The Effect And Mechanism Of Nicotine On L-dopa-induced Dyskinesia In A Rat Model Of Parkinson’s Disease

Objective: Abnormal involuntary movements(AIMs) or dyskinesias are a serious complication of long-term L-dopa treatment of Parkinson’s disease(PD), for which there are few treatment options. Accumulating preclinical data show that the nonselective nicotinic acetylcholine receptors(n ACh R) agonist nicotine decreases L-dopa-induced dyskinesia(LID), but the concrete mechanism is not fully understood. Here we determined the possible mechanisms of nicotine in reducing LID in the rat model.Methods: To address this issue, we produced a rat model of PD using 6-hydroxydompamine(6-OHDA) injections, and valid PD rats(n=14) were first administered i.p. L-dopa/benserazide(10/2.5 mg/kg) once daily two weeks. Then, nicotine(0.1 mg/kg, n=7) or vehicle(1ml/kg, n=7) was administered i.p. prior to L-dopa/benserazide treatment for three weeks. The acute and chronic effects of nicotine treatment on abnormal involuntary movements(AIMs) and L-dopa-induced rotations were investigated in LID rats. We measured the expression of ΔFos B、ERK and p-ERK through Western blot, detected the m RNA levels of preprodynorphin and preproenkephalin by real-time PCR and observed the changes of synaptic ultrastructure by Electron microscopy technique.Results: L-dopa elicited increased dyskinesia in PD rats. Acute nicotine treatment had no effect on LID, but chronic nicotine administration reduced LID in rats with dyskinesia. Importantly, L-dopa-induced rotations were not affected by chronic treatment with nicotine. Chronic nicotine administration did not modify L-dopa-induced increase in striatal preproenkephalin(PPE) m RNA, but attenuated the phosphorylated levels of extracellular signal-regulated kinases 1/2(ERK1/2) and the expression of ΔFos B and preprodynorphin(PDyn) m RNA of PD rats with dyskinesia. Electron microscopy technique results showed that the postsynapse density(PSD) depth was much thicker and synapse cleft width was narrower in the L-dopa-treated rats, while nicotine administration attenuated the changes of synaptic ultrastructure by L-dopa in striatum.Conclusion: Together, our results demonstrate that nicotine modulates the development of dyskinesia by targeting D1 dopamine receptor(D1R) mediated intracellular signaling, and suggest that nicotine may help to ameliorate LID.