Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) and its projections. Reports show a lower incidence of PD in smokers compared to nonsmokers. Nicotine reduce motor symptoms of patients already diagnosed with PD. However, the mechanisms underlying the effects of nicotine in the dopamine (DA) depleted striatum remain elusive. This study evaluates the effects of chronic nicotine administration on PD motor symptoms in an attempt to mimic the chronic self-administration of nicotine in smokers. To achieve this, we used the 6-OHDA hemiparkinson rat model evaluating the amphetamine/apomorphine induced circling behavior, in rats whose daily water intake included nicotine. We found that chronic nicotine reduced amphetamine (AMPH) induced circling behavior by 40%, whereas apomorphine (APO) increased this behavior by 230%. High-performance liquid chromatography (HPLC) revealed that AMPH produced a 50% decrease of DA release in the intact hemisphere, while on the striatum of the lesioned side, receptor binding assays showed an increased affinity to D1 receptors and a concurrent decrease in D2 receptors. c-Fos activity showed through double labeling, that cell types involved in nicotine action were low threshold (LTS) and fast spiking (FS) inter-neurons, which increased in the DA-depleted striatum. We also observed an increase in the activity of D1 medium spiny neurons (D1 MSN), a striatal population with a major role in motor control. Our results show that chronic nicotine does not specifically protect against degeneration, but rather modifies DA receptor dynamics, suggesting that it could be used as a therapeutic element in PD pathology.

Increasing evidence supports a close relationship between Ras-ERK1/2 activation in the striatum and L-DOPA-induced dyskinesia (LID). ERK1/2 activation by L-DOPA takes place through the crosstalk between D1R/AC/PKA/DARPP-32 pathway and NMDA/Ras pathway. Compelling genetic and pharmacological evidence indicates that Ras-ERK1/2 inhibition prevents LID onset and may even revert already established dyskinetic symptoms. However, it is currently unclear whether exacerbation of Ras-ERK1/2 activity in the striatum may further aggravate dyskinesia in experimental animal models. Here we took advantage of two genetic models in which Ras-ERK1/2 signaling is hyperactivated, the Nf1+/− mice, in which the Ras inhibitor neurofibromin is reduced, and the Ras-GRF1 overexpressing (Ras-GRF1 OE) transgenic mice in which a specific neuronal activator of Ras is enhanced. Nf1+/− and Ras-GRF1 OE mice were unilaterally lesioned with 6-OHDA and treated with an escalating L-DOPA dosing regimen. In addition, a subset of Nf1+/− hemi-parkinsonian animals was also co-treated with the Ras inhibitor lovastatin. Our results revealed that Nf1+/− and Ras-GRF1 OE mice displayed similar dyskinetic symptoms to their wild-type counterparts. This observation was confirmed by the lack of differences between mutant and wild-type mice in striatal molecular changes associated to LID (i.e., FosB, and pERK1/2 expression). Interestingly, attenuation of Ras activity with lovastatin does not weaken dyskinetic symptoms in Nf1+/− mice. Altogether, these data suggest that ERK1/2-signaling activation in dyskinetic animals is maximal and does not require further genetic enhancement in the upstream Ras pathway. However, our data also demonstrate that such a genetic enhancement may reduce the efficacy of anti-dyskinetic drugs like lovastatin.