Apremilast-induced increases in acute ethanol intoxication and decreases in ethanol drinking in mice involve PKA phosphorylation of GABAA β3 subunits

The urgent need for medical treatments of alcohol use disorders has motivated the search for novel molecular targets of alcohol response. Most studies exploit the strengths of lab animals without considering how these and other species may have adapted to respond to alcohol in an ecological context. Here, we provide an evolutionary perspective on the molecular and genetic underpinnings of alcohol consumption by reviewing evidence that alcohol metabolic enzymes have undergone adaptive evolution at 2 evolutionary junctures: first, to enable alcohol consumption accompanying the advent of a frugivorous diet in a primate ancestor, and second, to decrease the likelihood of excessive alcohol consumption concurrent with the spread of agriculture and fermentation in East Asia. By similarly considering how diverse vertebrate and invertebrate species have undergone natural selection for alcohol responses, novel conserved molecular targets of alcohol are likely be discovered that may represent promising therapeutic targets.

https://doi.org/10.1177/26331055231163589

The Promise of an Evolutionary Perspective of Alcohol Consumption

Previous studies (1) support a role of circadian genes in regulating alcohol intake, and (2) reveal that harmful alcohol use alters circadian rhythms. However, there is minimal knowledge of the effects of chronic alcohol processes on rhythmic circadian gene expression across brain regions important for circadian biology and alcohol intake. Therefore, the present study sought to test the effects of chronic binge-like drinking on diurnal circadian gene expression patterns in the master circadian pacemaker (SCN), the ventral tegmental area (VTA), and the nucleus accumbens (NAc) in High Drinking in the Dark-1 (HDID-1) mice, a unique genetic risk model for drinking to intoxication. Consistent with earlier findings, we found that 8 weeks of binge-like drinking reduced the amplitude of several core circadian clock genes in the NAc and SCN, but not the VTA. To better inform the use of circadian-relevant pharmacotherapies in reducing harmful drinking and ameliorating alcohol’s effects on circadian gene expression, we tested whether the casein kinase-1 inhibitor, PF-67046, or the phosphodiesterase type-4 (an upstream regulator of circadian signalling) inhibitor, apremilast, would reduce binge-like intake and mitigate circadian gene suppression. PF-67046 did not reduce intake but did have circadian gene effects. In contrast, apremilast reduced drinking, but had no effect on circadian expression patterns.

https://www.mdpi.com/1422-0067/23/19/11084/pdf?version=1663759342

Targeting the Maladaptive Effects of Binge Drinking on Circadian Gene Expression

Neuroimmune pathways as targets to reduce alcohol consumption

The collaborative cross (CC) founder strains include five classical inbred laboratory strains [129S1/SvlmJ (S129), A/J (AJ), C57BL/6J (B6), NOD/ShiLtJ (NOD), and NZO/HILtJ (NZO)] and three wild-derived strains [CAST/EiJ (CAST), PWK/PhJ (PWK), and WSB/EiJ (WSB)]. These strains encompass 89% of the genetic diversity available in Mus musculus and ∼10–20 times more genetic diversity than found in Homo sapiens. For more than 60 years the B6 strain has been widely used as a genetic model for high ethanol preference and consumption. However, another of the CC founder strains, PWK, has been identified as a high ethanol preference/high consumption strain. The current study determined how the transcriptomes of the B6 and PWK strains differed from the 6 low preference CC strains across 3 nodes of the brain addiction circuit. RNA-Seq data were collected from the central nucleus of the amygdala (CeA), the nucleus accumbens core (NAcc) and the prelimbic cortex (PrL). Differential expression (DE) analysis was performed in each of these brain regions for all 28 possible pairwise comparisons of the CC founder strains. Unique genes for each strain were identified by selecting for genes that differed significantly [false discovery rate (FDR) < 0.05] from all other strains in the same direction. B6 was identified as the most distinct classical inbred laboratory strain, having the highest number of total differently expressed genes (DEGs) and DEGs with high log fold change, and unique genes compared to other CC strains. Less than 50 unique DEGs were identified in common between B6 and PWK within all three brain regions, indicating the strains potentially represent two distinct genetic signatures for risk for high ethanol-preference. 338 DEGs were found to be commonly different between B6, PWK and the average expression of the remaining CC strains within all three regions. The commonly different up-expressed genes were significantly enriched (FDR < 0.001) among genes associated with neuroimmune function. These data compliment findings showing that neuroimmune signaling is key to understanding alcohol use disorder (AUD) and support use of these 8 strains and the highly heterogeneous mouse populations derived from them to identify alcohol-related brain mechanisms and treatment targets.

Brain gene expression differences related to ethanol preference in the collaborative cross founder strains

Treatment options for Alcohol Use Disorders (AUD) have minimally advanced since 2004, while the annual deaths and economic toll have become alarmingly high. Bringing potential therapeutics beyond the bench and into the clinic for AUD requires rigorous pharmacological screening across molecular, behavioral, pre-clinical, and clinical studies in neuroscience. The repurposing of FDA-approved compounds is an effective and expedited means of screening pharmacotherapies for AUD. Here, we demonstrate that apremilast, a phosphodiesterase type 4 inhibitor that is FDA approved for psoriasis and psoriatic arthritis, reduces binge-like alcohol intake and behavioral measures of motivation in unique, preclinical genetic risk models for drinking to intoxication and reduces excessive alcohol drinking in models of stress-facilitated drinking and alcohol dependence. In a double blind, placebo-controlled human laboratory study in non-treatment seeking individuals with AUD, apremilast significantly reduced the number of drinks per day. Lastly, using site-directed drug infusions and electrophysiology we determined that apremilast may act by increasing neural activity in the nucleus accumbens, an important alcohol-related brain region, to reduce alcohol intake in mice. These results demonstrate that apremilast reduces excessive alcohol drinking across a spectrum of AUD severity and support its importance as a potential therapeutic for AUD.

https://biorxiv.org/content/10.1101/2021.05.13.444033v1.full.pdf

The FDA-approved drug apremilast suppresses alcohol intake: clinical and pre-clinical validation

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The FDA-approved drug apremilast suppresses alcohol intake: clinical and pre-clinical validation