The Role of Nicotine and Nicotinic Agents in the Treatment of Levodopa Induced Dyskinesia in a Rat Model of Parkinson's Disease

Background: Levodopa remains the most effective therapy for Parkinson’s disease, but long-term use leads to many complications including L-DOPA induced dyskinesia, which affects approximately 80% all patients within a decade and limits treatment. Current antidyskinetic drugs offer only modest and temporary benefit. Nicotine and nicotinic agents are attractive potential treatments because they are safe, brain penetrable and have undergone numerous clinical trials for a variety of indications. Nicotine and nicotinic agents regulate striatal dopamine and glutamate release, and preclinical studies show that nicotinic stimulation can reduce dyskinesia by about half without weakening levodopa’s therapeutic effect. The strongest evidence implicates β2 containing receptors, especially α4β2 and α6β2 on dopaminergic terminals, and α7 receptors on interneurons and cortical inputs. Methods: In this thesis the pharmacological profile of nicotine and nicotinic agents were investigated in a rat model unilaterally lesioned with 6-hydroxydopamine, primed with levodopa plus benserazide, until such time that rats displayed abnormal involuntary movements (AIMs) – a model of levodopa-induced dyskinesia. AIMs was scored across axial, limb, orolingual, and locomotor subtypes. The acute doses of the following were tested on AIMs: nicotine, varenicline, selective α4β2 agonists (A-85380), and α4β2 desensitiser (Sazetidine-A). The effects of the antagonist and positive allosteric modulator was also investigated. The effects of α7 agonists, an α7 positive allosteric modulator, and an α7 antagonist were also studied. Postmortem tissue was examined for dopaminergic loss and glial activation using tyrosine hydroxylase, IBA1, and GFAP using immunohistochemistry. Results: Acute stimulation of nicotinic receptors reduced established AIMs in a dose dependent manner . Nicotine and varenicline both produced clear reductions in abnormal movements. When given throughout the priming period, these drugs also prevented levodopa priming for AIMs. Rats treated with nicotine or varenicline from the start of levodopa dosing for priming showed very little AIMs even 3 weeks after cessation nicotine or varenicline administration. Their levodopa responsiveness remained intact. Subtype selective compounds confirmed a dual mechanism. Activation and subsequent desensitization of α4β2 receptors strongly reduced AIMs, consistent with a reduction of dopamine release. At the same time, enhancing α7 signalling with either an agonist or a positive allosteric modulator lowered AIMs severity, while α7 blockade worsened symptoms. Nicotinic treatments also produced signs of reduced neuroinflammation. Rats receiving varenicline or nicotine had lower microglial and astrocytic activation in the lesioned hemisphere. These effects align with known anti-inflammatory actions of α7 receptor stimulation. This suggested that onset of AIMs may be directly linked to the onset of inflammation. Conclusion: Taken together, the work shows that targeting nicotinic receptors can reduce dyskinesia through multiple mechanism involving modulation of dopamine neurotransmission, modulation of the glutamatergic system and reduction of neuroinflammation which may become activated by chronic levodopa administration. These findings support advancing varenicline and α4β2 or α7 selective compounds toward clinical testing as adjuncts that could improve long-term motor outcomes in Parkinson’s disease.