A Drug That Cures Alcoholism May Be the Next Anti-anxiety Medication

Summary: Disulfiram, a drug commonly prescribed to treat chronic alcohol addiction, was shown to reduce anxiety levels in rodent models. The drug inhibits FROUNT protein and chemokine signaling pathways under its influence, suppressing overall glutamate transmission in the brain. This, in turn, helps reduce overall activity. The findings may signal a new way to treat anxiety in humans.

Source: Tokyo University of Science

Alcoholism, if left untreated, could have dangerous repercussions. Thus, it is no surprise that there are a range of drugs developed to treat this condition. Of these drugs, disulfiram (DSF) is approved by the Food and Drug Agency (FDA) for the treatment of alcoholism. DSF primarily inhibits the enzyme aldehyde dehydrogenase (ALDH), which is responsible for the metabolism of alcohol.

Could the inhibitory effects of DSF extend to signaling molecules as well?

According to recent studies, DSF in fact inhibits a cytoplasmic protein known as FROUNT, which controls the direction in which certain immune cells migrate. DSF blocks FROUNT from interacting with two chemokine receptors known as CCR2 and CCR5, which are involved in important cellular signaling pathways.

A few studies suggest that chemokine receptors may be involved in the regulation of emotional behaviors in rodents. However, there is a lack of data on the exact association between FROUNT-chemokine signaling and DSF.

To clarify this link, a team comprising Prof. Akiyoshi Saitoh from Tokyo University of Science and other researchers from institutes across Japan conducted a study examining the pharmacological properties of DSF.

The study, which was published online on March 7, 2022 in Frontiers in Pharmacology, describes how the research team used an elevated plus-maze (EPM) test—which is used to screen for anxiolytic drugs—to study the effects of DSF in mice.

The EPM apparatus consists of four arms set in a cross pattern, connected to a central square. Two arms are protected by vertical boundaries, whereas two have unprotected edges. Usually, mice with anxiety prefer to spend time in the closed arms.

In this case, some mice were administered diazepam (a drug commonly used to treat anxiety) and others, DSF. These mice were then placed in the EPM apparatus, and their activity was monitored. 

To their surprise, the team found that mice treated with DSF spent significantly more time in the open arms of the apparatus, which indicates that they were less anxious. The team also tested the anxiolytic effects of a more potent FROUNT inhibitor, known as DSF-41, and observed similar results.

What’s interesting is that these behavioral changes were similar to those observed in mice treated with diazepam. How exactly did DSF achieve this?

The team had previously discovered that increased extracellular glutamate (which is an important amino acid and neurotransmitter) levels are associated with increased anxiety in mice.

The team had previously discovered that increased extracellular glutamate (which is an important amino acid and neurotransmitter) levels are associated with increased anxiety in mice. Image is in the public domain

“We propose that DSF inhibits FROUNT protein and the chemokine signaling pathways under its influence, which may suppress presynaptic glutamatergic transmission in the brain,” says Prof. Saitoh. “This, in turn, attenuates the levels of glutamate in the brain, reducing overall anxiety.”

The team was also pleasantly surprised to find that in contrast with diazepam, DSF treatment did not lead to adverse effects such as amnesia, coordination disorders, or sedation.

According to Prof. Saitoh, “These results indicate that DSF can be used safely by elderly patients suffering from anxiety and insomnia and has the potential to become a breakthrough psychotropic drug.”

What are the long-term implications of these results? Dr. Saitoh explains, “We plan to further clarify how DSF exerts its pharmaceutical actions. Hopefully, we will also be able to elucidate the exact role of the FROUNT molecule in the central nervous system.”

This is one of the first studies to reveal that DSF exhibits anti-anxiety properties comparable to those of existing benzodiazepines without exhibiting any side effects observed with benzodiazepines. Hopefully, DSF’s inhibitory activity against FROUNT functioning could be explored for successful anxiolytic drug development.

Funding: This study was partially supported by the Tsukuba Clinical Research and Development Organization (T-CReDO) from the Japan Agency for Medical Research and Development (AMED).

About this anxiety and psychopharmacology research news

Author: Tsutomu Shimizu
Source: Tokyo University of Science
Contact: Tsutomu Shimizu – Tokyo University of Science
Image: The image is in the public domain

Original Research: Open access.
Disulfiram Produces Potent Anxiolytic-Like Effects Without Benzodiazepine Anxiolytics-Related Adverse Effects in Mice” by Saitoh et al. Frontiers in Pharmacology


Abstract

Disulfiram Produces Potent Anxiolytic-Like Effects Without Benzodiazepine Anxiolytics-Related Adverse Effects in Mice

Disulfiram is an FDA approved drug for the treatment of alcoholism. The drug acts by inhibiting aldehyde dehydrogenase, an enzyme essential to alcohol metabolism. However, a recent study has demonstrated that disulfiram also potently inhibits the cytoplasmic protein FROUNT, a common regulator of chemokine receptor CCR2 and CCR5 signaling.

Several studies have reported that chemokine receptors are associated with the regulation of emotional behaviors in rodents, such as anxiety.

Therefore, this study was performed to clarify the effect of disulfiram on emotional behavior in rodents.

The anxiolytic-like effects of disulfiram were investigated using an elevated plus-maze (EPM) test, a typical screening model for anxiolytics.

Disulfiram (40 or 80 mg/kg) significantly increased the amount of time spent in the open arms of the maze and the number of open arm entries without affecting the total open arms entries. Similar results were obtained in mice treated with a selective FROUNT inhibitor, disulfiram-41 (10 mg/kg).

These disulfiram-associated behavioral changes were similar to those observed following treatment with the benzodiazepine anxiolytic diazepam (1.5 mg/kg). Moreover, disulfiram (40 mg/kg) significantly and completely attenuated increased extracellular glutamate levels in the prelimbic-prefrontal cortex (PL-PFC) during stress exposure on the elevated open-platform.

However, no effect in the EPM test was seen following administration of the selective aldehyde dehydrogenase inhibitor cyanamide (40 mg/kg). In contrast to diazepam, disulfiram caused no sedation effects in the open-field, coordination disorder on a rotarod, or amnesia in a Y-maze.

This is the first report suggesting that disulfiram produces anxiolytic-like effects in rodents.

We found that the presynaptic inhibitory effects on glutaminergic neurons in the PL-PFC may be involved in its underlying mechanism. Disulfiram could therefore be an effective and novel anxiolytic drug that does not produce benzodiazepine-related adverse effects, such as amnesia, coordination disorder, or sedation, as found with diazepam.

We propose that the inhibitory activity of disulfiram against FROUNT function provides an effective therapeutic option in anxiety.

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