A new study has found that disulfiram, a drug used to treat chronic alcoholism, can safely reduce anxiety levels in rodents

Alcoholism, if left untreated, can have dangerous consequences. Therefore, it is not surprising that a number of drugs have been developed to treat this condition. Among 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 alcohol metabolism.

Could the inhibitory effect of DSF also extend to signaling molecules? According to recent studies, DSF actually inhibits a cytoplasmic protein called FROUNT, which controls the direction of migration of certain immune cells. DSF prevents FROUNT from interacting with two chemokine receptors called CCR2 and CCR5, which are involved in important cell signaling pathways.

Some studies suggest that chemokine receptors may be involved in regulating emotional behavior in rodents. However, data on the precise relationship between FROUNT chemokine signaling and DSF are lacking. To clarify this connection, a team including Professor 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, published online on March 7, 2022 in Frontiers in pharmacologydescribes how the research team used an EPM (Elevated Plus Maze) test – used to screen for anti-anxiety drugs – to study the effects of DSF in mice.

The EPM device consists of four crossed arms connected to a central square. Two arms are protected by vertical restraints while two have exposed edges. Usually, anxious mice prefer to spend their time in closed arms.

In this case, some mice received diazepam (a drug commonly used to treat anxiety) and others received DSF. These mice were then placed in the EPM device and their activity was monitored. To their surprise, the team found that the mice treated with DSF spent significantly more time in the device’s open arms, indicating 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.

Interestingly, these behavioral changes were similar to those observed in diazepam-treated mice. How exactly did DSF achieve this?

The team had previously found that increased levels of extracellular glutamate (which is an important amino acid and a key neurotransmitter) are linked to increased anxiety in mice.

“We propose that DSF inhibits the FROUNT protein and chemokine signaling pathways under its influence, which could suppress presynaptic glutamatergic transmission in the brain,” says Professor Saitoh. “This, in turn, dampens glutamate levels in the brain, thereby reducing overall anxiety. »

The team was also pleasantly surprised that, unlike diazepam, the DSF treatment did not cause side effects such as amnesia, incoordination or sedation.

According to Professor Saitoh, “These results show that DSF can be safely used by elderly patients with 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 effects. Hopefully we can also elucidate the exact role of the FROUNT molecule in the central nervous system.

This is one of the first studies to show that DSF has anti-anxiety properties comparable to existing benzodiazepines without exhibiting the side effects seen with benzodiazepines. Hopefully, the inhibitory activity of DSF against FROUNT function could be explored for the successful development of anxiolytics.

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Materials provided by Tokyo Science University. Note: Content can be edited for style and length.

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