title: Role of pedunculopontine cholinergic neurons in the vulnerability of nigral dopaminergic neurons in Parkinson's disease.
abstract: Pedunculopontine nucleus (PPN) cholinergic neurons, which exert excitatory nicotinic control over substantia nigra dopaminergic neurons, degenerate in Parkinson's disease (PD). This finding and other studies showing that nicotine, the preferential agonist of nicotinic acetylcholine receptors, is neuroprotective in experimental models of PD suggest that a deficit in PPN excitatory cholinergic inputs might contribute to the death of nigral dopaminergic neurons in PD. To explore this possibility, we used lesion paradigms of dopaminergic and/or cholinergic systems in rats and monkeys. Consistent with our hypothesis, we observed that stereotaxic lesioning of PPN cholinergic neurons with diphtheria toxin coupled to urotensin II resulted in a significant loss of nigral dopaminergic neurons in rats and induced morphological changes in these neurons in macaques. Unexpectedly, a lesion of dopaminergic neurons induced by unilateral striatal injection of 6-hydroxydopamine (6-OHDA) in rats, or by repeated systemic injections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in macaques, led to a 29% and 7% loss of PPN cholinergic neurons, respectively. Lastly, when the PPN cholinergic lesion was performed in rats in which the dopaminergic lesion induced by 6-OHDA was in progress, loss of cholinergic neurons was more drastic than when each neurotransmitter system was lesioned separately. Thus, our results suggest that strong PPN cholinergic and dopaminergic interactions may be an important mechanism in the pathophysiology of PD.
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, UM75, U1127, UMR 7225, ICM, F-75013 Paris, France.
authors.forename: Manale
authors.initials: M
authors.lastname: Bensaid
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, UM75, U1127, UMR 7225, ICM, F-75013 Paris, France.
authors.forename: Patrick P
authors.initials: PP
authors.lastname: Michel
authors.affiliation: Department of Pharmacology and Toxicology, University at Buffalo, Buffalo, New York 14214, United States.
authors.forename: Stewart D
authors.initials: SD
authors.lastname: Clark
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, UM75, U1127, UMR 7225, ICM, F-75013 Paris, France.
authors.forename: Etienne C
authors.initials: EC
authors.lastname: Hirsch
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, UM75, U1127, UMR 7225, ICM, F-75013 Paris, France. Electronic address: Chantal.francois@upmc.fr.
authors.forename: Chantal
authors.initials: C
authors.lastname: François
mesh_terms: D000818:Animals; D059329:Cholinergic Neurons / Q000473:pathology*; D059290:Dopaminergic Neurons / Q000473:pathology*; D008252:Macaca fascicularis; D008297:Male; D016627:Oxidopamine; D010300:Parkinson Disease / Q000473:pathology*; D045042:Pedunculopontine Tegmental Nucleus / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000473:pathology*
chemical_list: D016627:Oxidopamine
keywords: 6-OHDA; Cholinergic; Diphtheria toxin-urotensin II; Dopamine; MPTP; Parkinson's disease; Pedunculopontine nucleus; Substantia nigra