Alcoholism, if left untreated, can have dangerous repercussions. So, it’s no surprise that there is a range of drugs 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 effects 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.
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 including Professor Akiyoshi Saitoh of 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 March 7, 2022 in Frontiers in pharmacologydescribes how the research team used an elevated plus maze (EPM) test – which is used to screen for anti-anxiety drugs – to study the effects of DSF in mice.
The EPM device consists of four arms arranged in a cross, connected to a central square. Two arms are protected by vertical boundaries, while two have unprotected edges. Usually, anxious mice prefer to spend time in closed arms.
In this case, some mice were given diazepam (a drug commonly used to treat anxiety) and others were given DSF. These mice were then placed in the EPM device, and their activity was monitored. To their surprise, the team found that the DSF-treated mice spent significantly more time in the open arms of the device, indicating 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.
Interestingly, these behavioral changes were similar to those seen 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 neurotransmitter) are associated with increased anxiety in mice.
“We propose that DSF inhibits the FROUNT protein and the chemokine signaling pathways under its influence, which may suppress presynaptic glutamatergic transmission in the brain,” says Professor Saitoh. “This, in turn, attenuates glutamate levels in the brain, thereby reducing overall anxiety.”
The team was also pleasantly surprised to find that, unlike diazepam, DSF treatment did not cause adverse effects such as amnesia, impaired coordination or sedation.
According to Professor Saitoh, “These results indicate that DSF can be used safely 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 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 existing benzodiazepines without exhibiting the side effects seen with benzodiazepines. Hopefully, the inhibitory activity of DSF against FROUNT functioning could be explored for the successful development of anxiolytic drugs.