Increasing GABA could provide antidepressant effects

As part of a study led by Penn State researchers, researchers found that increasing the neurotransmitter GABA can have antidepressant effects in mice. The results were published in the journal Molecular Psychiatry.

Scientists experimented with the activity of a subclass of nerve cells that produce gamma-aminobutyric acid (GABA) by increasing it. The outcome resulted in antidepressant effects similar to pharmaceutical drugs used to treat clinical depression in mice. The new findings could help researchers enhance depressant drugs using the rapidly acting GABA to create more effective treatments.

In the study, researchers were able to increase GABA signaling by halting a GABA receptors synonymous with neurons involved in the development of major depressive disorder (MDD), according to Medical Xpress. SST+ interneurons (somatostatin-positive-GABAergic interneurons), the type of neurons suspected to be associated with MDD, produces GABA by reducing the activity of other neurons around them.

Glutamate, a neurotransmitter responsible for accelerating neuron activity, is released by surrounding neurons.
When researchers halted the GABA receptor, specifically in SST+ interneurons, the cells lost the signal to decrease activity, in which therefore GABA began releasing excessively. Additionally, the activity of glutamate-producing neurons slowed down.

The change in neurons, altered the mice’s behavior when they received the experimental treatment, which resulted in similar results compared to antidepressant drugs. Furthermore, the genetically altered mice, which had biochemical changes in their brain tissue, acted similarly to rodents who’ve received pharmacological treatment in the form of antidepressant drugs such as SSRIs, TCAs, and MAOIs.

Bernhard Lüscher, a professor of biology at Penn State and the lead researcher, firmly believes the dysfunction of GABA is one of the key factors in severe symptoms of MDD. “Increasing evidence suggests that dysfunction of GABA is also a major culprit in major depressive disorder, the most common and costly brain disorder and a principal cause of suicide, the primary cause of death among young people.”

He continued by saying, “Interestingly, drugs that are designed to increase the function of GABA—the benzodiazepines—are widely used as potent anti-anxiety drugs and sedatives, but for reasons that are poorly understood these drugs are largely ineffective as antidepressants.”

Moreover, benzodiazepines, a hallmark pharmaceutical drug class for anxiety and depressive disorders, often fail due to deficits in GABA signaling.

“The failure of benzodiazepines to alleviate depressive symptoms is a main reason why GABA-signaling deficits have been discounted as possible causes of depressive disorders. But our research suggests that GABA is involved and that there must be other reasons for the failure of benzodiazepines,” said Lüscher.

Today, antidepressants are used by millions to help alleviate symptoms of anxiety and depressive disorders.
Although the drug’s mechanism of action is to enhance serotonin and norepinephrine, about 40 percent of patients report the treatment as ineffective.

The therapeutic onset of antidepressants may take weeks before the patient notices any significant improvement.
However, GABA-enhancing drugs like benzodiazepines, start to alleviate symptoms of anxiety within hours of usage. And it’s that reason why researchers are eager to test GABA receptors.

“These cells have recently been implicated in major depression based on gene-expression changes found in postmortem brain tissue from depressed patients, and they differ from other GABA-producing cells in that they selectively innervate the dendritic trees of glutamate-releasing neurons.”

“The somatostatin-positive subset of GABA-releasing cells, therefore, appear ideally suited to limit the overexcitation of neural networks that occurs during the chronically stressful situations that figure as major culprits in depressive disorders,” Lüscher concluded.

Researchers hope the new finding’s of the study will lead science to a new form of antidepressant treatment with a faster onset of action, similar to GABA-enhancing benzodiazepines.