‘Discounted’ GABA drugs show promise as antidepressants

(Credit: Rob Baird/Flickr)

New tests in mice suggest drugs that target the neurotransmitter GABA could serve as rapidly acting and more effective antidepressants.

“GABA is the major inhibitory neurotransmitter in the brain—it acts as the ‘brakes’ of neural activity—and its dysfunction is implicated in a wide range of neuropsychiatric disorders,” says Bernhard Lüscher, professor of biology and of biochemistry and molecular biology at Penn State and the leader of the research team.

“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.”

The researchers increased GABA signaling by disabling a GABA receptor in a specific set of neurons that are suspected to be involved in major depressive disorder. Under normal circumstances, this set of neurons known as SST+ interneurons (somatostatin-positive-GABAergic interneurons) produce GABA, which reduces the activity of other neurons around them.

Most of these surrounding neurons release the neurotransmitter, glutamate—an “accelerator” of neuron activity. When the researchers disabled the GABA receptor selectively in SST+ interneurons, these cells could no longer receive the signal to slow down—their “brakes” were removed—so they released GABA excessively, which in turn slowed even further the activity of glutamate-producing neurons.

Thin section of brain showing GABA-releasing SST+ interneurons
Thin section of brain showing GABA-releasing SST+ interneurons (green) and other interneurons (red). Increasing GABA signaling specifically in SST+ interneurons has antidepressant effects similar to pharmaceutical antidepressants in depressed mice. (Credit: Lüscher laboratory/Penn State University)

As a result, the mice that received the treatment acted in a number of behavioral tests as if they had been given antidepressant drugs. Also, biochemical changes in brain tissue of the genetically altered mice mimicked biochemical changes seen in rodents treated with different classes of antidepressant drugs. The findings appear in the journal Molecular Psychiatry.

Ketamine brings depressed mice back to normal

“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,” says Lüscher.

“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.”

Why current drugs are often ineffective

Currently used antidepressants are designed to enhance the function of serotonin, or less often, norepinephrine. These drugs are ineffective for about 40 percent of patients and they suffer from a characteristically slow therapeutic onset, taking weeks before patients notice any significant improvement.

This slow mode of therapeutic action indicates that the mechanism of these drugs is only distantly related to their direct targets. Instead, the current work suggests that these drugs ultimately act by enhancing the function of GABA-releasing interneurons.

Earlier research in the Lüscher lab showed these drugs can alleviate a depressive-like brain state in mice that was induced by genetic defects in GABA transmission. Thus, antidepressants that act through serotonin or norepinephrine ultimately appear to normalize defects in GABA transmission, suggesting that new drugs that target GABA signaling may be effective antidepressants.

Other researchers at Penn State and Tufts University took part in the study. The National Institutes of Health funded the work.

Source: Penn State