Role of substantia Nigra dopaminergic neurons in respiratory modulation and limitations of levodopa in Parkinson's disease

Abstract

The substantia nigra pars compacta (SNpc), a midbrain region enriched with dopaminergic neurons projecting to the dorsal striatum, is essential for motor control and has been implicated in respiratory modulation. In Parkinson's disease (PD) models, the loss of SNpc dopaminergic neurons correlates with baseline respiratory deficits, suggesting a potential link between dopaminergic dysfunction and respiratory impairments.

To explore this, we used adult transgenic mice (Vglut₂^cre Ai6 and Vgat^cre Ai6) to map neurotransmitter phenotypes, as well as DAT^cre mice for pharmacogenetic modulation of SNpc dopaminergic neurons using excitatory (Gq) or inhibitory (Gi) designer receptors exclusively activated by designer drugs (DREADDs). Neuroanatomical tracing revealed SNpc projections to key respiratory nuclei, including the caudal and rostral ventral respiratory groups (cVRG and rVRG), Bötzinger complex (BötC), nucleus of the solitary tract (NTS), raphe magnus (RMg), and dorsal raphe (DR). While SNpc neurons were not activated by hypercapnia (7 % CO₂) or hypoxia (8 % O₂), pharmacogenetic stimulation of SNpc neurons altered respiratory parameters under both baseline and chemosensory challenge conditions. However, dopamine precursor treatment in PD models did not reverse respiratory deficits.

These findings suggest that SNpc dopaminergic neurons can modulate respiration when selectively stimulated, but we did not find evidence for an endogenous role in respiratory chemosensitivity. This study reinforces the complexity of dopaminergic contributions to respiratory control in PD and suggests that targeting these neurons may not be sufficient to restore respiratory function, emphasizing the need for broader therapeutic strategies.