DEPRESSIVE DISORDER IN PARKINSON’S DISEASE: INVOLVEMENT OF MONOAMINERGIC SYSTEMS

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by dopaminergic degeneration in the nigrostriatal system and motor deficiencies. In addition to these symptoms, parkinsonian patients experience various non-motor symptoms. Among these, depression represents a major clinical challenge, as it is often unresponsive to dopamine replacement therapy and its underlying neural substrates remain poorly understood. Moreover, PD is associated with dysfunction of noradrenergic and serotonergic systems, which are implicated in affective comorbidities.
To investigate the contribution of monoaminergic transmission to PD-associated depression, we examined noradrenergic neuronal activity and noradrenaline release in a PD mouse model exhibiting depression-like behavior. Using fiber photometry with calcium and noradrenaline (NA) sensors, we monitored neuronal activity in the locus coeruleus (LC) and NA release in the Dorsal Raphe Nucleus (DRN) during the tail suspension test, a despair-based paradigm for depression. Moreover, in the same test, we recorded calcium dynamics of serotonergic neurons in the DRN.
We found that struggling behavior during tail suspension increased the activity of noradrenergic neurons in the LC and enhanced NA release in the DRN. This behavioral response was accompanied by increased activity of DRN serotonergic neurons. In contrast, parkinsonian mice displayed reduced LC noradrenergic activity, impaired NA release in the DRN, and a blunted activation of serotonergic neurons during the task.
These results indicate that the LC-to-DRN pathway plays a key role in the response to inescapable stress. This mechanism is compromised in the PD model, suggesting that this circuit may represent a target to counteract depressive symptoms in PD.