Valbenazine is a medication approved to treat involuntary movements such as tardive dyskinesia in adults and chorea associated with Huntington’s disease. Tardive dyskinesia is a condition characterized by repetitive, uncontrollable movements, often of the face, trunk, or limbs, and can arise from prolonged use of certain medications, particularly antipsychotics. Chorea in Huntington’s disease also involves uncontrolled, dance-like movements.
Dopamine and Its Role in Movement
Dopamine is a chemical messenger, or neurotransmitter, in the brain that plays a role in various functions, including mood, motivation, and motor control. In the context of movement, dopamine neurons communicate with other brain regions, particularly those within the basal ganglia, to facilitate voluntary actions. Dopamine activity peaks before movement initiation.
Imbalances in dopamine signaling can lead to movement disorders. For example, a lack of dopamine-producing cells is linked to the stiffness, slow movements, and tremors seen in Parkinson’s disease. Conversely, conditions like tardive dyskinesia are associated with an overactivity or hypersensitivity of dopamine pathways, often resulting from long-term exposure to medications that block dopamine receptors. This overactivity or hypersensitivity contributes to involuntary movements.
The VMAT2 Protein: A Key Player
Neurons communicate by releasing neurotransmitters into the synaptic cleft, the small space between nerve cells. Before release, neurotransmitters like dopamine are packaged into tiny sacs called vesicles by specialized proteins on their membrane.
One such protein is the Vesicular Monoamine Transporter 2, or VMAT2. VMAT2 actively moves monoamine neurotransmitters, including dopamine, norepinephrine, serotonin, and histamine, from the neuron’s cytoplasm into vesicles. This transport is powered by an exchange mechanism, where two protons are moved out of the vesicle for each neurotransmitter molecule transported in.
VMAT2 regulates the amount of neurotransmitter available for release. By packaging neurotransmitters into vesicles, VMAT2 ensures that a controlled amount is ready to be released when the neuron sends a signal. This control of neurotransmitter storage and release is important for normal brain function and communication.
Valbenazine’s Specific Action on VMAT2
Valbenazine exerts its therapeutic effects by specifically interacting with and inhibiting the VMAT2 protein. This inhibition is reversible, meaning that valbenazine does not permanently disable VMAT2 but rather temporarily reduces its activity. Valbenazine is a selective VMAT2 inhibitor, with minimal binding to other receptors like those for dopamine, serotonin, or adrenaline.
When valbenazine inhibits VMAT2, it prevents the efficient packaging of dopamine into synaptic vesicles. As a direct consequence, less dopamine is stored within these vesicles. This reduction in packaged dopamine means that when a neuron is activated, fewer dopamine molecules are released into the synaptic cleft.
By reducing the amount of dopamine released, valbenazine effectively decreases the dopamine signaling in the brain. This targeted action on VMAT2 helps to normalize the levels of dopamine available to postsynaptic receptors, particularly the D2 receptors, which can become hypersensitive in conditions like tardive dyskinesia.
From Mechanism to Therapeutic Effect
The reduced dopamine release resulting from valbenazine’s action on VMAT2 directly contributes to its therapeutic effects in movement disorders. In conditions like tardive dyskinesia, where there is thought to be an overactivity or hypersensitivity of dopamine D2 receptors, the decreased availability of dopamine in the synapse helps to dampen this exaggerated response. This normalization of dopamine signaling reduces the excessive stimulation of dopamine receptors, which underlies the involuntary movements.
By modulating dopamine release, valbenazine helps to restore a more balanced neurotransmission in brain regions responsible for motor control. This leads to an alleviation of symptoms such as the uncontrolled movements seen in tardive dyskinesia and chorea associated with Huntington’s disease. The drug’s selective inhibition of VMAT2 improves motor control and reduces the severity of these disruptive movements.