Emerging dysfunctions consequent to combined monoaminergic depletions in parkinsonism

The loss of dopamine (DA) neurons has been the pathophysiological focus of the devastating conditions of Parkinson's disease, but depletion of DA alone in animal models has failed to simultaneously elicit both the motor and non-motor deficits of PD. The present study aimed to investigate, in rats, the respective role of dopamine (DA), noradrenaline (NA) and serotonin (5-HT) depletions on motor and non-motor behaviors and on subthalamic (STN) neuronal activity. We show that NA or DA depletion significantly decreased locomotor activity and enhanced the proportion of bursty and irregular STN neurons. Anxiety-like states required DA depletion plus the depletion of 5-HT or NA. Anhedonia and “depressive-like” behavior emerged only from the combined depletion of all three monoamines, an effect paralleled by an increase in the firing rate and the proportion of bursty and irregular STN neurons. Here, we provide evidence for the exacerbation of behavioral deficits when NA and/or 5-HT depletions are combined with DA depletion, bringing new insight into the combined roles of the three monoamines in PD.

► Noradrenaline depletion, like dopamine depletion, results in parkinsonian-like motor deficits.
► Anxiety emerges from dopamine depletion combined with noradrenaline or serotonin depletion.
► Combined depletion of the three monoamines induces depressive-like behavior.
► Combined depletion of monoamines induces dramatic changes of STN neuronal activity.