Neurotransmitter Imbalance in Movement Disorders

Pathophysiology of Movement Disorders

Dopaminergic neurons originate primarily in the substantia nigra pars compacta (SNpc) and project to the corpus striatum (caudate nucleus and putamen) 1, 2
Motor symptoms manifest only after 40-50% of SNpc dopaminergic neurons are lost, explaining the insidious onset of Parkinson's disease 1, 2
The dopamine transporter (DAT) on presynaptic terminals actively reuptakes dopamine from the synapse, terminating its signaling 2
Cholinergic neurons from the pedunculopontine and lateral dorsal tegmental nuclei in the pons promote REM sleep and modulate motor control 3
Serotonergic neurons from the raphe nuclei project throughout the basal ganglia and cortex, and serotonin inhibits REM-on neurons 3, 4
Norepinephric neurons from the locus coeruleus inhibit REM-on neurons and modulate motor control 3
Glutamatergic neurons from the prefrontal cortex project to the striatum, forming the critical corticostriatal pathway, and glutamate dysregulation contributes to stereotypic behaviors and obsessive-compulsive symptoms in movement disorders 5

The indirect pathway (movement inhibition) involves the cortex, striatum (D2 receptors), GPe, STN, GPi/SNpr, and thalamus, and dopamine inhibits D2 receptors in this pathway, reducing movement suppression 2
Decreased striatal D2 receptor density is observed in both Parkinson's disease and OCD 2, 5

Dopamine D2 receptor antagonists reduce excessive dopaminergic signaling in hyperkinetic disorders 2, 5
The American Academy of Sleep Medicine recommends IV iron (ferric carboxymaltose, ferumoxytol) as first-line treatment for restless legs syndrome in patients with ferritin <75 μg/L or transferrin saturation <20% 6
Alpha-2-delta ligands (gabapentin, pregabalin) are preferred over dopamine agonists for restless legs syndrome due to the risk of augmentation with dopamine agonists 6
SSRIs (serotonin reuptake inhibitors) are first-line treatment for OCD, and dopamine D2 receptor antagonists can be used as augmentation for treatment-resistant OCD 4, 5

SSRIs block serotonin transporter (SERT), increasing synaptic serotonin and eventually downregulating inhibitory autoreceptors, leading to increased serotonergic firing 4
Dopamine transporter imaging (DaTscan) demonstrates loss of normal "comma shape" of putamina in Parkinson's disease, reflecting dopaminergic neuron loss 1, 2