Backround While the molecular entity responsible for the rewarding effects of virtually all drugs of abuse is known; that for ethanol remains uncertain. Some lines of evidence suggest that the rewarding effects of alcohol are mediated not by ethanol per se but by acetaldehyde generated by catalase in the brain. However, the lack of specific inhibitors of catalase has not allowed strong conclusions to be drawn about its role on the rewarding properties of ethanol. The present studies determined the effect on voluntary alcohol consumption of two gene vectors; one designed to inhibit catalase synthesis and one designed to synthesize alcohol dehydrogenase, to respectively inhibit or increase brain acetaldehyde synthesis. Methods The lentiviral vectors, which incorporate the genes they carry into the cell genome, were: (i) one encoding a shRNA anticatalase synthesis and (ii) one encoding alcohol dehydrogenase (rADH1). These were stereotaxically microinjected into the brain ventral tegmental area (VTA) of Wistar-derived rats bred for generations for their high alcohol preference (UChB), which were allowed access to an ethanol solution and water. Results Microinjection into the VTA of the lentiviral vector encoding the anticatalase shRNA virtually abolished (-94% p<0.001) the voluntary consumption of alcohol by the rats. Conversely, injection into the VTA of the lentiviral vector coding for alcohol dehydrogenase greatly stimulated (2-3 fold p<0.001) their voluntary ethanol consumption. Conclusions The study strongly suggests that to generate reward and reinforcement, ethanol must be metabolized into acetaldehyde in the brain. Data suggest novel targets for interventions aimed at reducing chronic alcohol intake.

No abstract

Background In animal models of continuous alcohol self-administration, in which physical dependence does not constitute the major factor of ethanol intake, two factors likely contribute to the perpetuation of alcohol self-administration: (i) the rewarding effects of ethanol and (ii) the contextual conditioning cues that exist along with the process of self-administration. Present studies are aimed at understanding the relative contribution of these factors on the perpetuation of heavy alcohol self-administration, as an indication of relapse. Methods Wistar derived UChB high ethanol drinker rats were allowed access to 10% ethanol and water on a 24-hour basis. In initial studies, an anticatalase shRNA gene coding lentiviral vector aimed at inhibiting acetaldehyde generation was administered into the ventral tegmental area (VTA) of the animals prior to ethanol access. In subsequent studies the lentiviral vector was administered to animals, which had consumed ethanol on a 24-hour basis, or a one-hour basis, after the animals had reached high levels of ethanol intake for 60–80 days. In final studies, quinine (0.01%) was added to the ethanol solution to alter the conditioning taste/smell cues of alcohol that animals had chronically ingested. Results Data indicate that the administration into the VTA of an anti-catalase vector to naïve animals blocked reward and alcohol self-administration in naive animals while it was, nevertheless, inactive in inhibiting alcohol self-administration in rats that had been conditioned to ingest ethanol for over 2 months. The lack of inhibitory effect on ethanol intake of the anti-catalase vector in animals that had chronically self-administered ethanol was fully reversed when the contextual conditioning cues of the alcohol solution were changed. Conclusions Data highlight the importance of conditioning factors in relapse and suggest that only abolishing or blunting it, along with appropriate pharmacological treatments to reduce ethanol reward, may have protracted effects in reducing alcohol self-administration.

Short-chain fatty acids (SCFAs) are carboxylic acids produced as a result of gut microbial anaerobic fermentation. They activate signaling cascades, acting as ligands of G-protein-coupled receptors, such as GPR41, GPR43, and GPR109A, that can modulate the inflammatory response and increase the intestinal barrier integrity by enhancing the tight junction proteins functions. These junctions, located in the most apical zone of epithelial cells, control the diffusion of ions, macromolecules, and the entry of microorganisms from the intestinal lumen into the tissues. In this sense, several enteric pathogens secrete diverse toxins that interrupt tight junction impermeability, allowing them to invade the intestinal tissue and to favor gastrointestinal colonization. It has been recently demonstrated that SCFAs inhibit the virulence of different enteric pathogens and have protective effects against bacterial colonization. Here, we present an overview of SCFAs production by gut microbiota and their effects on the recovery of intestinal barrier integrity during infections by microorganisms that affect tight junctions. These properties make them excellent candidates in the treatment of infectious diseases that cause damage to the intestinal epithelium.