Quantitative Analysis of Locus Coeruleus Neurons and Thalamic Noradrenergic Axons in a Progressive 1‐Methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine Monkey Model of Parkinson's Disease

Background Parkinson's disease is mainly characterized by dopaminergic neurodegeneration in the substantia nigra pars compacta (SNc) and α‐synuclein accumulation. The locus coeruleus (LC) is also affected in Parkinson's disease and linked to some nonmotor symptoms, but the extent and timing of its degeneration remain unclear. Studies in 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)–treated monkeys have reported inconsistent findings ranging from no LC loss to substantial degeneration. Objectives We aimed (1) to determine whether noradrenergic neurons and thalamic noradrenergic axons undergo degeneration in a well‐characterized cohort of MPTP‐treated monkeys, and (2) to compare the degree of noradrenergic and dopaminergic loss. Methods We performed stereological quantification of noradrenergic neurons in the LC (A5, A6, and A7) and thalamic noradrenergic axons in Macaca fascicularis monkeys (n = 20) representing presymptomatic, recovered, moderate, and severe parkinsonian stages. Noradrenergic neurons and axons were immunostained for dopamine‐β‐hydroxylase, quantified, and compared with previous data from dopaminergic SNc neurons in the same animals. Results Noradrenergic cells were largely preserved, with estimated reductions of 4%, 12%, 3%, and 10% in presymptomatic, recovered, moderate, and severe stages, respectively, in parallel with marked and progressive dopaminergic neuronal loss. Densities of noradrenergic axons in the thalamus of MPTP monkeys did not differ significantly from control levels. Conclusions We found no evidence of noradrenergic neuronal loss and thalamic noradrenergic axon reduction in MPTP monkeys exhibiting severe SNc damage. These findings show significant differences in vulnerability to MPTP between the dopaminergic and noradrenergic systems.