The Serendipitous Discovery of Amantadine
Originally introduced in the 1960s as an antiviral agent for treating influenza A, amantadine's benefits for Parkinson's disease (PD) were discovered by chance [1.3.7, 1.3.4]. Patients taking the drug for the flu reported unexpected improvements in their PD symptoms, such as stiffness and tremors [1.3.3]. This observation shifted its clinical application and spurred decades of research into its neurological effects. Today, amantadine is used to manage symptoms of Parkinson's disease, control movement problems (extrapyramidal symptoms) caused by other medications, and treat levodopa-induced dyskinesia [1.3.1, 1.8.5]. While its antiviral use has declined due to resistance, its role in neurology remains significant [1.3.5].
Amantadine's Primary Mechanism: A Dopaminergic Boost
The core of amantadine's efficacy in movement disorders lies in its ability to increase the amount of dopamine in the brain [1.3.1]. Dopamine is a critical neurotransmitter for controlling movement, and its depletion in the substantia nigra region of the brain is the hallmark of Parkinson's disease. Amantadine's mechanism of action, though not fully understood, is believed to be a combination of several processes that collectively enhance dopaminergic transmission [1.4.3, 1.3.4].
Enhancing Dopamine Release and Inhibiting Reuptake
One of the primary ways amantadine works is by promoting the release of dopamine from central neurons and delaying its reuptake by neural cells [1.2.3, 1.4.3]. After dopamine is released into the synaptic cleft to transmit a signal, it is normally cleared through a reuptake process mediated by the dopamine transporter (DAT). Studies suggest that amantadine inhibits this reuptake, allowing dopamine to remain in the synapse for a longer period, thus prolonging its effect [1.2.1, 1.2.2]. Some research indicates that this inhibition of reuptake may be a stronger component of its action than its ability to release dopamine directly, which some studies have described as weak [1.6.2, 1.4.5]. By enhancing release and blocking reuptake, amantadine effectively increases the concentration of available dopamine to stimulate postsynaptic receptors [1.2.3].
The Role of NMDA Receptor Antagonism
Beyond its direct effects on dopamine, amantadine is also known as a non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, a type of glutamate receptor [1.2.3, 1.4.3]. Glutamate is the brain's primary excitatory neurotransmitter, and overactivity in glutamatergic pathways is implicated in the symptoms of Parkinson's disease and, notably, in the development of levodopa-induced dyskinesias (LIDs) [1.8.3, 1.7.3].
By blocking NMDA receptors, amantadine reduces this excessive glutamatergic signaling [1.7.2]. This action is believed to be the primary reason for its effectiveness in reducing LIDs, the involuntary, erratic movements that are a common and disabling side effect of long-term levodopa therapy [1.8.1, 1.8.3]. Studies have shown that amantadine can reduce dyskinesia severity by as much as 60% [1.8.1]. This antiglutamatergic property is unique among antiparkinsonian drugs and accounts for its dual effect on both parkinsonian symptoms and the side effects of other treatments [1.3.4].
Other Pharmacological Effects
Amantadine also exhibits other, less-defined pharmacological properties that may contribute to its overall effect. These include:
- Anticholinergic Effects: It has some anticholinergic properties, which can help reduce symptoms like tremors, though this is not considered its primary mechanism [1.2.3, 1.4.3].
- Anti-inflammatory Action: Research suggests that amantadine may inhibit the activation of microglia, the primary immune cells in the central nervous system. By reducing neuroinflammation, it could potentially offer a neuroprotective effect, though this mechanism requires further study [1.4.6, 1.4.7].
- Neurotrophic Factor Induction: Some studies indicate amantadine may increase the expression of glial cell line-derived neurotrophic factor (GDNF), a protein that supports the survival of dopamine neurons [1.2.6].
Amantadine vs. Other Dopaminergic Drugs
A comparison helps to contextualize amantadine's role in treatment.
| Feature | Amantadine | Levodopa | Dopamine Agonists (e.g., Pramipexole, Ropinirole) |
|---|---|---|---|
| Primary Mechanism | Increases dopamine release, inhibits reuptake, NMDA antagonist [1.2.3, 1.4.3] | A precursor that the brain converts into dopamine [1.2.4] | Directly stimulate dopamine receptors (primarily D2/D3) [1.2.4] |
| Effect on Dyskinesia | Reduces levodopa-induced dyskinesia (LID) [1.8.1] | Can cause dyskinesia with long-term use [1.8.3] | Can cause dyskinesia, though often less than levodopa [1.3.4] |
| Primary Use Case | Monotherapy in early PD, adjunct for motor fluctuations and LIDs [1.4.3, 1.8.5] | Gold-standard treatment for motor symptoms across all stages [1.8.3] | Monotherapy in early PD or adjunct to levodopa in later stages [1.3.4] |
| Potency | Mild to moderate antiparkinsonian effect [1.3.7] | Most effective symptomatic treatment [1.8.3] | Less potent than levodopa but more than amantadine [1.3.4] |
Conclusion: A Multi-Targeted Approach
In summary, the answer to 'how does amantadine work on dopamine?' is multifaceted. It does not simply mimic dopamine but instead modulates the entire neurotransmitter system through a unique combination of actions. Its ability to increase dopamine availability by promoting release and blocking reuptake addresses the core dopamine deficiency in Parkinson's disease [1.2.1, 1.2.3]. Simultaneously, its antagonism of NMDA receptors provides a crucial benefit by counteracting the glutamatergic overactivity that contributes to levodopa-induced dyskinesia [1.7.3, 1.8.1]. This dual mechanism makes amantadine a valuable and enduring tool in the pharmacological management of Parkinson's disease and other movement disorders.
For more information on the clinical applications and research, you can visit the National Institute of Neurological Disorders and Stroke.
