Greater inhibition of female rat binge alcohol intake by adrenergic receptor blockers using a novel Two-Shot rat binge drinking model.

Binge drinking (BD) contributes strongly to the harms of alcohol use disorder. Most rodent models do not result in binge-level blood alcohol concentrations (BACs), and to better understand individual and sex differences in neurobiological mechanisms related to BD, the use of outbred rat strains would be valuable. Here, we developed a novel BD model where after 3+ months of intermittent access to 20% alcohol Wistar rats drank, twice a week, with two 5-minute intake (what we called Two-shot) separated by a 10-minute break. Our findings showed during Two-Shot that most animals reached ≥ 80mg% BAC levels (when briefly food-restricted). However, when increasing alcohol concentrations from 20% to 30%, 40%, or 50%, rats titrated to similar intake levels, suggesting rapid sensing of alcohol effects even when front-loading. Two-Shot drinking was reduced in both sexes by naltrexone (1mg/kg), validating intake suppression by a clinical therapeutic agent. Further, both propranolol (ß adrenergic receptor antagonist) and prazosin (α1 adrenergic receptor antagonist) reduced female but not male BD at the lower dose. Thus, our results provide a novel model for BD in outbred rats and suggest that female binging is more sensitive to adrenergic modulation than males, perhaps providing a novel sex-related therapy.

PPM1B depletion induces premature senescence in human IMR-90 fibroblasts.

p53 and NF-κB are key transcription factors in regulating the gene expression program of cellular and organismal senescence. PPM1B is a member of the protein phosphatase 2C family and plays a role in negatively regulating p53 and NF-κB thereby possibly attenuating the gene expression program of cellular senescence. Here, possible involvement of PPM1B in replicative senescence has been investigated using the in vitro aging model of IMR-90 cells. PPM1B protein levels are progressively decreased in a replicative age-dependent manner. Importantly, PPM1B depletion induces a robust senescence phenotype as evidenced by significant growth arrest and senescence marker expression. Given that PPM1B depletion-induced senescence is partially rescued by inactivating p38 MAPK, our results identify PPM1B as a critical regulator of both p38 MAPK-dependent and independent senescence pathways during normal cellular aging process.