Probenecid Reduces Alcohol Drinking in Rodents. Is Pannexin1 a Novel Therapeutic Target for Alcohol Use Disorder?

AIMS: The development of novel and more effective medications for alcohol use disorder (AUD) is an important unmet medical need. Drug repositioning or repurposing is an appealing strategy to bring new therapies to the clinic because it greatly reduces the overall costs of drug development and expedites the availability of treatments to those who need them. Probenecid, p-(di-n-propylsulfamyl)-benzoic acid, is a drug used clinically to treat hyperuricemia and gout due to its activity as an inhibitor of the kidneys' organic anion transporter that reclaims uric acid from urine. Probenecid also inhibits pannexin1 channels that are involved in purinergic neurotransmission and inflammation, which have been implicated in alcohol's effects and motivation for alcohol. Therefore, we tested the effects of probenecid on alcohol intake in rodents. METHODS: We tested the effects of probenecid on operant oral alcohol self-administration in alcohol-dependent rats during acute withdrawal as well as in nondependent rats and in the drinking-in-the-dark (DID) paradigm of binge-like drinking in mice. RESULTS: Probenecid reduced alcohol intake in both dependent and nondependent rats and in the DID paradigm in mice without affecting water or saccharin intake, indicating that probenecid's effect was selective for alcohol and not the result of a general reduction in reward. CONCLUSIONS: These results raise the possibility that pannexin1 is a novel therapeutic target for the treatment of AUD. The clinical use of probenecid has been found to be generally safe, suggesting that it can be a candidate for drug repositioning for the treatment of AUD.

Larger sperm size may contribute to reproductive isolation between Etheostoma species.

Etheostoma is a genus of North American darter fish whose species have similar habitats and breeding seasons, yet hybridization is rare. Behavioral barriers have been demonstrated to play a key role in maintaining species boundaries. Further, conspecific (same species) sperm precedence has also been observed when the gametes of two different species come into contact. In this study, we investigated if physical characteristics of sperm could be a mechanism for the lower fertilization success of heterospecific (different species) males when eggs are simultaneously exposed to conspecific and heterospecific sperm. We chose to examine the sperm of two closely related species, E. zonale and E. barrenense. Using toluidine blue and immunofluorescent labeling methods, we compared head diameter and tail length of sperm cells between the two species. We found that head diameter was significantly larger for E. barrenense sperm compared to E. zonale. This difference in cell morphology may point to a physical mechanism underlying conspecific sperm precedence in Etheostoma. Our results are the first to describe a morphological difference in sperm between species in this genus and provide initial evidence for the role of sperm morphology in prezygotic reproductive isolation.