Chronic MAP4343 reverses escalated alcohol drinking in a mouse model of alcohol use disorder
Year: 2023
Type: article
Abstract: Alcohol use disorders can be driven by negative reinforcement. Alterations of the microtubule cytoskeleton have been associated with mood regulation in the context of depression. Notably, MAP4343, a pregnenolone derivative known to promote tubulin assembly, has antidepressant properties. In the present study, we tested the hypothesis that MAP4343 may reduce excessive alcohol drinking in a mouse model of alcohol dependence by normalizing affect during withdrawal. Adult male C57BL/6J mice were given limited access to voluntary alcohol drinking and ethanol intake escalation was induced by chronic intermittent ethanol (CIE) vapor inhalation. 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 affective behaviors. In the elevated plus maze, chronic MAP4343 tended to increase open-arm exploration in alcohol-naive mice but reduced it in alcohol-withdrawn mice. In the tail suspension test, chronic MAP4343 reduced immobility selectively in Air-exposed alcohol-drinking mice. Finally, chronic MAP4343 countered the plasma corticosterone reduction induced by CIE. Parallel analysis of tubulin post-translational modifications revealed lower α-tubulin acetylation in the medial prefrontal cortex of CIE-withdrawn mice. Altogether, these data support the relevance of microtubules as a therapeutic target for the treatment of AUD.
Source: Neuropsychopharmacology
Authors: Giovana C. Macedo, Max Kreifeldt, Scott P. Goulding, Agbonlahor Okhuarobo, Harpreet Sidhu, Candice Contet
Institutions: Scripps Research Institute, University of Benin
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,790
Awards: Adaptations to chronic activation of BK channels by ethanol: Contribution to dependence and tolerance, G3439722543, CNS Effects of Alcohol: Cellular Neurobiology, G3739546402, G5573150079, G56130422, G577377943, G5861251585, CNS EFFECTS OF ALCOHOL--CELLULAR NEUROBIOLOGY, G7269184192, Novel circuit mechanism of alcohol dependence vulnerability following early-life adversity, Activation of the parasubthalamic nucleus in alcohol dependence, G760921904, G8680154768, Adaptations to chronic activation of BK channels by ethanol: Contribution to dependence and tolerance, G9000122958, G9000243559, G9000264711
OpenAlex ID: W4317607705