Chronic MAP4343 reverses escalated alcohol drinking in a mouse model of alcohol use disorder

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plus maze, chronic MAP4343 tended to increase open-arm exploration in alcohol-naive mice but reduced it in alcohol-withdrawn mice.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of tubulin post-translational modifications revealed lower α-tubulin acetylation in the medial prefrontal cortex of CIE-withdrawn mice.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.

Mouse parasubthalamicCrhneurons drive alcohol drinking escalation and behavioral disinhibition

“…The increased digging, reduced grooming, and mechanical hypersensitivity we observed in CIEwithdrawn C57BL/6J males are consistent with previous reports, although changes are not always reliably detected (8,21,64,(80)(81)(82). In the tail suspension test, we had also found increased mobility in males withdrawn from CIE for 11 days, but no difference after 19 days (21,81). Our observation that CIE-withdrawn mice were more active in response to an acute unescapable stressor is consistent with the effect of early or protracted withdrawal from repeated binge drinking (83)(84)(85), but opposite to the effect of protracted withdrawal from chronic continuous alcohol drinking (a paradigm in which mice rarely reach intoxication) (86)(87)(88)(89).…”

“…The increased digging, reduced grooming, and mechanical hypersensitivity we observed in CIEwithdrawn C57BL/6J males are consistent with previous reports, although changes are not always reliably detected (8,21,64,(80)(81)(82). In the tail suspension test, we had also found increased mobility in males withdrawn from CIE for 11 days, but no difference after 19 days (21,81).…”

Chronic ethanol alters adrenergic receptor gene expression and produces cognitive deficits in male mice

“…Hyperkatefia increases AUD relapse risk by impairing cognitive function and promoting alcohol consumption to alleviate negative emotional symptoms, and ongoing clinical studies are evaluating the potential of several adrenergic compounds as treatments for AUD-associated hyperkatefia ( Fox et al, 2012 ; Haass-Koffler et al, 2018 ; Koob, 2021 ; Milivojevic et al, 2020 ; Simpson et al, 2018 ; Sinha et al, 2022 ; Wilcox et al, 2018 ). As mentioned earlier, one major limitation of the current study is that we only used male subjects, since female C57BL/6J mice do not always escalate their ethanol intake in this CIE-2BC model possibly due to their higher baseline ethanol consumption (( Jury et al, 2017 ; Macedo et al, 2023 ; Okhuarobo et al, 2020 ), but see ( Blednov et al, 2019 ; Ferguson et al, 2022 ; Huitron-Resendiz et al, 2018 ; Schweitzer et al, 2016 ) ( Borgonetti et al, 2023 ). The female LC is larger than the male LC in both humans and rodents, and the rodent female LC is more sensitive to repeated ethanol exposure ( Bangasser et al, 2016 ; Retson et al, 2015 ).…”