The Role of GABA in Anxiety

This Month’s Expert: Andrew Goddard , M.D., on The Role of GABA in Anxiety | Psych Central Professional – An interview with Andrew Goddard , M.D.

TCR: Dr. Goddard, you’ve done a lot of neurobiological research in anxiety disorders. It’s a very complex area, but basically what goes on in patients’ brains when they have a panic attack?

Dr. Goddard: It is complex, and initially researchers focused on the actions of monoamines in both depression and anxiety. The “monoamine theory” of depression holds that depression is caused by a depletion of norepinephrine and serotonin.

TCR: Is anxiety thought to result from the same thing?  

Dr. Goddard: One theory is that panic results from spontaneous overactivity in the locus coeruleus (LC), which is the part of the brain where most of the noradrenergic neurons are located.

One idea is that when somebody has a panic attack they have this sort of storm or surge of noradrenaline neurotransmission in the LC.

An important inhibitory input to this structure is from serotonergic neurons. The serotonin system comes on line to modulate the LC overactivity that leads to the panic. So essentially, what SSRIs do is to increase that normal compensatory mechanism, enhancing that inhibition.

It’s a nice theory, but we think it really doesn’t explain the underlying pathology of panic. To understand this, researchers are delving into the GABA and glutamate systems.

TCR: What is GABA anyway?

Dr. Goddard: GABA (gamma aminobutyric acid) is a small amino acid neurotransmitter. It is basically a byproduct of glucose metabolism, and it is a byproduct of glutamate.

TCR: We’ve certainly been hearing a lot about glutamate lately in psychiatry.

Dr. Goddard: Yes, that’s because glutamate is one of the main excitatory neurotransmitters in the brain, so it is one of the main “on buttons,” if you will, to neural activity.

And GABA is the flip side of that: it inhibits neural activity.

TCR: And a lot of us have heard about GABA in terms of the actions of both benzodiazepines and alcohol. Can you give us a brief review of what those two agents do to GABA?

Dr. Goddard: Sure. Native GABA (the GABA that we produce ourselves) acts in various brain regions by attaching to postsynaptic GABA-A receptors and opening ionic/chloride ion channels.

Right next to the GABA-A receptors there is a specific benzodiazepine modulatory site.

Benzodiazepines attach to this site on the receptor, and they enhance the opening of the ion channel. I think of it as turbocharging the efficacy of native GABA at the postsynaptic GABA-A receptor.

One molecule that has been identified in this search is a neuropeptide called diazepam binding inhibitor (DBI), which is an inverse agonist at the benzo receptor. However CSF levels of DBI are normal in panic disorder which is a bit puzzling.

there was a similar search for endogenous benzodiazepines in the ‘80s and ‘90s.

TCR: But how might GABA be involved in panic disorder?

Dr. Goddard: The short answer is that we don’t know.

It may be that subpopulations of the GABAA receptors are deficient in some panic patients or that there are deficits in the production and release of GABA presynaptically.

But many of us believe that the monoamines (serotonin and norepinephrine) are not the main players in anxiety, and that they basically serve to modulate or tweak the major systems, which are glutamate and GABA.

Some interesting information relating to this story has come about through studying the actions of some of the newer anticonvulsants.

There are five of them:

  1. tiagabine (Gabitril),
  2. pregabalin (Lyrica),
  3. gabapentin (Neurontin),
  4. lamotrigine (Lamictal), and
  5. Dcycloserine.

Tiagabine is essentially a GABA reuptake inhibitor, in the same way that SSRIs are serotonin reuptake inhibitors.

Part of the way in which the GABA chemical signal is ended is by reuptake into the presynaptic neuron. Tiagabine blocks the GABA reuptake transporter protein and so disrupts that process and makes GABA more likely to linger in the synapse.

tiagabine blocks GABA reuptake most strongly in areas of the brain that have a lot to do with anxiety, namely the amygdala and hippocampus, which are part of the limbic system.

Pregabalin and gabapentin are pretty closely related chemically, sort of chemical cousins, if you will, and pregabalin is more potent and more bioavailable to the central nervous system than gabapentin.

We really don’t know how they might work in anxiolysis, but one theory is that they enhance presynaptic release of GABA through alterations in calcium metabolism.

Lamictal may affect GABA indirectly. It seems to inhibit release of glutamate, thereby altering the excitatory/inhibitory balance between glutamatergic and GABAergic neurons.

Original article: This Month’s Expert: Andrew Goddard , M.D., on The Role of GABA in Anxiety | Psych Central Professional

1 thought on “The Role of GABA in Anxiety

  1. Richard Dobson

    Just one scientific observation: In the human body, GABA is formed from Glutamate by the actions of Glutamate Decarboxylase. If you look at the underlying chemical reaction, there is one free electron created each time a molecule of Glutamate is converted to GABA. Current theories in medicine do not account for this “free electron”. In all likelihood, the the conversion fo Glut to Gaba occurs on the cell surface and the electron is transported by quantum mechanical mechanisms into the interior of the cell, providing electrical power to the neuron. Cell sites that have a lot of Glutamate produce higher voltage an when GABA builds up the electrical power of the interior neuron is decreased. See http://www.neuronresearch.net for full discussion of the theory by James Fulton.

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