The Modulating Effects of Gabapentin: What Does Gabapentin Do to Neurotransmitters?

October 10, 2025 •

3 min read

In 2021, approximately 70.9 million prescriptions for gabapentin were dispensed in the United States, making it one of the country's most prescribed medications. But what does gabapentin do to neurotransmitters to achieve its therapeutic effects?

Quick Summary

Gabapentin primarily works not by directly interacting with GABA receptors, but by binding to the α2δ-1 subunit of voltage-gated calcium channels. This action indirectly modulates the release of several neurotransmitters, notably reducing excitatory ones like glutamate.

Key Points

Primary Mechanism: Gabapentin does not directly act on GABA receptors; its main effect is binding to the alpha-2-delta (α2δ) subunit of voltage-gated calcium channels.
Reduces Excitatory Neurotransmitters: By binding to the α2δ subunit, gabapentin inhibits calcium influx into presynaptic neurons, thereby decreasing the release of excitatory neurotransmitters like glutamate and Substance P.
Indirect GABA Effects: Although it's a GABA analog, its effects on GABA are indirect. Some studies show gabapentin can increase overall brain GABA concentrations or enhance the function of specific GABAA receptors.
Widespread Off-Label Use: While FDA-approved for seizures and postherpetic neuralgia, up to 95% of gabapentin prescriptions are for off-label conditions like anxiety, fibromyalgia, and other types of nerve pain.
Modulates, Doesn't Block: Gabapentin acts as a modulator, primarily calming overexcited neurons rather than causing a general blockade of neurotransmission, which explains its therapeutic effects in specific conditions.
Key Difference from Pregabalin: Pregabalin works by the same mechanism but has a higher binding affinity, more predictable absorption, and is considered more potent than gabapentin.
Safety Concerns: There is an increased risk of serious side effects, including respiratory depression, when gabapentin is used concurrently with other central nervous system depressants like opioids.

The Paradox of a GABA Analog

Gabapentin was designed as a structural analog of GABA, the main inhibitory neurotransmitter. Initially, it was thought to mimic GABA's effects, but research shows it doesn't bind to GABA receptors or directly affect GABA synthesis or uptake. Instead, it has a more complex, indirect mechanism.

Primary Mechanism: Targeting Calcium Channels

Gabapentin primarily works by binding to the alpha-2-delta (α2δ) subunit of voltage-gated calcium channels (VGCCs), particularly α2δ-1 and α2δ-2. These channels regulate calcium influx into presynaptic neurons, which is essential for releasing neurotransmitters. In conditions like epilepsy or neuropathic pain, excessive calcium influx leads to excessive excitatory neurotransmitter release.

By binding to the α2δ-1 subunit, gabapentin reduces this calcium influx, thereby decreasing the release of several excitatory neurotransmitters, including:

Glutamate: The main excitatory neurotransmitter, implicated in seizures and pain signaling.
Substance P: Involved in transmitting pain signals.
Noradrenaline: Can contribute to heightened arousal and pain.

This action stabilizes neuronal activity and reduces the hyperexcitability associated with seizures and neuropathic pain.

Indirect and Complex Effects on Neurotransmitters

While its main action is on calcium channels, gabapentin has significant downstream effects on neurotransmitter systems.

The Glutamate Connection

Gabapentin's most notable impact is on glutamate, reducing its release from overactive neurons. Animal studies show it can decrease cellular glutamate in some brain regions. However, this effect can be region-specific, with one study showing increased extracellular glutamate in the locus coeruleus via glial cells.

The GABA Question

Despite not binding to GABA receptors, some studies indicate gabapentin can increase overall brain GABA concentrations. A study in healthy individuals using 7T MRS imaging showed a 55.7% increase in GABA concentration in the visual cortex after a 900 mg dose. Proposed mechanisms include enhanced GABA synthesis or altered transport. Another theory suggests gabapentin increases the expression of extrasynaptic GABAA receptors, enhancing tonic inhibition.

Other Neurotransmitter Systems

Gabapentin also affects other systems, causing minor reductions in dopamine and serotonin release. It has been shown to increase total blood serotonin levels in healthy individuals, potentially contributing to some neurobehavioral effects, but it doesn't act directly on serotonin or dopamine receptors.

Comparison Table: Gabapentin vs. Pregabalin

Pregabalin, a related 'gabapentinoid', shares the same primary mechanism but has key differences.


Feature	Gabapentin	Pregabalin
Primary Target	Binds to α2δ subunit of VGCCs	Binds to α2δ subunit of VGCCs
Binding Affinity	Lower affinity for the α2δ subunit	Higher affinity for the α2δ subunit
Absorption	Saturable, non-linear	Linear, predictable (≥90%)
Time to Peak	Slower (approx. 3 hours)	Faster (approx. 1 hour)
Dosing Frequency	Typically 3 times per day	Typically 2 to 3 times per day
Titration Speed	Slower	Faster
Federal Control	Not a federally controlled substance (scheduled in some states)	Federally designated Schedule V controlled substance

Clinical Applications and Off-Label Use

Gabapentin is FDA-approved for postherpetic neuralgia and partial onset seizures. However, up to 95% of prescriptions are off-label for conditions like diabetic neuropathy, fibromyalgia, anxiety, alcohol withdrawal, and restless legs syndrome. Evidence for many off-label uses is mixed, and concerns exist regarding co-prescription with CNS depressants like opioids due to increased respiratory depression risk.

Conclusion

Gabapentin's effect on neurotransmitters is primarily indirect. As a modulator of voltage-gated calcium channels via the α2δ-1 subunit, it reduces the presynaptic release of excitatory neurotransmitters, mainly glutamate. This action calms hyperexcited neurons, explaining its use for seizures and neuropathic pain. While it may indirectly increase brain GABA and affect other neurotransmitters, its core function is to dampen excessive excitatory signals, promoting balanced neurotransmission.

Authoritative Link: For a detailed scientific look at gabapentin's mechanism, you can review this article from the National Center for Biotechnology Information (NCBI): Gabapentin - StatPearls

Frequently Asked Questions

No, not directly. Despite being structurally similar to GABA, gabapentin does not bind to GABA receptors. However, some studies suggest it may indirectly cause an increase in overall GABA concentrations in the brain through other mechanisms.

The main effect of gabapentin is the reduced release of excitatory neurotransmitters, especially glutamate. It achieves this by binding to the α2δ-1 subunit on voltage-gated calcium channels, which calms nerve hyperexcitability.

No, gabapentin does not directly act on serotonin receptors. However, some research has indicated it can reduce the release of monoamine neurotransmitters, including serotonin, and may increase serotonin levels in the blood, which could contribute to its behavioral effects.

Pregabalin and gabapentin share the same primary mechanism of action: binding to the α2δ subunit of calcium channels to reduce the release of excitatory neurotransmitters. The main difference is that pregabalin has a higher binding affinity and is therefore more potent, leading to more predictable absorption and effects.

Gabapentin does not directly block glutamate receptors. Instead, it reduces the release of glutamate from presynaptic nerve terminals by limiting the influx of calcium that triggers this release. It modulates, rather than blocks, glutamatergic transmission.

Gabapentin is prescribed for nerve pain (neuropathic pain) because this type of pain is often caused by hyperexcited neurons. By reducing the release of excitatory neurotransmitters like glutamate and Substance P, gabapentin helps to calm these overactive nerves and decrease pain signals.

Yes. Long-term use of gabapentin can lead to physical dependence as the brain adapts to its modulation of neurotransmitters. Abruptly stopping the medication can cause withdrawal symptoms like anxiety, insomnia, pain, sweating, and agitation as the central nervous system readjusts.