In vivo modulation of dopaminergic nigrostriatal pathways by cytisine derivatives:: Implications for Parkinson's Disease

Nicotinic acetylcholine receptor agonists are considered potential pharmacological agents for Parkinson's Disease treatment, due to their ability to improve experimental Parkinson symptomatology, reduce 3,4-dihydroxy-L-phenylalanine-incluced clyskinesias and stop the neurodegenerative process at an experimental level. In the present work, the ability of the nicotinic agonistcytisine and two halogenated derivatives (3-bromocytisine and 5-bromocytisine) to induce striatal dopamine release was characterized in vivo by microdialysis. Cytisine, 5-bromocytisine and nicotine were much more efficacious than 3-bromocytisine in eliciting dopamine release in response to their local application through the microdialysis probe. Moreover, the agonists were intermittently administered before and after an intranigral injection of 6-hydroxydopamine (6-OHDA), and striatal dopamine tissue levels were assessed 8 days after the lesion. Both cytisine and its 5-bromo derivative (but not the 3-bromo derivative) significantly prevented the decrease of striatal dopamine tissue levels induced by 6-OHDA. These results suggest that the efficacy of nicotinic agonists to stimulate dopamine release in vivo through presynaptic nicotinic receptors could be related to their potential to induce striatal protection. (C) 2008 Elsevier B.V. All rights reserved.