A 65-year-old woman with Parkinson's disease has markedly reduced striatal dopamine. The basal ganglia indirect pathway becomes overactive. Tracing the indirect pathway, the sequential consequences of reduced dopamine on the D2-receptor expressing striatal neurons are:

• A D2 receptor activation reduced → indirect pathway MSNs disinhibited → overactive GPe inhibition → overactive STN → overactive GPi/SNr → increased thalamic inhibition → reduced cortical motor activation ✓
• B D2 activation reduced → indirect MSNs inhibited → GPe disinhibited → STN inhibited → GPi/SNr underactive → thalamus overactive → increased motor output
• C D2 reduced → direct pathway overactive → GPi underactive → thalamus overactive
• D D2 reduced → striatum releases more GABA → GPe overactive → STN inhibited → reduced GPi output

Explanation

The indirect pathway: Striatum (D2 MSNs) → inhibitory GABA to GPe → inhibitory GABA from GPe to STN → excitatory glutamate from STN to GPi/SNr → inhibitory GABA from GPi/SNr to thalamus. Dopamine normally inhibits indirect pathway MSNs via D2 receptors (D2 is Gi-coupled, reducing MSN excitability), thereby reducing indirect pathway activity. When dopamine is depleted (Parkinson's): D2 MSNs are disinhibited → increased GABA to GPe → GPe is overinhibited → reduced GPe GABA output to STN → STN is disinhibited/overactive → increased STN glutamate to GPi/SNr → GPi/SNr is overactive → excessive GABA inhibition of thalamus → reduced thalamocortical excitation → reduced motor cortex activity → akinesia/bradykinesia. This is the pathophysiology underlying Parkinson's movement deficits.

Reference: Guyton & Hall, Textbook of Medical Physiology, 14th ed.

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Written and medically reviewed by the StethoPrep medical team.