Reduced noradrenergic innervation of ventral midbrain dopaminergic cell groups and the subthalamic nucleus in MPTP-treated parkinsonian monkeys

Abstract

There is anatomical and functional evidence that ventral midbrain dopaminergic (DA) cell groups and the sub-thalamic nucleus (STN) receive noradrenergic innervation in rodents, but much less is known about these interactions in primates. Degeneration of NE neurons in the locus coeruleus (LC) and related brainstem NE cell groups is a well-established pathological feature of Parkinson’s disease (PD), but the development of such pathology in animal models of PD has been inconsistent across species and laboratories. We recently demonstrated 30–40% neuronal loss in the LC, A5 and A6 NE cell groups of rhesus monkeys rendered parkinsonian by chronic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In this study, we used dopamine-beta-hydroxylase (DβH) immunocytochemistry to assess the impact of this neuronal loss on the number of NE terminal-like varicosities in the substantia nigra pars compacta (SNC), ventral tegmental area (VTA), retrorubral field (RRF) and STN of MPTP-treated parkinsonian monkeys. Our findings reveal that the NE innervation of the ventral mid-brain and STN of normal monkeys is heterogeneously distributed being far more extensive in the VTA, RRF and dorsal tier of the SNC than in the ventral SNC and STN. In parkinsonian monkeys, all regions underwent a significant (~50–70%) decrease in NE innervation. At the electron microscopic level, some DβH-positive terminals formed asymmetric axo-dendritic synapses in VTA and STN. These findings demonstrate that the VTA, RRF and SNCd are the main ventral midbrain targets of ascending NE inputs, and that these connections undergo a major break-down in chronically MPTP-treated parkinsonian monkeys. This severe degeneration of the ascending NE system may contribute to the pathophysiology of ventral midbrain and STN neurons in PD.

The Noradrenergic System in Parkinson’s Disease

“…Bilateral models of 6-OHDA show, however, more robust NA deficits in the cortex and striatum (Vieira et al, 2019). 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys exhibit clear noradrenergic damage, including LC cell loss, lower NA concentrations in several brain regions, and reduced noradrenergic innervation of the SNc and the subthalamic nucleus (Pifl et al, 1991;Masilamoni et al, 2017). Some publications have also reported low NA striatal and cortical tissue content in MPTP mice (Luchtman et al, 2009;Nayyar et al, 2009;Ando et al, 2018).…”

Nexus between mitochondrial function, iron, copper and glutathione in Parkinson's disease

“…Further evidence for mitochondrial impairment in the pathogenesis of PD comes from the selective sensitivity of the substantia nigra and locus coeruleus to mitochondrial toxins, including 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 6hydroxydopamine, rotenone and paraquat (Giannoccaro et al, 2017;Masilamoni et al, 2017). All are complex I inhibitors and administration causes neuronal death and gives rise to parkinsonism in animal models.…”

Clonidine modulates the activity of the subthalamic‐supplementary motor loop: evidence from a pharmacological study combining deep brain stimulation and electroencephalography recordings in Parkinsonian patients

“…Even more recently, NA innervation of the STN has been shown in primates, with convincing demonstration that the partial loss of NA innervation of the STN in monkeys rendered parkinsonian by chronic administration of 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) could contribute to STN dysfunctions in PD (Masilamoni et al . ). In humans, it has also been suggested that the modulatory action of the NA system might be mediated by the STN‐cortical loops (Albares et al .…”