Summary: MAP4343, an experimental antidepressant compound reversed alcohol intake in rat models of alcohol use disorder. The findings pave the way for using the compound to treat AUD in humans.
Source: Salk Institute
An experimental antidepressant compound with a potentially unique mechanism of action may also be effective against alcohol use disorder, according to a preclinical study from Scripps Research.
In the study, which appeared January 20, 2023, i Neuropsychopharmacologythe researchers found that several weeks of treatment with the molecule MAP4343 reversed excessive alcohol intake in mice that modeled this condition.
MAP4343, a steroid-type molecule, is currently being investigated in clinical trials as an antidepressant, although its likely mechanism of action – involving the modification of structural proteins in cells – is unlike any other antidepressant or alcohol use disorder treatment.
“These promising results suggest that we should test MAP4343 in humans as a potential treatment for alcohol use disorder,” says senior study author Candice Contet, Ph.D., associate professor in the Department of Medicine. Molecular at Scripps Research.
First author Giovana Macedo, Ph.D., was a postdoctoral research associate in Contet’s lab during the study.
Researchers estimate that more than 100 million people worldwide have an alcohol use disorder, and that it accounts for more than five percent of the total global burden of disease and injury. Better treatments are urgently needed since current options, including the drug naltrexone, fail to prevent relapse.
Traditionally, researchers have tried to treat alcohol use disorder by blocking the rewarding effects of drinking alcohol – as naltrexone does – or by reversing the anxiety and malaise that occurs after alcohol withdrawal and relapse. promotion.
However, recent rodent and human brain studies have found evidence that alcohol use disorder can disrupt the normal production and/or regulation of key structural proteins in brain cells. These proteins include tubulin, a key component of structures called microtubules, which cells use for a variety of functions including cell division and the internal transport of molecules.
It is not yet clear how tubule and microtubule disruptions relate to alcohol use, but available evidence suggests that these disruptions help maintain alcohol dependence – so making them could offer a more effective treatment strategy to reverse.
It is likely that MAP4343 could fill this treatment role, since it is known to promote the assembly of tubulin proteins in microtubules. Preclinical studies have also found that MAP4343 has antidepressant properties, and its developer MAPREG, a French biotechnology company, is now testing it in clinical trials in patients with depression.
In the new study, the team tested MAP4343 on mice that modeled alcohol use disorder. In this standard model, intermittent exposure to alcohol vapor creates a state of dependence, so that the animals drink more and more alcohol when given a good hour’s opportunity to drink each day – and within a few weeks , they are going to drunk DUI levels. voluntarily.
However, when treated for six weeks with elevated doses of MAP4343, alcohol-dependent mice reduced their average daily consumption to approximately the levels seen in non-dependent control mice, which were not significantly affected the treatment of them. MAP4343 also normalized blood levels of the stress hormone corticosterone, which is lower in alcohol-dependent animals forced to abstain from drinking alcohol.
Contet and her colleagues conclude that MAP4343 should be clinically tested against alcohol use disorder.
Another key remaining goal is to understand the exact mechanism of action of MAP4343. In this study, the researchers found that alcohol-dependent mice that have experienced alcohol withdrawal have abnormally low levels of a modified form of tubulin (called α-acetylated tubulin) in the medial prefrontal cortex. This brain region is known to help regulate alcohol consumption and often impairs alcohol use disorder.
“Tubulin acetacylation is known to alter the mechanical properties of microtubules and it is possible that MAP4343 works against excessive alcohol drinking by reversing this change,” says Contet. “That is something we now plan to investigate.”
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Author: Press Office
Source: Salk Institute
Contact: Press Office – Salk Institute
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Original Research: Open access.
“Chronic MAP4343 reverses increased alcohol consumption in a mouse model of alcohol use disorder” by Giovana C. Macedo et al. Neuropsychopharmacology
Chronic MAP4343 reverses increased alcohol consumption in a mouse model of alcohol use disorder
Alcohol use disorders can be driven by negative reinforcement. Changes in the microtubule cytoskeleton have been implicated in mood regulation in the context of depression.
In particular, MAP4343, a pregnenolone derivative known to promote tubulin assembly, has antidepressant properties.
In this study, we tested the hypothesis that MAP4343 could reduce excessive alcohol consumption in a mouse model of alcohol dependence by normalizing the effect during withdrawal.
Adult male C57BL/6J mice were given limited access to voluntarily drink alcohol and ethanol vapor inhalation (CIE) induced an increase in ethanol intake. Chronic, but not acute, administration of MAP4343 reduced ethanol intake and this effect was more pronounced in CIE-exposed mice.
There was a complex interaction between the effects of MAP4343 and alcohol on emotional behaviors. In the elevated plus maze, chronic MAP4343 tended to increase open arm exploration in alcohol-naive mice but decreased it in alcohol-withdrawn mice. In the tail suspension test, chronic MAP4343 selectively reduced immobility in Air-exposed alcohol drinking mice.
Finally, chronic MAP4343 antagonized the decrease in plasma corticosterone induced by CIE. Simultaneous analysis of tubulin post-translational modifications revealed lower α-tubulin acetylation in the medial prefrontal cortex of CIE withdrawal mice.
Overall, these data support the relevance of microtubules as a therapeutic target for the treatment of AUD.