Abstract
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.
Highlights
Disulfiram (DSF), a disulfide derivative of N,N-diethyl dithiocarbamate, is an FDA approved drug for the treatment of alcoholism
This is the first report on the anxiolytic-like effects of DSF in rodents
DSF-41 produced the anxiolytic-like effects at doses four times lower than those required for DSF to produce the same effects, suggesting that FROUNT inhibition produced the anxiolytic-like effects seen in elevated plus-maze (EPM) test
Summary
Disulfiram (DSF), a disulfide derivative of N,N-diethyl dithiocarbamate, is an FDA approved drug for the treatment of alcoholism. During the 19th century, employees in the rubber manufacturing industry who were exposed to DSF at work suffered severe adverse effects to alcohol and began to avoid the consumption of alcoholic beverages. Later, these effects were found to be caused by DSF’s inhibition of aldehyde dehydrogenase (ALDH), an enzyme essential to alcohol metabolism (Chen et al, 2006). It was found that DSF potently inhibits the cytoplasmic protein FROUNT (Table 1) (Terashima et al, 2020), a common regulator of chemokine receptor CCR2 and CCR5 signaling, which controls the directional migration that facilitates monocyte/macrophage infiltration (Terashima et al, 2005; Toda et al, 2009; Toda et al, 2014). DSF is being investigated in combination with the anti-PD-1 antibody in patients with gastric cancer (jRCTs031180183)
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