Overview
This lecture explains how VMAT2 inhibitors treat tardive dyskinesia by reducing dopamine activity in the motor striatum to rebalance motor control.
VMAT2 Function and Inhibition
- VMAT2 transports monoamines (dopamine, serotonin, norepinephrine, histamine) into synaptic vesicles for neurotransmitter storage and release.
- Tetrabenazine and related drugs selectively and reversibly inhibit VMAT2 in the CNS, leading to reduced dopamine storage and release.
- VMAT2 inhibition preferentially decreases dopamine levels at clinical doses, causing presynaptic dopamine degradation by monoamine oxidase (MAO).
Pathophysiology of Tardive Dyskinesia (TD)
- Chronic D2 dopamine receptor blockade leads to supersensitive D2 receptors in the motor striatum via maladaptive neuronal plasticity.
- This receptor supersensitivity results in excessive inhibition of stop signals and unopposed go signals, causing involuntary hyperkinetic movements (TD).
Therapeutic Mechanism of VMAT2 Inhibitors in TD
- VMAT2 inhibitors decrease dopamine release, reducing overactivation of supersensitive D2 receptors in the indirect motor pathway ("stop" signal).
- Dopamine reduction also lessens stimulation of D1 receptors in the direct pathway, weakening "go" signals.
- The combined effect is increased stop and decreased go signaling, reducing abnormal movements.
Treatment Considerations and Variables
- Dosing and effectiveness of VMAT2 inhibitors depend on ongoing use, dose, or discontinuation of D2 antagonists.
- The degree of inhibition needed varies by individual factors: presynaptic dopamine concentration, D2 receptor sensitivity, concurrent drugs, and disease state.
- VMAT2 inhibition is reversible and responsive to changes in dopamine levels due to external factors (e.g., stress, amphetamines).
Key Terms & Definitions
- VMAT2 (Vesicular Monoamine Transporter 2) — protein that loads monoamine neurotransmitters into vesicles for release.
- Tetrabenazine — drug that reversibly inhibits VMAT2, reducing dopamine storage/release in the CNS.
- D2 Receptor — dopamine receptor involved in the indirect pathway of movement control; upregulated in TD.
- Indirect Pathway — neural pathway reinforcing motor "stop" signals, disrupted in TD.
- Direct Pathway — pathway reinforcing motor "go" signals, also influenced by dopamine.
Action Items / Next Steps
- Review neural pathways of movement control and the role of dopamine in TD.
- Study the clinical uses and pharmacology of VMAT2 inhibitors for exam preparation.