behavioural sensitization. This specific behavioural change is associated with a selective regulation of neuropeptide expression specifically in the indirect striatal output pathway.